Isoxazolidine Conjugates of N3-Substituted 6-Bromoquinazolinones—Synthesis, Anti-Varizella-Zoster Virus, and Anti-Cytomegalovirus Activity
Identifieur interne : 000648 ( Pmc/Corpus ); précédent : 000647; suivant : 000649Isoxazolidine Conjugates of N3-Substituted 6-Bromoquinazolinones—Synthesis, Anti-Varizella-Zoster Virus, and Anti-Cytomegalovirus Activity
Auteurs : Magdalena Grabkowska-Dru Yc ; Graciela Andrei ; Dominique Schols ; Robert Snoeck ; Dorota G. PiotrowskaSource :
- Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry [ 1420-3049 ] ; 2018.
Abstract
1,3-Dipolar cycloaddition of
Url:
DOI: 10.3390/molecules23081889
PubMed: 30060562
PubMed Central: 6222691
Links to Exploration step
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Isoxazolidine Conjugates of N3-Substituted 6-Bromoquinazolinones—Synthesis, Anti-Varizella-Zoster Virus, and Anti-Cytomegalovirus Activity</title><author><name sortKey="Grabkowska Dru Yc, Magdalena" sort="Grabkowska Dru Yc, Magdalena" uniqKey="Grabkowska Dru Yc M" first="Magdalena" last="Grabkowska-Dru Yc">Magdalena Grabkowska-Dru Yc</name><affiliation><nlm:aff id="af1-molecules-23-01889">Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Lodz, Muszyńskiego 1, 90-151 Lodz, Poland;<email>magdalena.grabkowska-druzyc@umed.lodz.pl</email></nlm:aff></affiliation></author><author><name sortKey="Andrei, Graciela" sort="Andrei, Graciela" uniqKey="Andrei G" first="Graciela" last="Andrei">Graciela Andrei</name><affiliation><nlm:aff id="af2-molecules-23-01889">Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium;<email>Graciela.Andrei@rega.kleuven.be</email> (G.A.);<email>Dominique.Schols@rega.kleuven.be</email> (D.S.);<email>Robert.Snoeck@rega.kleuven.be</email> (R.S.)</nlm:aff></affiliation></author><author><name sortKey="Schols, Dominique" sort="Schols, Dominique" uniqKey="Schols D" first="Dominique" last="Schols">Dominique Schols</name><affiliation><nlm:aff id="af2-molecules-23-01889">Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium;<email>Graciela.Andrei@rega.kleuven.be</email> (G.A.);<email>Dominique.Schols@rega.kleuven.be</email> (D.S.);<email>Robert.Snoeck@rega.kleuven.be</email> (R.S.)</nlm:aff></affiliation></author><author><name sortKey="Snoeck, Robert" sort="Snoeck, Robert" uniqKey="Snoeck R" first="Robert" last="Snoeck">Robert Snoeck</name><affiliation><nlm:aff id="af2-molecules-23-01889">Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium;<email>Graciela.Andrei@rega.kleuven.be</email> (G.A.);<email>Dominique.Schols@rega.kleuven.be</email> (D.S.);<email>Robert.Snoeck@rega.kleuven.be</email> (R.S.)</nlm:aff></affiliation></author><author><name sortKey="Piotrowska, Dorota G" sort="Piotrowska, Dorota G" uniqKey="Piotrowska D" first="Dorota G." last="Piotrowska">Dorota G. Piotrowska</name><affiliation><nlm:aff id="af1-molecules-23-01889">Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Lodz, Muszyńskiego 1, 90-151 Lodz, Poland;<email>magdalena.grabkowska-druzyc@umed.lodz.pl</email></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30060562</idno><idno type="pmc">6222691</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222691</idno><idno type="RBID">PMC:6222691</idno><idno type="doi">10.3390/molecules23081889</idno><date when="2018">2018</date><idno type="wicri:Area/Pmc/Corpus">000648</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000648</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Isoxazolidine Conjugates of N3-Substituted 6-Bromoquinazolinones—Synthesis, Anti-Varizella-Zoster Virus, and Anti-Cytomegalovirus Activity</title><author><name sortKey="Grabkowska Dru Yc, Magdalena" sort="Grabkowska Dru Yc, Magdalena" uniqKey="Grabkowska Dru Yc M" first="Magdalena" last="Grabkowska-Dru Yc">Magdalena Grabkowska-Dru Yc</name><affiliation><nlm:aff id="af1-molecules-23-01889">Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Lodz, Muszyńskiego 1, 90-151 Lodz, Poland;<email>magdalena.grabkowska-druzyc@umed.lodz.pl</email></nlm:aff></affiliation></author><author><name sortKey="Andrei, Graciela" sort="Andrei, Graciela" uniqKey="Andrei G" first="Graciela" last="Andrei">Graciela Andrei</name><affiliation><nlm:aff id="af2-molecules-23-01889">Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium;<email>Graciela.Andrei@rega.kleuven.be</email> (G.A.);<email>Dominique.Schols@rega.kleuven.be</email> (D.S.);<email>Robert.Snoeck@rega.kleuven.be</email> (R.S.)</nlm:aff></affiliation></author><author><name sortKey="Schols, Dominique" sort="Schols, Dominique" uniqKey="Schols D" first="Dominique" last="Schols">Dominique Schols</name><affiliation><nlm:aff id="af2-molecules-23-01889">Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium;<email>Graciela.Andrei@rega.kleuven.be</email> (G.A.);<email>Dominique.Schols@rega.kleuven.be</email> (D.S.);<email>Robert.Snoeck@rega.kleuven.be</email> (R.S.)</nlm:aff></affiliation></author><author><name sortKey="Snoeck, Robert" sort="Snoeck, Robert" uniqKey="Snoeck R" first="Robert" last="Snoeck">Robert Snoeck</name><affiliation><nlm:aff id="af2-molecules-23-01889">Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium;<email>Graciela.Andrei@rega.kleuven.be</email> (G.A.);<email>Dominique.Schols@rega.kleuven.be</email> (D.S.);<email>Robert.Snoeck@rega.kleuven.be</email> (R.S.)</nlm:aff></affiliation></author><author><name sortKey="Piotrowska, Dorota G" sort="Piotrowska, Dorota G" uniqKey="Piotrowska D" first="Dorota G." last="Piotrowska">Dorota G. Piotrowska</name><affiliation><nlm:aff id="af1-molecules-23-01889">Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Lodz, Muszyńskiego 1, 90-151 Lodz, Poland;<email>magdalena.grabkowska-druzyc@umed.lodz.pl</email></nlm:aff></affiliation></author></analytic><series><title level="j">Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry</title><idno type="eISSN">1420-3049</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>1,3-Dipolar cycloaddition of <italic>N</italic>-methyl <italic>C</italic>-(diethoxyphosphoryl) nitrone to N3-substituted 6-bromo-2-vinyl-3<italic>H</italic>-quinazolin-4-ones gave (3-diethoxyphosphoryl) isoxazolidines substituted at C5 with quinazolinones modified at N3. All isoxazolidine cycloadducts were screened for antiviral activity against a broad spectrum of DNA and RNA viruses. Several isoxazolidines inhibited the replication of both thymidine kinase wild-type and deficient (TK<sup>+</sup> and TK<sup>−</sup>) varicella-zoster virus strains at EC<sub>50</sub> in the 5.4–13.6 μΜ range, as well as human cytomegalovirus (EC<sub>50</sub> = 8.9–12.5 μΜ). Isoxazolidines <italic>trans</italic>-<bold>11b</bold>, <italic>trans</italic>-<bold>11c</bold>, <italic>trans</italic>-<bold>11e</bold>, <italic>trans</italic>-<bold>11f</bold>/<italic>cis</italic>-<bold>11f</bold>, <italic>trans</italic>-<bold>11g</bold>, <italic>trans</italic>-<bold>11h</bold>, and <italic>trans</italic>-<bold>11i</bold>/<italic>cis</italic>-<bold>11i</bold> exhibited moderate cytostatic activity towards the human lymphocyte cell line CEM (IC<sub>50</sub> = 9.6–17 μM).</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Konig, B" uniqKey="Konig B">B. König</name></author><author><name sortKey="Gr Tzei, M A" uniqKey="Gr Tzei M">M.A. Grätzei</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hollier, L M" uniqKey="Hollier L">L.M. Hollier</name></author><author><name sortKey="Grissom, H" uniqKey="Grissom H">H. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Molecules</journal-id><journal-id journal-id-type="iso-abbrev">Molecules</journal-id><journal-id journal-id-type="publisher-id">molecules</journal-id><journal-title-group><journal-title>Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry</journal-title></journal-title-group><issn pub-type="epub">1420-3049</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30060562</article-id><article-id pub-id-type="pmc">6222691</article-id><article-id pub-id-type="doi">10.3390/molecules23081889</article-id><article-id pub-id-type="publisher-id">molecules-23-01889</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Isoxazolidine Conjugates of N3-Substituted 6-Bromoquinazolinones—Synthesis, Anti-Varizella-Zoster Virus, and Anti-Cytomegalovirus Activity</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Grabkowska-Drużyc</surname><given-names>Magdalena</given-names></name><xref ref-type="aff" rid="af1-molecules-23-01889">1</xref></contrib><contrib contrib-type="author"><name><surname>Andrei</surname><given-names>Graciela</given-names></name><xref ref-type="aff" rid="af2-molecules-23-01889">2</xref></contrib><contrib contrib-type="author"><name><surname>Schols</surname><given-names>Dominique</given-names></name><xref ref-type="aff" rid="af2-molecules-23-01889">2</xref></contrib><contrib contrib-type="author"><name><surname>Snoeck</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="af2-molecules-23-01889">2</xref></contrib><contrib contrib-type="author"><name><surname>Piotrowska</surname><given-names>Dorota G.</given-names></name><xref ref-type="aff" rid="af1-molecules-23-01889">1</xref><xref rid="c1-molecules-23-01889" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-molecules-23-01889"><label>1</label>Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Lodz, Muszyńskiego 1, 90-151 Lodz, Poland;<email>magdalena.grabkowska-druzyc@umed.lodz.pl</email></aff><aff id="af2-molecules-23-01889"><label>2</label>Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium;<email>Graciela.Andrei@rega.kleuven.be</email> (G.A.);<email>Dominique.Schols@rega.kleuven.be</email> (D.S.);<email>Robert.Snoeck@rega.kleuven.be</email> (R.S.)</aff><author-notes><corresp id="c1-molecules-23-01889"><label>*</label>Correspondence: <email>dorota.piotrowska@umed.lodz.pl</email>; Tel.: +48-42-677-92-33; Fax: +48-42-678-83-98</corresp></author-notes><pub-date pub-type="epub"><day>28</day><month>7</month><year>2018</year></pub-date><pub-date pub-type="collection"><month>8</month><year>2018</year></pub-date><volume>23</volume><issue>8</issue><elocation-id>1889</elocation-id><history><date date-type="received"><day>29</day><month>6</month><year>2018</year></date><date date-type="accepted"><day>27</day><month>7</month><year>2018</year></date></history><permissions><copyright-statement>© 2018 by the authors.</copyright-statement><copyright-year>2018</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>1,3-Dipolar cycloaddition of <italic>N</italic>-methyl <italic>C</italic>-(diethoxyphosphoryl) nitrone to N3-substituted 6-bromo-2-vinyl-3<italic>H</italic>-quinazolin-4-ones gave (3-diethoxyphosphoryl) isoxazolidines substituted at C5 with quinazolinones modified at N3. All isoxazolidine cycloadducts were screened for antiviral activity against a broad spectrum of DNA and RNA viruses. Several isoxazolidines inhibited the replication of both thymidine kinase wild-type and deficient (TK<sup>+</sup> and TK<sup>−</sup>) varicella-zoster virus strains at EC<sub>50</sub> in the 5.4–13.6 μΜ range, as well as human cytomegalovirus (EC<sub>50</sub> = 8.9–12.5 μΜ). Isoxazolidines <italic>trans</italic>-<bold>11b</bold>, <italic>trans</italic>-<bold>11c</bold>, <italic>trans</italic>-<bold>11e</bold>, <italic>trans</italic>-<bold>11f</bold>/<italic>cis</italic>-<bold>11f</bold>, <italic>trans</italic>-<bold>11g</bold>, <italic>trans</italic>-<bold>11h</bold>, and <italic>trans</italic>-<bold>11i</bold>/<italic>cis</italic>-<bold>11i</bold> exhibited moderate cytostatic activity towards the human lymphocyte cell line CEM (IC<sub>50</sub> = 9.6–17 μM).</p></abstract><kwd-group><kwd>phosphonate</kwd><kwd>isoxazolidine</kwd><kwd>quinazolinones</kwd><kwd>antiviral</kwd><kwd>cytostatic</kwd></kwd-group></article-meta></front><body><sec id="sec1-molecules-23-01889"><title>1. Introduction</title><p>Herpesviruses are enveloped, icosahedral viruses containing double-stranded DNA. What fundamentally distinguishes herpesviruses from others is the ability to establish latent infection and reactivating when the host immune system is impaired. Human cytomegalovirus (HCMV) and varicella zoster virus (VZV) belong to the family of herpesviruses which cause infections usually acquired in childhood [<xref rid="B1-molecules-23-01889" ref-type="bibr">1</xref>,<xref rid="B2-molecules-23-01889" ref-type="bibr">2</xref>,<xref rid="B3-molecules-23-01889" ref-type="bibr">3</xref>]. For the treatment of viral infections caused by herpesviruses, including VZV and HCMV, several drugs, such as acyclovir (e.g., <italic>Zovirax</italic>), valacyclovir (e.g., <italic>Valtrex</italic>), famciclovir (e.g., <italic>Famvir</italic>), brivudin (e.g., <italic>Zostex</italic>, <italic>Helpin</italic>), and ganciclovir (e.g., <italic>Cymevene</italic>), have been used [<xref rid="B3-molecules-23-01889" ref-type="bibr">3</xref>,<xref rid="B4-molecules-23-01889" ref-type="bibr">4</xref>,<xref rid="B5-molecules-23-01889" ref-type="bibr">5</xref>].</p><p>Despite the wide range of available drugs, effective treatment of viral infections is still limited. This is mainly due to the specificity of viral infections and the ability of viruses to mutate, which is associated with the acquisition of drug resistance. Therefore, new compounds with potential biological activity are being sought all the time. Quinazolinone and its derivatives have been extensively studied because of their wide range of biological activities, including antiviral [<xref rid="B6-molecules-23-01889" ref-type="bibr">6</xref>], anticancer [<xref rid="B7-molecules-23-01889" ref-type="bibr">7</xref>,<xref rid="B8-molecules-23-01889" ref-type="bibr">8</xref>], antifungal [<xref rid="B9-molecules-23-01889" ref-type="bibr">9</xref>], antibacterial [<xref rid="B10-molecules-23-01889" ref-type="bibr">10</xref>,<xref rid="B11-molecules-23-01889" ref-type="bibr">11</xref>], antitubercular [<xref rid="B12-molecules-23-01889" ref-type="bibr">12</xref>,<xref rid="B13-molecules-23-01889" ref-type="bibr">13</xref>], anti-inflammatory [<xref rid="B11-molecules-23-01889" ref-type="bibr">11</xref>,<xref rid="B14-molecules-23-01889" ref-type="bibr">14</xref>], anticonvulsant [<xref rid="B15-molecules-23-01889" ref-type="bibr">15</xref>], hypolipidemic [<xref rid="B16-molecules-23-01889" ref-type="bibr">16</xref>], analgesic [<xref rid="B17-molecules-23-01889" ref-type="bibr">17</xref>], or immunotropic properties [<xref rid="B18-molecules-23-01889" ref-type="bibr">18</xref>].</p><p>The antiviral activity of compounds containing the C6-substituted quinazolin-4-one framework has been discovered in recent years (<xref ref-type="fig" rid="molecules-23-01889-f001">Figure 1</xref>). For example, 5-bromo-2-(6-bromo-4-oxo-2-phenyl-4<italic>H</italic>-quinazolin-3-yl)-benzoic acid <bold>1</bold> was reported to possess distinct antiviral activity against both herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) and vaccinia virus (VACV) (EC<sub>50</sub> = 12 μg/mL) [<xref rid="B19-molecules-23-01889" ref-type="bibr">19</xref>], whereas compound <bold>2</bold> exhibited activity against vaccinia virus in E<sub>6</sub>SM cell cultures (MIC of 1.92 μg/mL) [<xref rid="B20-molecules-23-01889" ref-type="bibr">20</xref>]. Another analogue, i.e., 2-methyl-3-(substituted-benzalamino)-4(3<italic>H</italic>)-quinazolinone <bold>3</bold>, was found to exhibit antiviral activity against tobacco mosaic virus (TMV) in vivo. Compound <bold>3</bold> showed curative effects of 54%, which was slightly higher than that of a reference drug, Ningnanmycin [<xref rid="B21-molecules-23-01889" ref-type="bibr">21</xref>]. Very recently quinazolin-4(3<italic>H</italic>)-ones <bold>4</bold>–<bold>6</bold> were synthesized and evaluated for inhibitory action on the replication of influenza A virus (H<sub>5</sub>N<sub>1</sub>), as well as to test toxicity on in vitro cell lines. In general, quinazolin-4(3<italic>H</italic>)-ones containing a chalcone skeleton <bold>4</bold>, thiosemicarbazone <bold>5</bold>, and hydrazide <bold>6</bold> showed moderate antiviral activity against H<sub>5</sub>N<sub>1</sub> (inhibition rate: 38%, 47%, 25%, respectively, for <bold>4</bold>, <bold>5</bold>, <bold>6</bold>) compared to a reference drug, Zanamivir [<xref rid="B22-molecules-23-01889" ref-type="bibr">22</xref>]. In addition, compounds <bold>7</bold> and <bold>8</bold> possessing a nitro group at C6 were reported as potent inhibitors of Venezuelan Equine Encephalitis Virus (VEEV) (EC<sub>50</sub> = 0.8 μM, CC<sub>50</sub> = 50 μM) [<xref rid="B23-molecules-23-01889" ref-type="bibr">23</xref>]. Quinazolinone (<italic>aS</italic>)-<bold>9</bold> displayed high selectivity for PI4KIIIα and appeared to be potent inhibitors of hepatitis C virus (HCV) replication in vitro. Moreover, compound (<italic>aS</italic>)-<bold>9</bold> exhibited higher potency for PI4KIIIα than its atropisomer <italic>aR</italic> (pIC<sub>50</sub> of 8.3 vs. 6.9) and an improved selectivity range (2.7–3.2 vs. 1.4–2.1) against the other lipid kinases [<xref rid="B24-molecules-23-01889" ref-type="bibr">24</xref>].</p><p>Recently, we have succeeded in synthesis of a series of quinazolinones substituted at C3 with a (diethoxyphosphoryl)isoxazolidine moiety <bold>10</bold>. Several of the synthesized analogues exhibited moderate activity against varicella zoster virus (VZV) and human cytomegalovirus (HCMV) [<xref rid="B25-molecules-23-01889" ref-type="bibr">25</xref>]. On the basis of these observations, and in continuation of our search for new biologically active compounds [<xref rid="B25-molecules-23-01889" ref-type="bibr">25</xref>], a novel series of quinazolinone derivatives of general formula <bold>11</bold> having an isoxazolidine ring at C2, different substituents at N3, and an additional bromine atom at C6 was synthesized. The synthetic strategy for our new isoxazolidine-conjugates of quinazolinones relies on the 1,3-dipolar cycloaddition of <italic>N</italic>-methyl-<italic>C</italic>-(diethoxyphosphoryl)nitrone <bold>12</bold> [<xref rid="B26-molecules-23-01889" ref-type="bibr">26</xref>] with selected 6-bromo-2-vinyl-3<italic>H</italic>-quinazolin-4-ones <bold>13</bold> (<xref ref-type="scheme" rid="molecules-23-01889-sch001">Scheme 1</xref>).</p></sec><sec id="sec2-molecules-23-01889"><title>2. Results and Discussion</title><sec id="sec2dot1-molecules-23-01889"><title>2.1. Chemistry</title><p>The respective 3-substituted 6-bromo-2-vinyl-3<italic>H</italic>-quinazolin-4-ones <bold>13a</bold>–<bold>k</bold> were synthesized starting from the commercially available isatoic acid anhydride, which was first reacted with bromine and then transformed into 5-bromoanthranilic acid amide <bold>14</bold> according to the procedure in the literature [<xref rid="B27-molecules-23-01889" ref-type="bibr">27</xref>,<xref rid="B28-molecules-23-01889" ref-type="bibr">28</xref>]. Reaction 5-bromoanthranilic acid amide <bold>14</bold> with 3-chloropropionyl chloride followed by cyclization and dehydrohalogenation led to the formation of 6-bromo-2-vinyl-3<italic>H</italic>-quinazolin-4-one <bold>13a</bold>, which was then used as a key intermediate in the preparation of N3-substituted derivatives <bold>13b</bold>–<bold>13k</bold> via alkylation with the respective benzyl bromides, as well as with methyl or ethyl iodide [<xref rid="B29-molecules-23-01889" ref-type="bibr">29</xref>] (<xref ref-type="scheme" rid="molecules-23-01889-sch002">Scheme 2</xref>).</p><p>The 1,3-dipolar cycloadditions of nitrone <bold>12</bold> with the respective 6-bromo-2-vinylquinazolinones <bold>13a</bold>–<bold>13k</bold> were carried out at 70 °C in toluene and afforded mixtures of diastereoisomeric isoxazolidines <italic>trans</italic>-<bold>11a</bold>–<bold>11k</bold> and <italic>cis</italic>-<bold>11a</bold>–<bold>11k</bold> (<xref ref-type="scheme" rid="molecules-23-01889-sch003">Scheme 3</xref>, <xref rid="molecules-23-01889-t001" ref-type="table">Table 1</xref>). Ratios of trans/cis diastereoisomers were determined on the basis of the <sup>31</sup>P-NMR spectra of crude products and confirmed by the analysis of <sup>1</sup>H-NMR spectra data. In all cases good trans/cis diastereoselectivities were observed (in the range of 76–88%) and <italic>trans</italic>-isomers predominated. The mixtures of isoxazolidine cycloadducts were separated chromatographically on silica gel. The isolation of pure isomers was successfully accomplished for the major isomers <italic>trans</italic>-<bold>11a</bold> (R = H), <italic>trans</italic>-<bold>11b</bold> (R = C<sub>6</sub>H<sub>5</sub>CH<sub>2</sub>), <italic>trans</italic>-<bold>11c</bold> (R = 2-NO<sub>2</sub>-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub>), <italic>trans</italic>-<bold>11d</bold> (R = 3-NO<sub>2</sub>-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub>), <italic>trans</italic>-<bold>11e</bold> (R = 4-NO<sub>2</sub>-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub>), <italic>trans</italic>-<bold>11g</bold> (R = 3-F-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub>), <italic>trans</italic>-<bold>11h</bold> (R = 4-F-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub>), <italic>trans</italic>-<bold>11j</bold> (R = CH<sub>3</sub>), and <italic>trans</italic>-<bold>11k</bold> (R = CH<sub>3</sub>CH<sub>2</sub>), as well as for a minor isomer <italic>cis</italic>-<bold>11a</bold> (R = H).</p><p>Stereochemistry of the cycloaddition of a nitrone <bold>12</bold> to N3-substituted derivatives of 2-vinyl-3<italic>H</italic>-quinazolin-4-ones has recently been described and relative configurations of <italic>trans</italic>- and <italic>cis</italic>-isoxazolidine cycloadducts were established based on conformational analysis [<xref rid="B25-molecules-23-01889" ref-type="bibr">25</xref>]. Since the introduction of the bromine atom at C6 of the quinazolin-4-one framework has no influence on the stereochemical outcome of the reaction of nitrone <bold>12</bold> with N3-susbstituted 2-vinyl-3<italic>H</italic>-quinazolin-4-ones, the trans and cis configurations of the major <italic>trans</italic>-<bold>11a</bold>–<bold>k</bold> and minor <italic>cis</italic>-<bold>11a</bold>–<bold>k</bold> isomers were assigned taking advantage of our previous observations.</p></sec><sec id="sec2dot2-molecules-23-01889"><title>2.2. Antiviral and Cytostatic Evaluation</title><sec id="sec2dot2dot1-molecules-23-01889"><title>2.2.1. Antiviral Activity</title><p>Pure isomers <italic>trans</italic>-<bold>11a</bold>, <italic>trans</italic>-<bold>11b</bold>, <italic>trans</italic>-<bold>11c</bold>, <italic>trans</italic>-<bold>11d</bold>, <italic>trans</italic>-<bold>11e</bold>, <italic>trans</italic>-<bold>11g</bold>, <italic>trans</italic>-<bold>11h</bold>, <italic>trans</italic>-<bold>11j</bold>, <italic>trans</italic>-<bold>11k</bold>, and <italic>cis</italic><bold>-11a</bold>, as well as diastereoisomeric mixtures of isoxazolidines <italic>trans</italic>-<bold>11f/</bold><italic>cis</italic>-<bold>11f</bold> (95:5) and <italic>trans</italic>-<bold>11i/</bold><italic>cis</italic>-<bold>11i</bold> (92:8), were tested for inhibitory activity against a wide variety of DNA and RNA viruses. The following cell-based assays were used: (a) human embryonic lung (HEL) cells (herpes simplex virus-1 (KOS strain), herpes simplex virus-2 (G strain), thymidine kinase deficient (acyclovir resistant) herpes simplex virus-1 (TK<sup>−</sup> KOS ACV<sup>r</sup>), vaccinia virus, adenovirus-2, vesicular stomatitis virus, cytomegalovirus (AD-169 and Davis strains), varicella-zoster virus (TK<sup>+</sup> VZV and TK<sup>−</sup> VZV strains)); (b) HeLa cell cultures (vesicular stomatitis virus, Coxsackie virus B4, and respiratory syncytial virus); (c) Vero cell cultures (parainfluenza-3 virus, reovirus-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus, yellow fever virus); (d) CrFK cell cultures (feline corona virus (FIPV) and feline herpes virus (FHV)); and (e) MDCK cell cultures (influenza A virus (H1N1 and H3N2 subtypes) and influenza B virus). Ganciclovir, cidofovir, acyclovir, brivudin, zalcitabine, zanamivir, alovudine, amantadine, rimantadine, ribavirin, dextran sulfate (molecular weight 10000, DS-10000), mycophenolic acid, Hippeastrum hybrid agglutinin (HHA), and Urtica dioica agglutinin (UDA) were used as the reference compounds. The antiviral activity was expressed as the EC<sub>50</sub>: the compound concentration required to reduce virus plaque formation (VZV) by 50% or to reduce virus-induced cytopathogenicity by 50% (other viruses).</p><p>Almost all synthesized isoxazolidines inhibited the replication of both TK<sup>+</sup> and TK<sup>−</sup> VZV strains at EC<sub>50</sub>’s in the 5.4–13.6 μΜ range (<xref rid="molecules-23-01889-t002" ref-type="table">Table 2</xref>), at the same time they were inactive toward other tested viruses, except for HCMV. In general, the inhibitory activity of the tested compounds toward TK<sup>−</sup> VZV 07-1 strain was better than that of the reference drugs acyclovir and brivudin (EC<sub>50</sub> = 39.2 μΜ and EC<sub>50</sub> = 31.9 μΜ, respectively), which require activation by the viral enzyme. On the other hand, the activity of these compounds against the TK<sup>+</sup> VZV OKA strain was five to nine-fold and 360 to 587-fold lower than that of the reference drugs acyclovir and brivudin, respectively. While exhibiting significant activity toward both TK<sup>+</sup> and TK<sup>−</sup> VZV stains, compounds <italic>trans</italic>-<bold>11b</bold>, <italic>trans</italic>-<bold>11d</bold>, <italic>trans</italic>-<bold>11g</bold>, and <italic>trans</italic>-<bold>11h</bold> exhibited the lowest cytotoxicity (CC<sub>50</sub> = 33–42 μΜ). It is worth mentioning that incorporation of the bromine atom at C6 in the quinazolinone skeleton resulted in a significant increase in potency of isoxazolidine-conjugates <bold>11b</bold>–<bold>11i</bold> against VZV (up to five-fold higher) when compared with previously described analogous conjugates <bold>10b</bold>–<bold>10i</bold> having an unsubstituted quinazoline skeleton [<xref rid="B25-molecules-23-01889" ref-type="bibr">25</xref>].</p><p>The synthesized isoxazolidine phosphonates also showed marked activity against human cytomegalovirus (HCMV) (<xref rid="molecules-23-01889-t003" ref-type="table">Table 3</xref>) and, among them, <italic>trans</italic>-<bold>11d</bold>, <italic>trans</italic>-<bold>11g</bold>, <italic>trans</italic>-<bold>11h</bold>, and <italic>trans</italic>-<bold>11i</bold>/<italic>cis</italic>-<bold>11i</bold> (92:8) were the most potent ones. Activities of the tested compounds against both AD-169 and Davis strains were comparable (EC<sub>50</sub> = 8.9–12.5 μΜ) to that of Ganciclovir (EC<sub>50</sub> = 16.9 and 7.7 μΜ) used as a reference drug, but still lower than that of the other reference drug, Cidofovir (EC<sub>50</sub> = 1.5–1.7 μΜ).</p></sec><sec id="sec2dot2dot2-molecules-23-01889"><title>2.2.2. Cytostatic Activity</title><p>The 50% cytostatic inhibitory concentration (IC<sub>50</sub>) causing a 50% decrease in cell proliferation was determined against murine leukemia L1210, human lymphocyte CEM, human cervix carcinoma HeLa, and immortalized human dermal microvacsular endothelial cells (HMEC-1). Almost all compounds <bold>11a</bold>–<bold>11k</bold> showed inhibitory activity against the proliferation of tumour cell lines (<xref rid="molecules-23-01889-t004" ref-type="table">Table 4</xref>). They appeared to be the most cytostatic toward the human T-lymphocyte (CEM) cell line with an inhibitory effect in the 9.6–33 μM range. Thus, isoxazolidines <italic>trans</italic>-<bold>11b</bold> (IC<sub>50</sub> = 16 ± 3 μM), <italic>trans</italic>-<bold>11c</bold> (IC<sub>50</sub> = 14 ± 4 μM), <italic>trans</italic>-<bold>11e</bold> (IC<sub>50</sub> = 17 ± 12 μM), <italic>trans</italic>-<bold>11f</bold>/<italic>cis</italic>-<bold>11f</bold> (95:5) (IC<sub>50</sub> = 13 ± 1 μM), <italic>trans</italic>-<bold>11g</bold> (IC<sub>50</sub> = 10 ± 0 μM), <italic>trans</italic>-<bold>11h</bold> (IC<sub>50</sub> = 9.6 ± 2.2 μM), and <italic>trans</italic>-<bold>11i</bold>/<italic>cis</italic>-<bold>11i</bold> (92:8) (IC<sub>50</sub> = 9.8 ± 4.8 μM) exhibited activity toward the CEM line higher than of 5-fluorouracil (IC<sub>50</sub> = 18 ± 5 μM).</p><p>Structure–activity relationship studies indicated that the isoxazolidine derivatives possessing hydrogen (<italic>cis</italic>-<bold>11a</bold>, <italic>trans</italic>-<bold>11a</bold>), methyl (<italic>trans</italic>-<bold>11j</bold>), or ethyl (<italic>trans</italic>-<bold>11k</bold>) at N3 in the quinazolinone ring were not active against tested viruses and they did not inhibit proliferation of the tested cell lines. Compounds substituted at N3 with benzyl moieties were found effective against VZV, HCMV, and were able to inhibit tumour cell line growth. Moreover, isoxazolidine phosphonates having 3-nitrobenzyl (<italic>trans</italic>-<bold>11d</bold>) and 3-fluorobenzyl (<italic>trans</italic>-<bold>11g</bold>) substituents at N3 of the quinazolinone core showed the highest antiviral activity with an EC<sub>50</sub> values in the range of 5.8–11.6 μM.</p><p>On the other hand, compounds possessing 3-fluorobenzyl (<italic>trans</italic>-<bold>11g</bold>), 4-fluorobenzyl (<italic>trans</italic>-<bold>11h</bold>) and 2,4-difluorobenzyl (<italic>trans</italic>-<bold>11i</bold>/<italic>cis</italic>-<bold>11i</bold> (92:8)) substituents at the N3 position showed an inhibitory effect against the proliferation of murine leukemia (L1210) and human T-lymphocyte (CEM) cell lines, whereas isoxazolidines having 2-nitrobenzyl (<italic>trans</italic>-<bold>11c</bold>) and 2,4-difluorobenzyl (<italic>trans</italic>-<bold>11i</bold>/<italic>cis</italic>-<bold>11i</bold> (92:8)) substituents at the same position of a quinazolinone moiety appeared to be the most active toward the human cervix carcinoma (HeLa) cell line, however, their inhibitory concentration was much lower than that of the reference drugs.</p></sec></sec></sec><sec id="sec3-molecules-23-01889"><title>3. Experimental Section</title><sec id="sec3dot1-molecules-23-01889"><title>3.1. General</title><p><sup>1</sup>H-NMR spectra were taken in CDCl<sub>3</sub> on the following spectrometers: Gemini 2000BB (200 MHz Varian, Palo Alto, CA, USA), and Bruker Avance III (600 MHz, Bruker Instrument, Karlsruhe, Germany) with TMS as internal standard. <sup>13</sup>C-NMR spectra were recorded for CDCl<sub>3</sub> solution on the Bruker Avance III at 151.0 MHz. <sup>31</sup>P-NMR spectra were performed in CDCl<sub>3</sub> solution on the Varian Gemini 2000 BB at 81.0 MHz or on Bruker Avance III at 243.0 MHz. </p><p>IR spectra were measured on an Infinity MI-60 FT-IR spectrometer (ATI Instruments North America—Mattson, Madison, WI, USA). Melting points were determined on a Boetius apparatus (VEB Kombinat NAGEMA, Dresden, DDR—currently Germany) and are uncorrected. Elemental analyses were performed by the Microanalytical Laboratory of this faculty on a Perkin-Elmer PE 2400 CHNS analyzer (Perkin-Elmer Corp., Norwalk, CT, USA). </p><p>The following adsorbents were used: column chromatography, Merck silica gel 60 (70–230 mesh); analytical TLC, Merck (Merck KGaA, Darmstadt, Germany) TLC plastic sheet silica gel 60 F<sub>254</sub>.</p><p><italic>N</italic>-methyl-<italic>C</italic>-(diethoxyphosphoryl)nitrone [<xref rid="B26-molecules-23-01889" ref-type="bibr">26</xref>] and 5-bromoanthranilic acid amide [<xref rid="B27-molecules-23-01889" ref-type="bibr">27</xref>,<xref rid="B28-molecules-23-01889" ref-type="bibr">28</xref>] were obtained according to the procedures in the literature.</p></sec><sec id="sec3dot2-molecules-23-01889"><title>3.2. Synthesis of 6-Bromo-2-vinyl-3H-quinazolin-4-one <italic><bold>13a</bold></italic></title><p>To a solution 5-bromoanthranilic amide (2.40 g, 11.2 mmol) in 1,4-dioxane (5 mL) 3-chloropropionyl chloride (0.527 mL, 5.60 mmol) was added over 20 min. at 0 °C under an argon atmosphere. The mixture was stirred at room temperature for 1 h and then diluted with water until a precipitate appeared, which was collected and washed with water (3 × 10 mL). A mixture of 2-(3-chloropropionylamino)benzamide (2.03 g, 6.63 mmol) in 5% sodium hydroxide (16.4 mL) and ethanol (8.2 mL) was stirred under reflux for 5 min., the solution was allowed to cool for 15 min. and then acidified with acetic acid (1.6 mL). The precipitate was collected and washed with water (3 × 10 mL). The crude 6-bromo-2-vinylquinazolin-4(3<italic>H)</italic>-one was purified by crystallization from methanol. </p><p>Off-white amorphous solid, m.p. = 223–225 °C (re-crystallized from methanol). IR (KBr, cm<sup>−1</sup>) ν<sub>max</sub>: 3165, 3088, 3019, 2943, 2738, 1673, 1638, 1591, 1462, 1337, 1292, 1245, 1207, 1114, 1065, 977, 829, 793, 687, 633. <sup>1</sup>H-NMR (200 MHz, DMSO): δ = 12.51 (s, 1H, NH), 8.17 (d, <sup>4</sup><italic>J</italic> = 2.4 Hz, 1H, <italic>H</italic>C5), 7.90 (dd, <sup>3</sup><italic>J</italic> = 8.7 Hz, <sup>4</sup><italic>J</italic> = 2.4 Hz, 1H, <italic>H</italic>C7), 7.81 (d, <sup>3</sup><italic>J</italic> = 8.7 Hz, 1H, <italic>H</italic>C8), 6.63 (dd, <sup>3</sup><italic>J</italic> = 17.5 Hz, <sup>2</sup><italic>J</italic> = 3.7 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 6.53 (dd, <sup>3</sup><italic>J</italic> = 17.5 Hz, <sup>3</sup><italic>J</italic> = 8.1 Hz, 1H, C<italic>H</italic>=CH<sub>2</sub>), 5.86 (dd, <sup>3</sup><italic>J</italic> = 8.1 Hz, <sup>2</sup><italic>J</italic> = 3.7 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>). <sup>13</sup>C-NMR (151 MHz, DMSO): δ = 161.11 (C=O), 152.00, 148.23, 137.80, 131.00, 130.18, 128.45, 126.31, 123.40, 119.37. Anal. Calcd. for C<sub>10</sub>H<sub>7</sub>BrN<sub>2</sub>O: C, 47.84; H, 2.81; N, 11.16. Found: C, 47.88; H, 2.49; N, 11.01.</p></sec><sec id="sec3dot3-molecules-23-01889"><title>3.3. General Procedure for the Synthesis of N3-Benzylated 6-bromo-2-vinyl-3H-quinazolin-4-ones <italic><bold>13b</bold></italic>–<italic><bold>13i</bold></italic></title><p>To a solution of 6-bromo-2-vinyl-3<italic>H</italic>-quinazolin-4-one (0.251 g, 1.00 mmol) in acetonitrile (15 mL) potassium hydroxide (0.168 g, 3.00 mmol) was added. After 15 min. the respective benzyl bromide (1.10 mmol) was added and the reaction mixture was stirred under reflux for 4 h. The solvent was removed and the residue was re-dissolved in methylene chloride (10 mL) and extracted with water (3 × 10 mL). An organic phase was dried (MgSO<sub>4</sub>), concentrated, and the crude product was purified on a silica gel column with a methylene chloride:hexane (7:3, <italic>v/v</italic>) mixture followed by crystallization (chloroform-petroleum ether or ethyl acetate) to give pure quinazolinones.</p><p><italic>3-Benzyl-6-bromo-2-vinylquinazolin-4(3H)-one</italic> (<bold>13b</bold>). A white amorphous solid, m.p. = 71–72 °C (re-crystallized from ethyl acetate). IR (KBr, cm<sup>−1</sup>) ν<sub>max</sub>: 3097, 3036, 2926, 1608, 1571, 1553, 1470, 1290, 1153, 1112, 989, 841, 678, 581, 437. <sup>1</sup>H-NMR (200 MHz, CDCl<sub>3</sub>): δ = 8.30–8.27 (m, 1H), 7.88–7.82 (m, 1H), 7.77–7.73 (m, 1H), 7.57–7.50 (m, 2H), 7.48–7.37 (m, 3H), 6.91 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>3</sup><italic>J</italic> = 9.9 Hz, 1H, C<italic>H</italic>=CH<sub>2</sub>), 6.73 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>2</sup><italic>J</italic> = 2.5 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 5.82 (dd, <sup>3</sup><italic>J</italic> = 9.9 Hz, <sup>2</sup><italic>J</italic> = 2.5 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 5.67 (s, 2H, N-C<italic>H</italic><sub>2</sub>). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 165.16 (C=O), 160.28, 150.36, 137.00, 136.88, 136.02, 129.45, 128.67, 128.45, 126.09, 124.36, 120.03, 116.67, 68.69 (N-CH<sub>2</sub>). Anal. Calcd. for C<sub>17</sub>H<sub>13</sub>BrN<sub>2</sub>O: C, 59.84; H, 3.84; N, 8.21. Found: C, 59.92; H, 3.68; N, 8.29.</p><p><italic>6-Bromo-3-(2-nitrobenzyl)-2-vinylquinazolin-4(3H)-one</italic> (<bold>13c</bold>). A yellowish amorphous solid, m.p. 117–119 °C (re-crystallized from chloroform-petroleum ether). IR (KBr, cm<sup>−1</sup>) ν<sub>max</sub>: 3078, 2980, 2925, 2854, 1689, 1613, 1573, 1526, 1489, 1390, 1354, 1287, 1242, 1116, 1053, 1024, 968, 836, 791, 730. <sup>1</sup>H-NMR (600 MHz, CDCl<sub>3</sub>): δ = 8.33 (d, <sup>4</sup><italic>J</italic> = 2.2 Hz, 1H, <italic>H</italic>C5), 8.18–8.16 (m, 1H), 7.90 (dd, <sup>3</sup><italic>J</italic> = 8.9 Hz, <sup>4</sup><italic>J</italic> = 2.2 Hz, 1H, <italic>H</italic>C7), 7.81 (d, <sup>3</sup><italic>J</italic> = 8.9 Hz, 1H, <italic>H</italic>C8), 7.80–7.78 (m, 1H), 7.71–7.69 (m, 1H), 7.56–7.53 (m, 1H), 6.87 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>3</sup><italic>J</italic> = 10.4 Hz, 1H, C<italic>H</italic>=CH<sub>2</sub>), 6.64 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>2</sup><italic>J</italic> = 1.5 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 6.10 (s, 2H, N-C<italic>H</italic><sub>2</sub>), 5.80 (dd, <sup>3</sup><italic>J</italic> = 10.4 Hz, <sup>2</sup><italic>J</italic> = 1.5 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 164.62 (C=O), 160.12, 150.32, 147.84, 137.31, 136.31, 133.78, 132.33, 129.51, 129.05, 128.87, 125.76, 125.07, 124.92, 120.38, 116.31, 65.14 (N-CH<sub>2</sub>). Anal. Calcd. for C<sub>17</sub>H<sub>12</sub>BrN<sub>3</sub>O<sub>3</sub>: C, 52.87; H, 3.13; N, 10.88. Found: C, 52.50; H, 2.80; N, 10.80.</p><p><italic>6-Bromo-3-(3-nitrobenzyl)-2-vinylquinazolin-4(3H)-one</italic> (<bold>13d</bold>). A yellowish amorphous solid, m.p. 147–149 °C (re-crystallized from chloroform-petroleum ether). IR (KBr, cm<sup>−1</sup>) ν<sub>max</sub>: 3112, 3071, 2924, 2854, 1610, 1573, 1529, 1456, 1382, 1294, 1119, 836, 668. <sup>1</sup>H-NMR (600 MHz, CDCl<sub>3</sub>): δ = 8.44 (brs, 1H), 8.32–8.30 (m, 1H), 8.26–8.24 (m, 1H), 7.91–7.88 (m, 2H), 7.80–7.78 (m, 1H), 7.64–7.61 (m, 1H), 6.91 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>3</sup><italic>J</italic> = 10.4 Hz, 1H, C<italic>H</italic>=CH<sub>2</sub>), 6.73 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>2</sup><italic>J</italic> = 1.4 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 5.84 (dd, <sup>3</sup><italic>J</italic> = 10.4 Hz, <sup>2</sup><italic>J</italic> = 1.4 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 5.78 (s, 2H, N-C<italic>H</italic><sub>2</sub>). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 164.69 (C=O), 160.05, 150.49, 148.51, 138.14, 137.28, 136.68, 134.10, 129.73, 129.60, 125.84, 124.47, 123.37, 123.27, 120.35, 116.34, 67.22 (N-CH<sub>2</sub>). Anal. Calcd. for C<sub>17</sub>H<sub>12</sub>BrN<sub>3</sub>O<sub>3</sub>: C, 52.87; H, 3.13; N, 10.88. Found: C, 52.81; H, 2.98; N, 10.60.</p><p><italic>6-Bromo-3-(4-nitrobenzyl)-2-vinylquinazolin-4(3H)-one</italic> (<bold>13e</bold>). Off-white amorphous solid, m.p. 121–123 °C (re-crystallized from chloroform-petroleum ether). IR (KBr, cm<sup>−1</sup>) ν<sub>max</sub>: 3418, 2924, 2853, 1739, 1608, 1573, 1524, 1343, 1292, 1117, 945, 833, 661. <sup>1</sup>H-NMR (200 MHz, CDCl<sub>3</sub>): δ = 8.30–8.26 (m, 3H), 7.96–7.92 (m, 1H), 7.81–7.76 (m, 1H), 7.73–7.67 (m, 2H), 6.88 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>3</sup><italic>J</italic> = 10.1 Hz, 1H, C<italic>H</italic>=CH<sub>2</sub>), 6.65 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>2</sup><italic>J</italic> = 2.1 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 5.80 (dd, <sup>3</sup><italic>J</italic> = 10.1 Hz, <sup>2</sup><italic>J</italic> = 2.1 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 5.77 (s, 2H, N-C<italic>H</italic><sub>2</sub>). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 164.69 (C=O), 160.03, 150.41, 147.93, 143.27, 137.37, 136.59, 129.58, 128.50, 125.80, 124.58, 123.93, 120.44, 116.33, 67.14 (N-CH<sub>2</sub>). Anal. Calcd. for C<sub>17</sub>H<sub>12</sub>BrN<sub>3</sub>O<sub>3</sub>: C, 52.87; H, 3.13; N, 10.88. Found: C, 52.81; H, 2.98; N, 10.60.</p><p><italic>6-Bromo-3-(2-fluorobenzyl)-2-vinylquinazolin-4(3H)-one</italic> (<bold>13f</bold>). A white amorphous solid, m.p. 91–92 °C (re-crystallized from ethyl acetate). IR (KBr, cm<sup>−1</sup>) ν<sub>max</sub>: 3078, 2967, 1568, 1555, 1486, 1420, 1348, 1293, 1238, 1115, 938, 828, 760, 675. <sup>1</sup>H-NMR (600 MHz, CDCl<sub>3</sub>): δ = 8.31 (d, <sup>4</sup><italic>J</italic> = 2.2 Hz, 1H, <italic>H</italic>C5), 7.89 (dd, <sup>3</sup><italic>J</italic> = 8.9 Hz, <sup>4</sup><italic>J</italic> = 2.2 Hz, 1H, <italic>H</italic>C7), 7.68 (d, <sup>3</sup><italic>J</italic> = 8.9 Hz, 1H, <italic>H</italic>C8), 7.61–7.58 (m, 1H), 7.42–7.38 (m, 1H), 7.23–7.20 (m, 1H), 7.18–7.15 (m, 1H), 6.92 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>3</sup><italic>J</italic> = 10.4 Hz, 1H, C<italic>H</italic>=CH<sub>2</sub>), 6.78 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>2</sup><italic>J</italic> = 1.7 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 5.84 (dd, <sup>3</sup><italic>J</italic> = 10.4 Hz, <sup>2</sup><italic>J</italic> = 1.7 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 5.78 (s, 2H, N-C<italic>H</italic><sub>2</sub>). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 164.99 (C=O), 161.20 (d, <sup>1</sup><italic>J</italic><sub>(CF)</sub> = 248.8 Hz, C2′), 160.24, 150.39, 137.03, 136.81, 130.70 (d, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 4.0 Hz, C4′), 130.39 (d, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 7.9 Hz, C6′), 129.47, 126.04, 124.44, 124.25 (d, <sup>4</sup><italic>J</italic><sub>(CCCCF)</sub> = 3.4 Hz, C5′), 123.24 (d, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 14.5 Hz, C3′), 120.06, 116.59, 115.63 (d, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 21.5 Hz, C1′), 62.51 (d, <sup>3</sup><italic>J</italic><sub>(CCF)</sub> = 4.4 Hz, N-CH<sub>2</sub>). Anal. Calcd. for C<sub>17</sub>H<sub>12</sub>BrFN<sub>2</sub>O: C, 56.85; H, 3.37; N, 7.80. Found: C, 56.62; H, 2.99; N, 7.79.</p><p><italic>6-Bromo-3-(3-fluorobenzyl)-2-vinylquinazolin-4(3H)-one</italic> (<bold>13g</bold>). A yellowish amorphous solid, m.p. 78–80 °C (re-crystallized from ethyl acetate). IR (KBr, cm<sup>−1</sup>) ν<sub>max</sub>: 3070, 2980, 2925, 2853, 1614, 1568, 1490, 1416, 1336, 1286, 1115, 1055, 967, 836, 790. <sup>1</sup>H-NMR (600 MHz, CDCl<sub>3</sub>): δ = 8.32 (d, <sup>4</sup><italic>J</italic> = 2.2 Hz, 1H, <italic>H</italic>C5), 7.89 (dd, <sup>3</sup><italic>J</italic> = 8.9 Hz, <sup>4</sup><italic>J</italic> = 2.2 Hz, 1H, <italic>H</italic>C7), 7.80 (d, <sup>3</sup><italic>J</italic> = 8.9 Hz, 1H, <italic>H</italic>C8), 7.43–7.39 (m, 1H), 7.34–7.32 (m, 1H), 7.28–7.26 (m, 1H), 7.11–7.08 (m, 1H), 6.92 (dd, <sup>3</sup><italic>J</italic> = 17.1 Hz, <sup>3</sup><italic>J</italic> = 10.4 Hz, 1H, C<italic>H</italic>=CH<sub>2</sub>), 6.73 (dd, <sup>3</sup><italic>J</italic> = 17.1 Hz, <sup>2</sup><italic>J</italic> = 1.7 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 5.84 (dd, <sup>3</sup><italic>J</italic> = 10.4 Hz, <sup>2</sup><italic>J</italic> = 1.7 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 5.69 (s, 2H, N-C<italic>H</italic><sub>2</sub>). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 164.95 (C=O), 162.95(d, <sup>1</sup><italic>J</italic><sub>(CF)</sub> = 246.6 Hz, C3′), 160.19, 150.43, 138.50 (d, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 7.5 Hz, C5′), 137.13, 136.79, 130.25 (d, <italic>J</italic> = 8.1 Hz, C1′), 129.53, 125.98, 124.42, 123.74 (d, <sup>4</sup><italic>J</italic><sub>(CCCCF)</sub> = 3.1 Hz, C6′), 120.18, 116.54, 115.33 (d, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 21.0 Hz, C4′), 115.14 (d, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 22.0 Hz, C2′), 67.77 (d, <sup>4</sup><italic>J</italic><sub>CCCCF</sub> = 1.5 Hz, N-CH<sub>2</sub>). Anal. Calcd. for C<sub>17</sub>H<sub>12</sub>BrFN<sub>2</sub>O: C, 56.85; H, 3.37; N, 7.80. Found: C, 56.99; H, 2.97; N, 7.84.</p><p><italic>6-Bromo-3-(4-fluorobenzyl)-2-vinylquinazolin-4(3H)-one</italic> (<bold>13h</bold>). A yellowish amorphous solid, m.p. 100–103 °C (re-crystallized from chloroform-petroleum ether). IR (KBr, cm<sup>−1</sup>) ν<sub>max</sub>: 3064, 2926, 1608, 1565, 1510, 1487, 1354, 1219, 1118, 989, 832, 697, 501. <sup>1</sup>H-NMR (200 MHz, CDCl<sub>3</sub>): δ = 8.26 (d, <sup>4</sup><italic>J</italic> = 2.1 Hz, 1H, <italic>H</italic>C5), 7.85 (dd, <sup>3</sup><italic>J</italic> = 8.9 Hz, <sup>4</sup><italic>J</italic> = 2.1 Hz, 1H, <italic>H</italic>C7), 7.75 (d, <sup>3</sup><italic>J</italic> = 8.9 Hz, 1H, <italic>H</italic>C8), 7.55–7.48 (m, 2H), 7.15–7.06 (m, 2H), 6.90 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>3</sup><italic>J</italic> = 11.5 Hz, 1H, C<italic>H</italic>=CH<sub>2</sub>), 6.72 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>2</sup><italic>J</italic> = 2.3 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 5.82 (dd, <sup>3</sup><italic>J</italic> = 11.5 Hz, <sup>2</sup><italic>J</italic> = 2.3 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 5.63 (s, 2H, N-C<italic>H</italic><sub>2</sub>). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 165.04 (C=O), 162.82 (d, <sup>1</sup><italic>J</italic><sub>(CF)</sub> = 247.1 Hz, C4′), 160.20, 150.40, 137.04, 136.88, 131.84 (d, <sup>4</sup><italic>J</italic><sub>(CCCCF)</sub> = 3.1 Hz, C1′), 130.39 (d, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 8.6 Hz, C2′, C6′), 129.50, 125.99, 124.28, 120. 08, 116.60, 115.62 (d, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 21.9 Hz, C3′, C5′), 67.94 (N-CH<sub>2</sub>). Anal. Calcd. for C<sub>17</sub>H<sub>12</sub>BrFN<sub>2</sub>O: C, 56.85; H, 3.37; N, 7.80. Found: C, 56.50; H, 3.01; N, 7.76.</p><p><italic>6-Bromo-3-(2,4-difluorobenzyl)-2-vinylquinazolin-4(3H)-one</italic> (<bold>13i</bold>). A yellowish amorphous solid, m.p. 88–90 °C (re-crystallized from chloroform-petroleum ether). IR (KBr, cm<sup>−1</sup>) ν<sub>max</sub>: 3079, 2923, 2852, 1614, 1565, 1508, 1488, 1416, 1349, 1279, 1099, 955, 834, 728, 538. <sup>1</sup>H-NMR (600 MHz, CDCl<sub>3</sub>): δ = 8.27 (d, <sup>4</sup><italic>J</italic> = 2.1 Hz, 1H, <italic>H</italic>C5), 7.88 (dd, <sup>3</sup><italic>J</italic> = 8.9 Hz, <sup>4</sup><italic>J</italic> = 2.1 Hz, 1H, <italic>H</italic>C7), 7.78 (d, <sup>3</sup><italic>J</italic> = 8.9 Hz, 1H, <italic>H</italic>C8), 7.59–7.55 (m, 1H), 6.96–6.89 (m, 2H), 6.89 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>3</sup><italic>J</italic> = 10.0 Hz, 1H, C<italic>H</italic>=CH<sub>2</sub>), 6.72 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>2</sup><italic>J</italic> = 2.4 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 5.82 (dd, <sup>3</sup><italic>J</italic> = 10.0 Hz, <sup>2</sup><italic>J</italic> = 2.4 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 5.68 (s, 2H, N-C<italic>H</italic><sub>2</sub>). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>) δ: 164.86 (C=O), 163.23 (dd, <sup>1</sup><italic>J</italic><sub>(CF)</sub> = 250.4 Hz, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 12.0 Hz, C2′), 161.45 (dd, <sup>1</sup><italic>J</italic><sub>(CF)</sub> = 251.8 Hz, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 12.1 Hz, C4′), 160.15, 150.38, 137.06, 136.80, 131.83 (dd, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 9.8 Hz, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 5.4 Hz, C6′), 129.49, 125.95, 124.39, 120.12, 119.29 (dd, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 15.0 Hz, <sup>4</sup><italic>J</italic><sub>(CCCCF)</sub> = 4.0 Hz, C1′), 116.48, 111.50 (dd, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 21.7 Hz, <sup>4</sup><italic>J</italic><sub>(CCCCF)</sub> = 4.1 Hz, C5′), 104.16 (dd, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 25.3 Hz, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 25.3 Hz, C3′), 61.93 (d, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 3.4 Hz, N-CH<sub>2</sub>) Anal. Calcd. for C<sub>17</sub>H<sub>11</sub>BrF<sub>2</sub>N<sub>2</sub>O: C, 54.13; H, 2.94; N, 7.43. Found: C, 54.42; H, 3.14; N, 7.04.</p></sec><sec id="sec3dot4-molecules-23-01889"><title>3.4. General Procedure for the Synthesis of N3-Alkylated 6-bromo-2-vinyl-3H-quinazolin-4-ones <italic><bold>13j</bold></italic> and <italic><bold>13k</bold></italic></title><p>To the solution of 6-bromo-2-vinyl-3<italic>H</italic>-quinazolin-4-one (0.251 g, 1.00 mmol) in acetonitrile (15 mL) potassium hydroxide (0.168 g, 3.00 mmol) was added. After 15 min iodomethane (0.124 mL, 2.00 mmol) or iodoethane (0.088 mL, 1.10 mmol) was added and the reaction mixture was stirred at 60 °C for 5 h. The solvent was removed and the residue was re-dissolved in methylene chloride (10 mL) and extracted with water (3 × 10 mL). The organic layer was dried (MgSO<sub>4</sub>), concentrated, and the crude product was purified on a silica gel column with a methylene chloride:hexane mixture (7:3, <italic>v/v</italic>) mixture followed by crystallization (chloroform:petroleum ether).</p><p><italic>6-Bromo-3-methyl-2-vinylquinazolin-4(3H)-one</italic> (<bold>13j</bold>). A white amorphous solid, m.p. = 147–148 °C (re-crystallized from chloroform-petroleum ether). IR (KBr, cm<sup>−1</sup>) ν<sub>max</sub>: 2956, 2924, 1675, 1661, 1555, 1468, 1337, 1260, 1025, 981, 791, 645. <sup>1</sup>H-NMR (200 MHz, CDCl<sub>3</sub>): δ = 8.21 (d, <sup>4</sup><italic>J</italic> = 2.1 Hz, 1H, <italic>H</italic>C5), 7.79 (dd, <sup>3</sup><italic>J</italic> = 8.9 Hz, <sup>4</sup><italic>J</italic> = 2.1 Hz, 1H, <italic>H</italic>C7), 7.67 (d, <sup>3</sup><italic>J</italic> = 8.9 Hz, 1H, <italic>H</italic>C8), 6.83 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>3</sup><italic>J</italic> = 9.9 Hz, 1H, C<italic>H</italic>=CH<sub>2</sub>), 6.66 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>2</sup><italic>J</italic> = 2.5 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 5.74 (dd, <sup>3</sup><italic>J</italic> = 9.9 Hz, <sup>2</sup><italic>J</italic> = 2.5 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 4.14 (s, 3H, C<italic>H</italic><sub>3</sub>). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 161.06 (C=O), 152.56, 146.20, 137.33, 129.34, 129.29, 128.92, 127.19, 121.95, 120.12, 30.95. Anal. Calcd. for C<sub>11</sub>H<sub>9</sub>BrN<sub>2</sub>O: C, 49.84; H, 3.42; N, 10.57. Found: C, 50.11; H, 3.42; N, 10.56.</p><p><italic>6-Bromo-3-ethyl-2-vinylquinazolin-4(3H)-one</italic> (<bold>13k</bold>). A white amorphous solid, m.p. = 62–64 °C (re-crystallized from chloroform-petroleum ether). IR (KBr, cm<sup>−1</sup>) ν<sub>max</sub>: 3097, 3035, 2956, 2926, 2853, 1610, 1571, 1554, 1488, 1428, 1347, 1291, 1153, 1018, 842, 807, 678. <sup>1</sup>H-NMR (200 MHz, CDCl<sub>3</sub>): δ = 8.22 (d, <sup>4</sup><italic>J</italic> = 2.2 Hz, 1H, <italic>H</italic>C5), 7.79 (dd, <sup>3</sup><italic>J</italic> = 8.9 Hz, <sup>4</sup><italic>J</italic> = 2.2 Hz, 1H, <italic>H</italic>C7), 7.68 (d, <sup>3</sup><italic>J</italic> = 8.9 Hz, 1H, <italic>H</italic>C8), 6.82 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>3</sup><italic>J</italic> = 10.0 Hz, 1H, C<italic>H</italic>=CH<sub>2</sub>), 6.63 (dd, <sup>3</sup><italic>J</italic> = 17.2 Hz, <sup>2</sup><italic>J</italic> = 2.4 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 5.73 (dd, <sup>3</sup><italic>J</italic> = 10.0 Hz, <sup>2</sup><italic>J</italic> = 2.4 Hz, 1H, CH=C<italic>H</italic><sub>2</sub>), 4.62 (q, <sup>3</sup><italic>J</italic> = 7.1 Hz, 2H, CH<sub>3</sub>C<italic>H</italic><sub>2</sub>), 1.47 (t, <sup>3</sup><italic>J</italic> = 7.1 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 161.06 (C=O), 160.37, 150.12, 136.90, 136.78, 129.34, 126.10, 124.19, 119.83, 116.71, 63.10, 14.28. Anal. Calcd. for C<sub>12</sub>H<sub>11</sub>BrN<sub>2</sub>O: C, 51.63; H, 3.97; N, 10.04. Found: C, 51.94; H, 3.75; N, 9.94.</p></sec><sec id="sec3dot5-molecules-23-01889"><title>3.5. General Procedure for the Synthesis of Isoxazolidines trans-<italic><bold>11</bold></italic> and cis-<italic><bold>11</bold></italic></title><p>A solution of the nitrone (0.195 g, 1.00 mmol) and the respective 6-bromo-2-vinylquinazolin-4(3<italic>H</italic>)-one (1.00 mmol) in toluene (2 mL) was stirred at 70 °C until the disappearance (TLC) of the starting nitrone. Solvents were evaporated in vacuo and crude products were subjected to chromatography on silica gel columns with chloroform:methanol (100:1, 50:1, 20:1, <italic>v/v</italic>) mixtures.</p><p><italic>Diethyl trans-[5-(6-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylisoxazolidin-3-yl]phosphonate</italic> (<italic>trans-</italic><bold>11a</bold>). Colorless oil. IR (film, cm<sup>−1</sup>) ν<sub>max</sub>: 3316, 3171, 3090, 2980, 2974, 2783, 1660, 1625, 1486, 1412, 1301, 1234, 1054, 968, 834, 775, 575. <sup>1</sup>H-NMR (600 MHz, CDCl<sub>3</sub>): δ = 10.63 (s, 1H, NH), 8.44 (d, <sup>4</sup><italic>J</italic> = 2.3 Hz, 1H, <italic>H</italic>C5′), 7.84 (dd, <sup>3</sup><italic>J</italic> = 8.6 Hz, <sup>4</sup><italic>J</italic> = 2.3 Hz, 1H, <italic>H</italic>C7′), 7.54 (d, <sup>3</sup><italic>J</italic> = 8.6 Hz, 1H, <italic>H</italic>C8′), 5.02 (dd, <sup>3</sup><italic>J</italic><sub>(H5–H4β)</sub> = 8.4 Hz, <sup>3</sup><italic>J</italic><sub>(H5–H4α)</sub> = 6.2 Hz, 1H, <italic>H</italic>C5), 4.30–4.21 (m, 4H, 2 × C<italic>H</italic><sub>2</sub>OP), 3.25–3.21 (m, 1H, <italic>H</italic>C3), 3.04 (s, 3H, C<italic>H</italic><sub>3</sub>N), 3.12 (dddd, <sup>3</sup><italic>J</italic><sub>(H4β–P)</sub> = 16.7 Hz, <sup>2</sup><italic>J</italic><sub>(H4β–H4α)</sub> = 12.9 Hz, <sup>3</sup><italic>J</italic><sub>(H4β–H5)</sub> = 8.6 Hz, <sup>3</sup><italic>J</italic><sub>(H4β–H3)</sub> = 8.3 Hz, 1H, <italic>H</italic><sub>β</sub>C4), 2.94 (dddd, <sup>3</sup><italic>J</italic><sub>(H4α–P)</sub> = 12.9 Hz, <sup>2</sup><italic>J</italic><sub>(H4α–H4β)</sub> = 12.9 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H3)</sub> = 10.0 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H5)</sub> = 6.2 Hz, 1H, <italic>H</italic><sub>α</sub>C4), 1.40 (t, <sup>3</sup><italic>J</italic> = 7.1 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP), 1.38 (t, <sup>3</sup><italic>J</italic> = 7.0 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 160.30 (C=O), 156.50, 147.35, 137.66, 129.26, 128.96, 123.27, 120.46, 74.68 (d, <sup>3</sup><italic>J</italic><sub>(CCCP)</sub> = 8.6 Hz, C5), 64.60 (d, <sup>1</sup><italic>J</italic><sub>(CP)</sub> = 168.1 Hz, C3), 63.51 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.6 Hz, CH<sub>2</sub>OP), 62.61 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.9 Hz, CH<sub>2</sub>OP), 46.07 (CH<sub>3</sub>N), 40.92 (C4), 16.55 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 6.2 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP), 16.48 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.5 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP). <sup>31</sup>P-NMR (243 MHz, CDCl<sub>3</sub>): δ = 20.51. Anal. Calcd. for C<sub>16</sub>H<sub>21</sub>BrN<sub>3</sub>O<sub>5</sub>P: C, 43.07; H, 4.74; N, 9.42. Found: C, 43.09; H, 4.52; N, 9.35.</p><p><italic>Diethyl cis-[5-(6-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylisoxazolidin-3-yl]phosphonate</italic> (<italic>cis</italic>-<bold>11a</bold>). Colorless oil. IR (film, cm<sup>−1</sup>) ν<sub>max</sub>: 3090, 2959, 2925, 2865, 1661, 1626, 1601, 1461, 1336, 1234, 1054, 969, 834, 575. <sup>1</sup>H-NMR (600 MHz, CDCl<sub>3</sub>): δ = 10.63 (s, 1H, NH), 8.44 (d, <sup>4</sup><italic>J</italic> = 2.3 Hz, 1H, <italic>H</italic>C5′), 7.84 (dd, <sup>3</sup><italic>J</italic> = 8.6 Hz, <sup>4</sup><italic>J</italic> = 2.3 Hz, 1H, <italic>H</italic>C7′), 7.54 (d, <sup>3</sup><italic>J</italic> = 8.6 Hz, 1H, <italic>H</italic>C8′), 5.07 (dd, <sup>3</sup><italic>J</italic><sub>(H5–H4α)</sub> = 9.2 Hz, <sup>3</sup><italic>J</italic><sub>(H5–H4β)</sub> = 4.3 Hz, 1H, <italic>H</italic>C5), 4.23–4.12 (m, 4H, 2 × C<italic>H</italic><sub>2</sub>OP), 3.21 (dddd, <sup>3</sup><italic>J</italic><sub>(H4β–P)</sub> = 19.8 Hz, <sup>2</sup><italic>J</italic><sub>(H4β–H4α)</sub> = 10.9 Hz, <sup>3</sup><italic>J</italic><sub>(H4β–H3)</sub> = 6.8 Hz, <sup>3</sup><italic>J</italic><sub>(H4β–H5)</sub> = 4.3 Hz, 1H, <italic>H</italic><sub>β</sub>C4), 3.12 (ddd, <sup>3</sup><italic>J</italic><sub>(H3–H4β)</sub> = 6.8 Hz, <sup>3</sup><italic>J</italic><sub>(H3–H4α)</sub> = 9.6 Hz, <sup>2</sup><italic>J</italic><sub>(H3–P)</sub> = 4.4 Hz 1H, <italic>H</italic>C3), 3.00 (s, 3H, C<italic>H</italic><sub>3</sub>N), 2.83 (dddd, <sup>3</sup><italic>J</italic><sub>(H4α–P)</sub> = 13.1 Hz, <sup>2</sup><italic>J</italic><sub>(H4α–H4β)</sub> = 10.9 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H3)</sub> = 9.6 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H5)</sub> = 9.2 Hz, 1H, <italic>H</italic><sub>α</sub>C4), 1.32 (t, <sup>3</sup><italic>J</italic> = 7.0 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP), 1.27 (t, <sup>3</sup><italic>J</italic> = 7.1 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 160.33 (C=O), 156.50, 147.35, 137.65, 129.26, 128.96, 123.27, 120.46, 75.58 (d, <sup>3</sup><italic>J</italic><sub>(CCCP)</sub> = 6.6 Hz, C5), 63.58 (d, <sup>1</sup><italic>J</italic><sub>(CP)</sub> = 169.1 Hz, C3), 63.18 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.5 Hz, CH<sub>2</sub>OP), 63.15 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.4 Hz, CH<sub>2</sub>OP), 45.58 (d, <sup>3</sup><italic>J</italic><sub>(CNCP)</sub> = 5.8 Hz, CH<sub>3</sub>N), 37.71 (C4), 16.38 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.3 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP), 16.37 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.4 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP). <sup>31</sup>P-NMR (243 MHz, CDCl<sub>3</sub>): δ = 20.92. Anal. Calcd. for C<sub>16</sub>H<sub>21</sub>BrN<sub>3</sub>O<sub>5</sub>P: C, 43.07; H, 4.74; N, 9.42. Found: C, 43.12; H, 4.35; N, 9.33.</p><p><italic>Diethyl trans-[5-(3-benzyl-6-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylisoxazolidin-3-yl]phosphonate</italic> (<italic>trans</italic>-<bold>11b</bold>). A yellowish oil. IR (film, cm<sup>−1</sup>) ν<sub>max</sub>: 3040, 2980, 2926, 2853, 1613, 1568, 1490, 1418, 1353, 1239, 1056, 1025, 835, 822, 699. <sup>1</sup>H-NMR (600 MHz, CDCl<sub>3</sub>): δ = 8.33 (d, <sup>4</sup><italic>J</italic> = 2.3 Hz, 1H, <italic>H</italic>C5′), 7.90 (dd, <sup>3</sup><italic>J</italic> = 8.9 Hz, <sup>4</sup><italic>J</italic> = 2.3 Hz, 1H, <italic>H</italic>C7′), 7.83 (d, <sup>3</sup><italic>J</italic> = 8.9 Hz, 1H, <italic>H</italic>C8′), 7.55–7.53 (m, 2H), 7.45–7.42 (m, 2H), 7.40–7.37 (m, 1H), 5.66 (s, 2H, N-C<italic>H</italic><sub>2</sub>), 5.25 (dd, <sup>3</sup><italic>J</italic><sub>(H5–H4β)</sub> = 6.8 Hz, <sup>3</sup><italic>J</italic><sub>(H5–H4α)</sub> = 6.4 Hz, 1H, <italic>H</italic>C5), 4.33–4.19 (m, 4H, 2 × C<italic>H</italic><sub>2</sub>OP), 3.42–3.39 (m, 1H, <italic>H</italic>C3), 3.07–2.94 (m, 2H, <italic>H</italic><sub>α</sub>C4, <italic>H</italic><sub>β</sub>C4), 3.05 (s, 3H, C<italic>H</italic><sub>3</sub>N), 1.42 (t, <sup>3</sup><italic>J</italic> = 7.0 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP), 1.39 (t, <sup>3</sup><italic>J</italic> = 6.9 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 166.08 (C=O), 163.35, 149.91, 137.20, 135.69, 129.67, 128.67, 128.65, 128.52, 128.45, 125.97, 120.69, 80.15 (d, <sup>3</sup><italic>J</italic><sub>(CCCP)</sub> = 8.5 Hz, C5), 69.14 (N-CH<sub>2</sub>), 64.41 (d, <sup>1</sup><italic>J</italic><sub>(CP)</sub> = 168.8 Hz, C3), 63.26 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.5 Hz, CH<sub>2</sub>OP), 62.42 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 7.2 Hz, CH<sub>2</sub>OP), 46.62 (CH<sub>3</sub>N), 37.90 (C4), 16.58 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.6 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP), 16.52 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.6 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP). <sup>31</sup>P-NMR (243 MHz, CDCl<sub>3</sub>): δ = 22.04. Anal. Calcd. for C<sub>23</sub>H<sub>27</sub>BrN<sub>3</sub>O<sub>5</sub>P: C, 51.50; H, 5.07; N, 7.83. Found: C, 51.78; H, 5.11; N, 7.70.</p><p><italic>Diethyl trans-{5-[6-bromo-3-(2-nitrobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-methylisoxazolidin-3-yl}phosphonate</italic> (<italic>trans</italic>-<bold>11c</bold>). A yellowish oil. IR (film, cm<sup>−1</sup>) ν<sub>max</sub>: 3444, 3077, 2979, 2925, 2853, 1690, 1614, 1575, 1527, 1489, 1413, 1355, 1337, 1055, 1024, 835, 791, 730, 574. <sup>1</sup>H-NMR (600 MHz, CDCl<sub>3</sub>): δ = 8.36 (d, <sup>4</sup><italic>J</italic> = 2.0 Hz, 1H, <italic>H</italic>C5′), 8.20–8.18 (m, 1H), 7.95 (dd, <sup>3</sup><italic>J</italic> = 8.9 Hz, <sup>4</sup><italic>J</italic> = 2.3 Hz, 1H, <italic>H</italic>C7′), 7.87 (d, <sup>4</sup><italic>J</italic> = 8.9 Hz, 1H, <italic>H</italic>C8′), 7.78–7.76 (m, 1H), 7.72–7.69 (m, 1H), 7.57–7.55 (m, 1H), 6.10 (AB, <italic>J</italic><sub>AB</sub> = 14.6 Hz, 1H, N-C<italic>H</italic><sub>2b</sub>), 6.07 (AB, <italic>J</italic><sub>AB</sub> = 14.6 Hz, 1H, N-C<italic>H</italic><sub>2a</sub>), 5.21 (dd, <sup>3</sup><italic>J</italic><sub>(H5–H4β)</sub> = 8.0 Hz, <sup>3</sup><italic>J</italic><sub>(H5–H4α)</sub> = 6.1 Hz, 1H, <italic>H</italic>C5), 4.31–4.22 (m, 4H, 2 × C<italic>H</italic><sub>2</sub>OP), 3.36–3.33 (m, 1H, <italic>H</italic>C3), 3.00 (s, 3H, C<italic>H</italic><sub>3</sub>N), 2.99 (dddd, <sup>2</sup><italic>J</italic><sub>(H4β–P)</sub> = 16.6 Hz, <sup>3</sup><italic>J</italic><sub>(H4β–H4α)</sub> = 12.6 Hz, <sup>3</sup><italic>J</italic><sub>(H4β–H3)</sub> = 8.2 Hz, <sup>3</sup><italic>J</italic><sub>(H4β–H5)</sub> = 8.0 Hz, 1H, <italic>H</italic><sub>β</sub>C4), 2.38 (dddd, <sup>2</sup><italic>J</italic><sub>(H4α–H4β)</sub> = 12.6 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–P)</sub> = 10.2 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H3)</sub> = 8.8 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H5)</sub> = 6.1 Hz, 1H, <italic>H</italic><sub>α</sub>C4), 1.41 (t, <sup>3</sup><italic>J</italic> = 7.1 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP), 1.39 (t, <sup>3</sup><italic>J</italic> = 7.1 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 165.56 (C=O), 163.42, 150.09, 147.81, 137.49, 133.80, 132.03, 129.85, 129.14, 129.00, 125.66, 125.15, 121.03, 116.40, 80.08 (d, <sup>3</sup><italic>J</italic><sub>(CCCP)</sub> = 7.8 Hz, C5), 65.64 (N-<italic>C</italic>H<sub>2</sub>), 64.30 (d, <sup>1</sup><italic>J</italic><sub>(CP)</sub> = 168.5 Hz, C3), 63.21 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.3 Hz, CH<sub>2</sub>OP), 62.49 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.8 Hz, CH<sub>2</sub>OP), 46.61 (d, <sup>3</sup><italic>J</italic><sub>(CNCP)</sub> = 4.2 Hz, CH<sub>3</sub>N), 37.91 (C4), 16.54 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.6 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP), 16.49 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.5 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP). <sup>31</sup>P-NMR (243 MHz, CDCl<sub>3</sub>): δ = 21.85. Anal. Calcd. for C<sub>23</sub>H<sub>26</sub>BrN<sub>4</sub>O<sub>7</sub>P: C, 47.52; H, 4.51; N, 9.64. Found: C, 47.22; H, 4.40; N, 9.35.</p><p><italic>Diethyl trans-{5-[6-bromo-3-(3-nitrobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-methylisoxazolidin-3-yl}phosphonate</italic> (<italic>trans</italic>-<bold>11d</bold>). A yellowish oil. IR (film, cm<sup>−1</sup>) ν<sub>max</sub>: 3078, 2980, 2926, 2854, 1613, 1566, 1531, 1489, 1416, 1348, 1242, 1115, 1053, 1024, 966, 836, 805, 733, 671. <sup>1</sup>H-NMR (600 MHz, CDCl<sub>3</sub>): δ = 8.44–8.42 (m, 1H), 8.32 (d, <sup>4</sup><italic>J</italic> = 2.0 Hz, 1H, <italic>H</italic>C5′), 8.24–8.22 (m, 1H), 7.92 (dd, <sup>3</sup><italic>J</italic> = 8.9 Hz, <sup>4</sup><italic>J</italic> = 2.0 Hz, 1H, <italic>H</italic>C7′), 7.90–7.88 (m, 1H), 7.84 (d, <sup>3</sup><italic>J</italic> = 8.9 Hz, 1H, <italic>H</italic>C8′), 7.63–7.60 (m, 1H), 5.77 (s, 2H, N-C<italic>H</italic><sub>2</sub>), 5.29 (dd, <sup>3</sup><italic>J</italic><sub>(H5–H4β)</sub> = 8.0 Hz, <sup>3</sup><italic>J</italic><sub>(H5–H4α)</sub> = 6.4 Hz, 1H, <italic>H</italic>C5), 4.34–4.23 (m, 4H, 2 × C<italic>H</italic><sub>2</sub>OP), 3.44–3.37 (m, 1H, <italic>H</italic>C3), 3.10–2.94 (m, 2H, <italic>H</italic><sub>α</sub>C4, <italic>H</italic><sub>β</sub>C4), 3.07 (s, 3H, C<italic>H</italic><sub>3</sub>N), 1.43 (t, <sup>3</sup><italic>J</italic> = 7.1 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP), 1.41 (t, <sup>3</sup><italic>J</italic> = 7.0 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 165.59 (C=O), 163.05, 150.03, 148.49, 137.81, 137.49, 134.31, 129.78, 129.76, 125.74, 123.45, 123.29, 121.03, 116.42, 80.00 (d, <sup>3</sup><italic>J</italic><sub>(CCCP)</sub> = 8.4 Hz, C5), 65.61 (N-CH<sub>2</sub>), 64.38 (d, <sup>1</sup><italic>J</italic><sub>(CP)</sub> = 168.5 Hz, C3), 63.26 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.5 Hz, CH<sub>2</sub>OP), 62.50 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.8 Hz, CH<sub>2</sub>OP), 46.57 (CH<sub>3</sub>N), 37.77 (C4), 16.56 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.6 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP), 16.50 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.9 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP). <sup>31</sup>P-NMR (243 MHz, CDCl<sub>3</sub>): δ = 21.52. Anal. Calcd. for C<sub>23</sub>H<sub>26</sub>BrN<sub>4</sub>O<sub>7</sub>P: C, 47.52; H, 4.51; N, 9.64. Found: C, 47.71; H, 4.51; N, 9.44.</p><p><italic>Diethyl trans-{5-[6-bromo-3-(4-nitrobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-methylisoxazolidin-3-yl}phosphonate</italic> (<italic>trans</italic>-<bold>11e</bold>). A yellowish oil. IR (film, cm<sup>−1</sup>) ν<sub>max</sub>: 3069, 2969, 2925, 2854, 1610, 1571, 1523, 1490, 1343, 1285, 1241, 1114, 1027, 968, 837. <sup>1</sup>H-NMR (600 MHz, CDCl<sub>3</sub>): δ = 8.35 (d, <sup>4</sup><italic>J</italic> = 2.0 Hz, 1H, <italic>H</italic>C5′), 1H), 8.30–8.28 (m, 2H), 7.95 (dd, <sup>3</sup><italic>J</italic> = 8.9 Hz, <sup>4</sup><italic>J</italic> = 2.0 Hz, 1H, <italic>H</italic>C7′), 7.86 (d, <sup>3</sup><italic>J</italic> = 8.9 Hz, 1H, <italic>H</italic>C8′), 7.72–7.71 (m, 2H), 5.76 (s, 1H, N-C<italic>H</italic><sub>2</sub>), 5.24 (dd, <sup>3</sup><italic>J</italic><sub>(H5–H4β)</sub> = 6.4 Hz, <sup>3</sup><italic>J</italic><sub>(H5–H4α)</sub> = 6.0 Hz, 1H, <italic>H</italic>C5), 4.32–4.22 (m, 4H, 2 × C<italic>H</italic><sub>2</sub>OP), 3.37–3.33 (m, 1H, <italic>H</italic>C3), 3.07–2.98 (m, 1H, <italic>H</italic><sub>β</sub>C4), 3.03 (s, 3H, C<italic>H</italic><sub>3</sub>-N), 2.94 (dddd, <sup>3</sup><italic>J</italic><sub>(H4α–P)</sub> = 12.4 Hz, <sup>2</sup><italic>J</italic><sub>(H4α–H4β)</sub> = 12.4 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H3)</sub> = 9.2 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H5)</sub> = 6.0 Hz, 1H, <italic>H</italic><sub>α</sub>C4), 1.41 (t, <sup>3</sup><italic>J</italic> = 7.0 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP), 1.39 (t, <sup>3</sup><italic>J</italic> = 7.0 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 165.57 (C=O), 163.06, 150.04, 147.95, 142.93, 137.55, 129.83, 128.67, 125.69, 123.92, 121.09, 116.42, 79.97 (d, <sup>3</sup><italic>J</italic><sub>(CCCP)</sub> = 8.6 Hz, C5), 67.55 (s, N-CH<sub>2</sub>), 64.40 (d, <sup>1</sup><italic>J</italic><sub>(CP)</sub> = 168.3 Hz, C3), 63.28 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.5 Hz, CH<sub>2</sub>OP), 62.46 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 7.1 Hz, CH<sub>2</sub>OP), 46.55 (CH<sub>3</sub>N), 37.77 (C4), 16.56 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.7 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP), 16.50 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.8 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP). <sup>31</sup>P-NMR (243 MHz, CDCl<sub>3</sub>): δ = 21.85. Anal. Calcd. for C<sub>23</sub>H<sub>26</sub>BrN<sub>4</sub>O<sub>7</sub>P: C, 47.52; H, 4.51; N, 9.64. Found: C, 47.75; H, 4.54; N, 9.39.</p><p><italic>Diethyl trans-{5-[6-bromo-3-(2-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-methylisoxazolidin-3-yl}phosphonate</italic> (<italic>trans</italic>-<bold>11f</bold>). Data presented below were extracted from spectra of a 88:12 mixture of trans-<bold>11f</bold> and cis-<bold>11f</bold>. Yellowish oil. IR (film, cm<sup>−1</sup>) ν<sub>max</sub>: 3069, 2981, 2929, 2909, 1614, 1567, 1490, 1456, 1353, 1285, 1116, 1025, 964, 869, 760, 691. <sup>1</sup>H-NMR (600 MHz, CDCl<sub>3</sub>): δ = 8.31 (d, <sup>4</sup><italic>J</italic> = 2.1 Hz, 1H, HC5′), 7.90 (dd, <sup>3</sup><italic>J</italic> = 8.9 Hz, <sup>4</sup><italic>J</italic> = 2.1 Hz, 1H, HC7′), 7.84 (d, <sup>3</sup><italic>J</italic> = 8.9 Hz, 1H, HC8′), 7.58–7.55 (m, 1H), 7.40–7.36 (m, 1H), 7.21–7.18 (m, 1H), 7.16–7.13 (m, 1H), 5.73 (AB, <italic>J</italic><sub>AB</sub> = 12.4 Hz, 1H, N-CH<sub>2b</sub>), 5.71 (AB, <italic>J</italic><sub>AB</sub> = 12.4 Hz, 1H, N-CH<sub>2a</sub>), 5.25 (dd, <sup>3</sup><italic>J</italic><sub>(H5–H4β)</sub> = 7.9 Hz, <sup>3</sup><italic>J</italic><sub>(H5–H4α)</sub> = 6.2 Hz, 1H, HC5), 4.33–4.18 (m, 4H, 2 × CH<sub>2</sub>OP), 3.42–3.39 (m, 1H, C3), 3.05 (s, 3H, CH<sub>3</sub>-N), 3.03–2.96 (m, 1H, H<sub>β</sub>C4), 2.96 (dddd, <sup>3</sup><italic>J</italic><sub>(H4α–P)</sub> = 12.5 Hz, <sup>2</sup><italic>J</italic><sub>(H4α–H4β)</sub> = 12.5 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H3)</sub> = 8.9 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H5)</sub> = 6.2 Hz, 1H, H<sub>α</sub>C4), 1.42 (t, <sup>3</sup><italic>J</italic> = 7.0 Hz, 3H, CH<sub>3</sub>CH<sub>2</sub>OP), 1.39 (t, <sup>3</sup><italic>J</italic> = 7.1 Hz, 3H, CH<sub>3</sub>CH<sub>2</sub>OP). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 165.94 (C=O), 163.31, 161.19 (d, <sup>1</sup><italic>J</italic><sub>(CF)</sub> = 248.8 Hz, C2″), 149.96, 137.25, 130.81 (d, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 3.5 Hz, C4″), 130.52 (d, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 8.0 Hz, C6″), 129.68, 125.94, 124.26 (d, <sup>4</sup><italic>J</italic><sub>(CCCCF)</sub> = 3.4 Hz, C5″), 122.93 (d, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 14.5 Hz, C3″), 120.75, 116.65, 115.66 (d, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 21.0 Hz, C1″), 80.14 (dd, <sup>3</sup><italic>J</italic><sub>(CCCP)</sub> = 8.1 Hz, C5), 64.42 (d, <sup>1</sup><italic>J</italic><sub>(CP)</sub> = 168.3 Hz, C3), 63.25 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.5 Hz, CH<sub>2</sub>OP), 63.03 (d, <sup>3</sup><italic>J</italic> = 4.3 Hz, N-CH<sub>2</sub>), 62.43 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 7.2 Hz, CH<sub>2</sub>OP), 46.59 (CH<sub>3</sub>N), 37.89 (C4), 16.55 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.7 Hz, CH<sub>3</sub>CH<sub>2</sub>OP), 16.50 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.8 Hz, CH<sub>3</sub>CH<sub>2</sub>OP). <sup>31</sup>P-NMR (243 MHz, CDCl<sub>3</sub>): δ = 22.01. Anal. Calcd. for C<sub>23</sub>H<sub>26</sub>BrFN<sub>3</sub>O<sub>5</sub>P: C, 49.83; H, 4.73; N, 7.58. Found: C, 49.49; H, 4.53; N, 7.71 (obtained on a 88:12 mixture of trans-<bold>11f</bold> and cis-<bold>11f</bold>).</p><p><italic>Diethyl trans-{5-[6-bromo-3-(3-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-methylisoxazolidin-3-yl}phosphonate</italic> (<italic>trans</italic>-<bold>11g</bold>). Yellowish oil. IR (film, cm<sup>−1</sup>) ν<sub>max</sub>: 3071, 2979, 2926, 2853, 1613, 1572, 1490, 1452, 1415, 1345, 1285, 1255, 1114, 1055, 1025, 966, 836, 789, 749. <sup>1</sup>H-NMR (200 MHz, CDCl<sub>3</sub>): δ = 8.35–8.33 (m, 1H), 7.91–7.89 (m, 1H), 7.84–7.82 (m, 1H), 7.41–7.37 (m, 1H), 7.30–7.28 (m, 1H), 7.26–7.24 (m, 1H), 7.08–7.05 (m, 1H), 5.64 (s, 1H, N-CH<sub>2</sub>), 5.24 (dd, <sup>3</sup><italic>J</italic><sub>(H5–H4β)</sub> = 7.9 Hz, <sup>3</sup><italic>J</italic><sub>(H5–H4α)</sub> = 6.5 Hz, 1H, <italic>H</italic>C5), 4.33–4.17 (m, 4H, 2 × C<italic>H</italic><sub>2</sub>OP), 3.39–3.36 (m, 1H, C3), 3.04 (s, 3H, C<italic>H</italic><sub>3</sub>-N), 3.05–2.99 (m, 1H, <italic>H</italic><sub>β</sub>C4), 2.95 (dddd, <sup>3</sup><italic>J</italic><sub>(H4α–P)</sub> = 12.7 Hz, <sup>2</sup><italic>J</italic><sub>(H4α–H4β)</sub> = 12.7 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H3)</sub> = 9.7 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H5)</sub> = 6.5 Hz, 1H, <italic>H</italic><sub>α</sub>C4), 1.41 (t, <sup>3</sup><italic>J</italic> = 7.0 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP), 1.39 (t, <sup>3</sup><italic>J</italic> = 6.9 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 165.84 (C=O), 163.22, 162.91, (d, <sup>1</sup><italic>J</italic><sub>(CF)</sub> = 246.7 Hz, C3′), 149.97, 138.18 (d, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 7.6 Hz, C5′), 137.31, 130.26 (d, <italic>J</italic> = 7.9 Hz, C1′), 129.72, 125.84, 123.80 (d, <sup>4</sup><italic>J</italic><sub>(CCCCF)</sub> = 2.4 Hz, C6′), 120.83, 116.59, 115.45 (d, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 21.0 Hz, C4′), 115.21 (d, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 22.0 Hz, C2′), 80.06 (dd, <sup>3</sup><italic>J</italic><sub>(CCCP)</sub> = 8.0 Hz, C5), 68.19 (d, <sup>3</sup><italic>J</italic> = 1.7 Hz, N-CH<sub>2</sub>), 64.42 (d, <sup>1</sup><italic>J</italic><sub>(CP)</sub> = 168.3 Hz, C3), 63.24 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.4 Hz, CH<sub>2</sub>OP), 62.44 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 7.3 Hz, CH<sub>2</sub>OP), 46.57 (d, <sup>3</sup><italic>J</italic><sub>(CNCP)</sub> = 3.7 Hz, CH<sub>3</sub>N), 37.84 (s, C4), 16.55 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.6 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP), 16.49 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.9 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP). <sup>31</sup>P-NMR (121.5 MHz, CDCl<sub>3</sub>): δ = 21.97. Anal. Cald. for C<sub>23</sub>H<sub>26</sub>BrFN<sub>3</sub>O<sub>5</sub>P: C, 49.83; H, 4.73; N, 7.58. Found: C, 49.49; H, 4.53; N, 7.71.</p><p><italic>Diethyl trans{5-[6-bromo-3-(4-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-methylisoxazolidin-3-yl}phosphonate</italic> (<italic>trans</italic>-<bold>11h</bold>). A yellowish oil. IR (film, cm<sup>−</sup><sup>1</sup>) ν<sub>max</sub>: 3072, 2981, 2926, 2853, 1611, 1568, 1512, 1490, 1430, 1351, 1285, 1227, 1160, 1114, 1099,1056, 1026, 965, 835.<sup>1</sup>H-NMR (600 MHz, CDCl<sub>3</sub>): δ = 8.31 (d, <sup>4</sup><italic>J</italic> = 2.2 Hz, 1H, <italic>H</italic>C5′), 7.91 (dd, <sup>3</sup><italic>J</italic> = 8.9 Hz, <sup>4</sup><italic>J</italic> = 2.2 Hz, 1H, <italic>H</italic>C7′), 7.84 (d, <sup>3</sup><italic>J</italic> = 8.9 Hz, 1H, <italic>H</italic>C8′), 7.55–7.53 (m, 2H), 7.14–7.11 (m, 2H), 5.63 (s, 1H, N-C<italic>H</italic><sub>2</sub>), 5.26 (dd, <sup>3</sup><italic>J</italic><sub>(H5–H4</sub><sub>β</sub><sub>)</sub> = 6.4 Hz, <sup>3</sup><italic>J</italic><sub>(H5–H4</sub><sub>α</sub><sub>)</sub> = 6.4 Hz, 1H, <italic>H</italic>C5), 4.34–4.22 (m, 4H, 2 × C<italic>H</italic><sub>2</sub>OP), 3.41–3.39 (m, 1H, C3), 3.07–3.00 (m, 1H, <italic>H</italic><sub>β</sub>C4), 3.06 (s, 3H, C<italic>H</italic><sub>3</sub>-N), 2.98 (dddd, <sup>3</sup><italic>J</italic><sub>(H4</sub><sub>α</sub><sub>–P)</sub> = 13.4 Hz, <sup>2</sup><italic>J</italic><sub>(H4</sub><sub>α</sub><sub>–H4β</sub><sub>)</sub> = 13.4 Hz, <sup>3</sup><italic>J</italic><sub>(H4</sub><sub>α</sub><sub>–H3)</sub> = 10.4 Hz, <sup>3</sup><italic>J</italic><sub>(H4</sub><sub>α</sub><sub>–H5)</sub> = 6.4 Hz, 1H, <italic>H</italic><sub>α</sub>C4), 1.42 (t, <sup>3</sup><italic>J</italic> = 7.0 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP), 1.40 (t, <sup>3</sup><italic>J</italic> = 7.1 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 165.94 (C=O), 163.26, 162.84 (d, <sup>1</sup><italic>J</italic><sub>(CF)</sub> = 247.6 Hz, C4″), 149.94, 137.25, 131.52 (d, <sup>4</sup><italic>J</italic><sub>(CCCCF)</sub> = 3.1 Hz, C1″), 130.49 (d, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 8.0 Hz, C2″, C6″), 129.69, 125.89, 120.75, 116.65, 115.62 (d, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 21.9 Hz, C3″, C5″), 80.09 (d, <sup>3</sup><italic>J</italic><sub>(CCP)</sub> = 8.1 Hz, C5), 68.40 (N-CH<sub>2</sub>), 64.43 (d, <sup>1</sup><italic>J</italic><sub>(CP)</sub> = 168.3 Hz, C3), 63.26 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.5 Hz, CH<sub>2</sub>OP), 62.45 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.8 Hz, CH<sub>2</sub>OP), 46.59 (CH<sub>3</sub>N), 37.87 (C4), 16.56 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.8 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP), 16.46 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.3 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP). <sup>31</sup>P-NMR (243 MHz, CDCl<sub>3</sub>): δ = 22.00. Anal. Calcd. for C<sub>23</sub>H<sub>26</sub>BrFN<sub>3</sub>O<sub>5</sub>P: C, 49.83; H, 4.73; N, 7.58. Found: C, 50.20; H, 4.62; N, 7.32.</p><p><italic>Diethyl trans-{5-[6-bromo-3-(2,4-difluorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-methylisoxazolidin-3-yl}phosphonate</italic> (<italic>trans</italic>-<bold>11i</bold>). Data presented below were extracted from spectra of a 92:8 mixture of trans-<bold>11i</bold> and cis-<bold>11i</bold>. Yellowish oil. IR (film, cm<sup>−1</sup>) ν<sub>max</sub>: 3079, 2959, 2924, 2853, 1738, 1689, 1613, 1565, 1509, 1490, 1416, 1351, 1280, 1141, 1100, 961, 836, 798. <sup>1</sup>H-NMR (600 MHz, CDCl<sub>3</sub>): δ = 8.30 (d, <sup>4</sup><italic>J</italic> = 2.1 Hz, 1H, HC5′), 7.92 (dd, <sup>3</sup><italic>J</italic> = 8.8 Hz, <sup>4</sup><italic>J</italic> = 2.1 Hz, 1H, HC7′), 7.85 (d, <sup>3</sup><italic>J</italic> = 8.8 Hz, 1H, HC8′), 7.59–7.55 (m, 1H), 6.95–6.89 (m, 2H), 5.68 (AB, <italic>J</italic><sub>AB</sub> = 13.3 Hz, 1H, N-CH<sub>2b</sub>), 5.66 (AB, <italic>J</italic><sub>AB</sub> = 13.3 Hz, 1H, N-CH<sub>2a</sub>), 5.25 (dd, <sup>3</sup><italic>J</italic><sub>(H5–H4β)</sub> = 7.7 Hz, <sup>3</sup><italic>J</italic><sub>(H5–H4α)</sub> = 6.5 Hz, 1H, HC5), 4.33–4.18 (m, 4H, 2 × CH<sub>2</sub>OP), 3.41–3.38 (m, 1H, HC3), 3.07–3.01 (m, 1H, H<sub>β</sub>C4), 3.05 (s, 3H, CH<sub>3</sub>-N), 2.98 (dddd, <sup>3</sup><italic>J</italic><sub>(H4α–P)</sub> = 12.8 Hz, <sup>2</sup><italic>J</italic><sub>(H4α–H4β)</sub> = 12.8 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H3)</sub> = 9.7 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H5)</sub> = 6.5 Hz, 1H, H<sub>α</sub>C4), 1.41 (t, <sup>3</sup><italic>J</italic> = 7.0 Hz, 3H, CH<sub>3</sub>CH<sub>2</sub>OP), 1.40 (t, <sup>3</sup><italic>J</italic> = 7.0 Hz, 3H, CH<sub>3</sub>CH<sub>2</sub>OP). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 165.82 (C=O), 163.32 (dd, <sup>1</sup><italic>J</italic><sub>(CF)</sub> = 250.9 Hz, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 12.1 Hz, C2″), 163.20, 161.50 (dd, <sup>1</sup><italic>J</italic><sub>(CF)</sub> = 251.4 Hz, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 12.2 Hz, C4″), 149.87, 137.31, 132.09 (dd, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 9.8 Hz, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 4.9 Hz, C6″), 129.71, 125.87, 120.81, 118.98 (dd, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 14.4 Hz, <sup>4</sup><italic>J</italic><sub>(CCCCF)</sub> = 3.4 Hz, C1″), 116.58, 111.51 (dd, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 21.1 Hz, <sup>4</sup><italic>J</italic><sub>(CCCCF)</sub> = 3.5 Hz, C5″), 104.21 (dd, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 25.3 Hz, <sup>2</sup><italic>J</italic><sub>(CCF)</sub> = 25.4 Hz, C3″), 80.09 (dd, <sup>3</sup><italic>J</italic><sub>(CCCP)</sub> = 7.9 Hz, C5), 64.43 (d, <sup>1</sup><italic>J</italic><sub>(CP)</sub> = 168.3 Hz, C3), 63.26 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.5 Hz, CH<sub>2</sub>OP), 62.47 (d, <sup>3</sup><italic>J</italic><sub>(CCCF)</sub> = 2.7 Hz, N-CH<sub>2</sub>), 62.43 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.3 Hz, CH<sub>2</sub>OP), 46.57 (d, <sup>3</sup><italic>J</italic><sub>(CNCP)</sub> = 4.0 Hz, CH<sub>3</sub>N), 37.89 (C4), 16.56 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.7 Hz, CH<sub>3</sub>CH<sub>2</sub>OP), 16.50 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.6 Hz, CH<sub>3</sub>CH<sub>2</sub>OP). <sup>31</sup>P-NMR (243 MHz, CDCl<sub>3</sub>): δ = 21.98. Anal. Calcd. for C<sub>23</sub>H<sub>25</sub>BrF<sub>2</sub>N<sub>3</sub>O<sub>5</sub>P × 0.75 H<sub>2</sub>O: C, 47.15; H, 4.56; N, 7.17. Found: C, 46.84; H, 4.18; N, 6.96 (obtained on a 92:8 mixture of <italic>trans</italic>-<bold>11i</bold> and <italic>cis</italic>-<bold>11i</bold>).</p><p><italic>Diethyl trans-{5-[6-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]-2-methylisoxazolidin-3-yl}phosphonate</italic> (<italic>trans</italic>-<bold>11j</bold>). A yellowish oil. IR (film, cm<sup>−1</sup>) ν<sub>max</sub>: 3521, 3477, 2976, 2912, 2855, 1687, 1606, 1470, 1308, 1265, 1050, 1023, 972, 849, 574. <sup>1</sup>H-NMR (600 MHz, CDCl<sub>3</sub>): δ = 8.42 (d, <sup>4</sup><italic>J</italic> = 2.3 Hz, 1H, <italic>H</italic>C5′), 7.82 (dd, <sup>3</sup><italic>J</italic> = 8.7 Hz, <sup>4</sup><italic>J</italic> = 2.3 Hz, 1H, <italic>H</italic>C7′), 7.56 (d, <sup>3</sup><italic>J</italic> = 8.7 Hz, 1H, <italic>H</italic>C8′), 5.18 (dd, <sup>3</sup><italic>J</italic><sub>(H5–H4β)</sub> = 7.6 Hz, <sup>3</sup><italic>J</italic><sub>(H5–H4α)</sub> = 5.7 Hz, 1H, <italic>H</italic>C5), 4.29–4.23 (m, 4H, 2 × C<italic>H</italic><sub>2</sub>OP), 3.75 (s, 3H, CH<sub>3</sub>), 3.71 (dddd, <sup>3</sup><italic>J</italic><sub>(H4α–P)</sub> = 12.6 Hz, <sup>2</sup><italic>J</italic><sub>(H4α–H4β)</sub> = 11.3 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H3)</sub> = 9.1 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H5)</sub> = 5.7 Hz, 1H, <italic>H</italic><sub>α</sub>C4), 3.35 (ddd, <sup>3</sup><italic>J</italic><sub>(H3–H4α)</sub> = 9.1 Hz, <sup>3</sup><italic>J</italic><sub>(H3–H4β)</sub> = 7.6 Hz, <sup>2</sup><italic>J</italic><sub>(H3-P)</sub> = 2.8 Hz, 1H, <italic>H</italic>C3), 2.87 (s, 3H, C<italic>H</italic><sub>3</sub>N), 2.80 (dddd, <sup>3</sup><italic>J</italic><sub>(H4β–P)</sub> = 15.3 Hz, <sup>2</sup><italic>J</italic><sub>(H4β–H4α)</sub> = 11.3 Hz, <sup>3</sup><italic>J</italic><sub>(H4β–H3)</sub> = 7.6 Hz, <sup>3</sup><italic>J</italic><sub>(H4β–H5)</sub> = 7.6 Hz, 1H, <italic>H</italic><sub>β</sub>C4), 1.41 (t, <sup>3</sup><italic>J</italic> = 7.0 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP), 1.40 (t, <sup>3</sup><italic>J</italic> = 7.1 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ = 161.31 (C=O), 152.70, 145.34, 137.33, 129.44, 129.37, 122.31, 121.02, 76.29 (d, <sup>3</sup><italic>J</italic><sub>(CCCP)</sub> = 7.8 Hz, C5), 64.35 (d, <sup>1</sup><italic>J</italic><sub>(CP)</sub> = 170.1 Hz, C3), 62.89 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.6 Hz, CH<sub>2</sub>OP), 62.73 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 7.2 Hz, CH<sub>2</sub>OP), 47.15 (d, <sup>3</sup><italic>J</italic><sub>(CNCP)</sub> = 6.4 Hz CH<sub>3</sub>N), 34.38 (C4), 30.97 (CH<sub>3</sub>), 16.56 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 4.9 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP), 16.53 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.1 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP). <sup>31</sup>P-NMR (243 MHz, CDCl<sub>3</sub>): δ = 21.93. Anal. Calcd. for C<sub>17</sub>H<sub>23</sub>BrN<sub>3</sub>O<sub>5</sub>P: C, 44.36; H, 5.04; N, 9.13. Found: C, 44.15; H, 4.75; N, 9.03.</p><p><italic>Diethyl trans-{5-[6-bromo-3-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl]-2-methylisoxazolidin-3-yl}phosphonate</italic> (<italic>trans</italic>-<bold>11k</bold>). Colorless oil. IR (film, cm<sup>−1</sup>) ν<sub>max</sub>: 3055, 2981, 2929, 2854, 1687, 1613, 1569, 1493, 1430, 1383, 1285, 1241, 1117, 1056, 1024, 967, 836. <sup>1</sup>H-NMR (600 MHz, CDCl<sub>3</sub>): δ = 8.32 (d, <sup>4</sup><italic>J</italic> = 2.2 Hz, 1H, <italic>H</italic>C5′), 7.90 (dd, <sup>3</sup><italic>J</italic> = 8.8 Hz, <sup>4</sup><italic>J</italic> = 2.2.Hz, 1H, <italic>H</italic>C7′), 7.82 (d, <sup>3</sup><italic>J</italic> = 8.8 Hz, 1H, <italic>H</italic>C8′), 5.23 (dd, <sup>3</sup><italic>J</italic><sub>(H5–H4β)</sub> = 8.0 Hz, <sup>3</sup><italic>J</italic><sub>(H5–H4α)</sub> = 6.0 Hz, 1H, <italic>H</italic>C5), 4.68 (q, <sup>3</sup><italic>J</italic> = 7.2 Hz, 2H, CH<sub>3</sub>C<italic>H</italic><sub>2</sub>), 4.33–4.21 (m, 4H, 2 × C<italic>H</italic><sub>2</sub>OP), 3.45–3.43 (m, 1H, <italic>H</italic>C3), 3.07 (s, 3H, C<italic>H</italic><sub>3</sub>N), 3.06–3.01 (m, 1H, <italic>H</italic><sub>β</sub>C4), 2.97 (dddd, <sup>3</sup><italic>J</italic><sub>(H4α–P)</sub> = 12.6 Hz, <sup>2</sup><italic>J</italic><sub>(H4α–H4β)</sub> = 12.6 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H3)</sub> = 9.4 Hz, <sup>3</sup><italic>J</italic><sub>(H4α–H5)</sub> = 6.0 Hz, 1H, <italic>H</italic><sub>α</sub>C4), 1.55 (t, <sup>3</sup><italic>J</italic> = 7.2 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>), 1.42 (t, <sup>3</sup><italic>J</italic> = 7.0 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP), 1.39 (t, <sup>3</sup><italic>J</italic> = 6.8 Hz, 3H, C<italic>H</italic><sub>3</sub>CH<sub>2</sub>OP). <sup>13</sup>C-NMR (151 MHz, CDCl<sub>3</sub>): δ =166.33 (C=O), 163.63, 149.78, 137.01, 129.63, 126.03, 120.47, 116.78, 80.22 (d, <sup>3</sup><italic>J</italic><sub>(CCCP)</sub> = 7.9 Hz, C5), 64.38 (d, <sup>1</sup><italic>J</italic><sub>(CP)</sub> = 168.0 Hz, C3), 63.28 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.4 Hz, CH<sub>2</sub>OP), 62.41 (d, <sup>2</sup><italic>J</italic><sub>(COP)</sub> = 6.7 Hz, CH<sub>2</sub>OP), 47.21 (CH<sub>3</sub>N), 38.01 (C4), 29.69 (CH<sub>3</sub><italic>C</italic>H<sub>2</sub>) 16.56 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 5.5 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP), 16.50 (d, <sup>3</sup><italic>J</italic><sub>(CCOP)</sub> = 6.2 Hz, <italic>C</italic>H<sub>3</sub>CH<sub>2</sub>OP), 14.29 (<italic>C</italic>H<sub>3</sub>CH<sub>2</sub>). <sup>31</sup>P-NMR (243 MHz, CDCl<sub>3</sub>): δ = 22.08. Anal. Calcd. for C<sub>18</sub>H<sub>25</sub>BrN<sub>3</sub>O<sub>5</sub>P: C, 45.58; H, 5.31; N, 8.86. Found: C, 45.37; H, 5.31; N, 8.54.</p></sec><sec id="sec3dot6-molecules-23-01889"><title>3.6. Antiviral Activity Assays</title><p>The compounds were evaluated against different herpesviruses, including herpes simplex virus type 1 (HSV-1) strain KOS, thymidine kinase-deficient (TK<sup>−</sup>) HSV-1 KOS strain resistant to ACV (ACV<sup>r</sup>), herpes simplex virus type 2 (HSV-2) strain G, varicella-zoster virus (VZV) strain Oka, TK<sup>−</sup> VZV strain 07-1, human cytomegalovirus (HCMV) strains AD-169 and Davis, as well as vaccinia virus, adeno virus-2, vesicular stomatitis virus, para-influenza-3 virus, reovirus-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus, respiratory syncytial virus (RSV), feline coronovirus (FIPV), and influenza A virus subtypes H1N1 (A/PR/8), H3N2 (A/HK/7/87) and influenza B virus (B/HK/5/72). The antiviral assays were based on the inhibition of virus-induced cytopathicity or plaque formation in human embryonic lung (HEL) fibroblasts, African green monkey kidney cells (Vero), human epithelial cervix carcinoma cells (HeLa), Crandell-Rees feline kidney cells (CRFK), or Madin Darby canine kidney cells (MDCK). Confluent cell cultures in microtiter 96-well plates were inoculated with 100 CCID<sub>50</sub> of virus (1 CCID<sub>50</sub> being the virus dose to infect 50% of the cell cultures) or with 20 plaque forming units (PFU) and the cell cultures were incubated in the presence of varying concentrations of the test compounds. Viral cytopathicity or plaque formation (VZV) was recorded as soon as it reached completion in the control virus-infected cell cultures that were not treated with the test compounds. Antiviral activity was expressed as the EC<sub>50</sub> or compound concentration required to reduce virus-induced cytopathicity or viral plaque formation by 50%. Cytotoxicity of the test compounds was expressed as the minimum cytotoxic concentration (MCC) or the compound concentration that caused a microscopically detectable alteration of cell morphology. Alternatively, the cytostatic activity of the test compounds was measured based on inhibition of cell growth. HEL cells were seeded at a rate of 5 × 10<sup>3</sup> cells/well into 96-well microtiter plates and allowed to proliferate for 24 h. Then, medium containing different concentrations of the test compounds was added. After three days of incubation at 37 °C, the cell number was determined with a Coulter counter. The cytostatic concentration was calculated as the CC<sub>50</sub>, or the compound concentration required to reduce cell proliferation by 50% relative to the number of cells in the untreated controls.</p></sec><sec id="sec3dot7-molecules-23-01889"><title>3.7. Cytostatic Activity against Immortalized Cell Lines</title><p>Murine leukemia (L1210), human T-lymphocyte (CEM), human cervix carcinoma (HeLa), and immortalized human dermal microvascular endothelial cells (HMEC-1) were suspended at 300,000–500,000 cells/mL of culture medium, and 100 μL of a cell suspension was added to 100 μL of an appropriate dilution of the test compounds in 200 μL-wells of 96-well microtiter plates. After incubation at 37 °C for two (L1210), three (CEM), or four (HeLa) days, the cell number was determined using a Coulter counter. The IC<sub>50</sub> was defined as the compound concentration required to inhibit cell proliferation by 50%.</p></sec></sec><sec id="sec4-molecules-23-01889"><title>4. Conclusions</title><p>A series of isoxazolidine-conjugates of quinazolinones <italic>trans</italic>-<bold>11a</bold>–<bold>k</bold> and <italic>cis</italic>-<bold>11a</bold>–<bold>k</bold> were obtained from <italic>N</italic>-methyl <italic>C</italic>-(diethoxyphosphoryl)nitrone and selected N3-substituted 6-bromo-2-vinylquinazolinones. The <italic>trans</italic>-isoxazolidine cycloadducts (<italic>trans</italic>-<bold>11a</bold>, <italic>trans</italic>-<bold>11b</bold>, <italic>trans</italic>-<bold>11c</bold>, <italic>trans</italic>-<bold>11d</bold>, <italic>trans</italic>-<bold>11e</bold>, <italic>trans</italic>-<bold>11g</bold>, <italic>trans</italic>-<bold>11h</bold>, <italic>trans</italic>-<bold>11j</bold>, <italic>trans</italic>-<bold>11k</bold>) and isoxazolidine <italic>cis</italic><bold>-11a</bold>, or the respective mixtures of isoxazolidines (<italic>trans</italic>-<bold>11f/</bold><italic>cis</italic>-<bold>11f</bold> (95:5) and <italic>trans</italic>-<bold>11i/</bold><italic>cis</italic>-<bold>11i</bold> (92:8)) were evaluated for their antiviral activity toward variety of DNA and RNA viruses. Almost all compounds were active against VZV and among them <italic>trans</italic>-<bold>11b</bold>, <italic>trans</italic>-<bold>11d</bold>, <italic>trans</italic>-<bold>11g</bold>, and <italic>trans</italic>-<bold>11h</bold> were the most potent (EC<sub>50</sub> = 5.8–11.6 μΜ) and, at the same time, exhibited lower cytotoxicity toward uninfected cell lines (CC<sub>50</sub> = 33–42 μΜ). Furthermore, (isoxazolidine)phosphonates <italic>trans</italic>-<bold>11d</bold>, <italic>trans</italic>-<bold>11g</bold>, <italic>trans</italic>-<bold>11h</bold>, and <italic>trans</italic>-<bold>11i</bold>/<italic>cis</italic>-<bold>11i</bold> (92:8) showed the highest activity against HCMV (EC<sub>50</sub> = 8.9–12.5 μΜ). On the other hand, several compounds exhibited moderate cytostatic effect toward the CEM cell line (IC<sub>50</sub> = 9.6–17 μM), however, slightly higher than that of 5-fluorouracil used as the reference drug.</p><p>It was proved that installation of functionalized benzyl groups at N3 in the quinazolinone moiety is essential for inhibitory properties toward both VZV and HCMV. At the same time, it was noticed that incorporation of the bromine atom at C6 in a quinazolinone skeleton resulted in a significant increase in potency of isoxazolidine-conjugates <bold>11b</bold>–<bold>11i</bold> toward both VZV (up to five-fold higher) and HCMV (up to three-fold higher) when compared with previously described analogous conjugates <bold>10b</bold>–<bold>10i</bold> lacking a bromine substituent at C6 of the quinazolinone moiety. Moreover, inhibitory properties of the newly synthesized compounds <bold>11b</bold>–<bold>11k</bold> toward tested cell lines were also slightly higher than those of previously described analogues <bold>10b</bold>–<bold>10k</bold>.</p></sec></body><back><ack><title>Acknowledgments</title><p>The authors wish to express their gratitude to Leentje Persoons, Ellen De Waegenaere, Bianca Stals, Kirsten Lepaige, Niels Willems, and Nathalie Van Winkel for their excellent technical assistance.</p></ack><fn-group><fn><p><bold>Sample Availability:</bold> Samples of the compounds are not available from the authors.</p></fn></fn-group><notes><title>Author Contributions</title><p>The research group from the Medical University of Lodz (D.G.P. and M.G.D.) conceived the research project, participated in all steps of the research, interpreted the results, discussed the experimental data, and prepared the manuscript. The research group from KU Leuven (G.A., D.S., and R.S.) conducted the biological assays and provided the experimental procedures and results. All authors read, commented on, and approved the manuscript.</p></notes><notes><title>Funding</title><p>This research was funded by the Medical University of Lodz (internal fund 503/3-014-01/503-31-001) and by the KU Leuven (GOA 15/19 TBA).</p></notes><notes notes-type="COI-statement"><title>Conflicts of Interest</title><p>The authors declare no conflict of interest.</p></notes><ref-list><title>References</title><ref id="B1-molecules-23-01889"><label>1.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>König</surname><given-names>B.</given-names></name><name><surname>Grätzei</surname><given-names>M.A.</given-names></name></person-group><article-title>Novel Immunosensor for Herpes Viruses</article-title><source>Anal. 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Reaction and conditions: a. 3-chloropropionyl chloride, 1,4-dioxane, 0 °C; b. 5% NaOH–EtOH (2:1); c. RBr, KOH, 105 °C; d. MeI or EtI, KOH, CH<sub>3</sub>CN, 60 °C.</p></caption><graphic xlink:href="molecules-23-01889-sch002"></graphic></fig><fig id="molecules-23-01889-sch003" orientation="portrait" position="float"><object-id pub-id-type="pii">molecules-23-01889-sch003_Scheme 3</object-id><label>Scheme 3</label><caption><p>Synthesis of isoxazolidines <italic>trans</italic>-<bold>11a</bold>–<bold>k</bold> and <italic>cis</italic>-<bold>11a</bold>–<bold>k</bold>. Reaction and conditions: a. toluene, 70 °C, 24 h.</p></caption><graphic xlink:href="molecules-23-01889-sch003"></graphic></fig><table-wrap id="molecules-23-01889-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">molecules-23-01889-t001_Table 1</object-id><label>Table 1</label><caption><p>Isoxazolidines <italic>trans</italic>-<bold>11</bold> and <italic>cis</italic>-<bold>11</bold> obtained according to <xref ref-type="scheme" rid="molecules-23-01889-sch003">Scheme 3</xref>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">Entry</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Quinazolinone 13</th><th rowspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">Ratio of <italic>trans</italic>-11:<italic>cis</italic>-11</th><th rowspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">Yield (%)</th></tr><tr><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">R</th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>a</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">H</td><td align="center" valign="middle" rowspan="1" colspan="1">92:8</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11a</bold> (23) <sup>a</sup> + <italic>cis</italic>-<bold>11a</bold> (5) <sup>a</sup> + <italic>trans</italic>-<bold>11a</bold> and <italic>cis</italic>-<bold>11a</bold> (62) <sup>b</sup></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>b</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">C<sub>6</sub>H<sub>5</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">92:8</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11b</bold> (8) <sup>a</sup> + <italic>trans</italic>-<bold>11b</bold> and <italic>cis</italic>-<bold>11b</bold> (83) <sup>b</sup></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>c</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">2-NO<sub>2</sub>-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">94:6</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11c</bold> (30) <sup>a</sup> + <italic>trans</italic>-<bold>11c</bold> and <italic>cis</italic>-<bold>11c</bold> (62) <sup>b</sup></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>d</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">3-NO<sub>2</sub>-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">92:8</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11</bold><bold>d</bold> (14) <sup>a</sup> + <italic>trans</italic>-<bold>11d</bold> and <italic>cis</italic>-<bold>11</bold><bold>d</bold> (80) <sup>b</sup></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>e</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">4-NO<sub>2</sub>-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">90:10</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11</bold><bold>e</bold> (18) <sup>a</sup> + <italic>trans</italic>-<bold>11e</bold> and <italic>cis</italic>-<bold>11</bold><bold>e</bold> (72) <sup>b</sup></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>f</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">2-F-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">90:10</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11f</bold> and <italic>cis</italic>-<bold>11</bold><bold>f</bold> (96) <sup>b</sup></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>g</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">3-F-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">92:8</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11g</bold> (10) <sup>a</sup> + <italic>trans</italic>-<bold>11g</bold> and <italic>cis</italic>-<bold>11g</bold> (72) <sup>b</sup></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>h</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">4-F-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">92:8</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11h</bold> (12) <sup>a</sup> + <italic>trans</italic>-<bold>11h</bold> and <italic>cis</italic>-<bold>11h</bold> (86) <sup>b</sup></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>i</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">2,4-diF-C<sub>6</sub>H<sub>3</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">93:7</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11i</bold> and <italic>cis</italic>-<bold>11i</bold> (82) <sup>b</sup></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>j</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">CH<sub>3</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">94:6</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11j</bold> (32) <sup>a</sup> + <italic>trans</italic>-<bold>11j</bold> and <italic>cis</italic>-<bold>11j</bold> (65) <sup>b</sup></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>k</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CH<sub>3</sub>CH<sub>2</sub></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">88:12</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11k</bold> (14) <sup>a</sup> + <italic>trans</italic>-<bold>11k</bold> and <italic>cis</italic>-<bold>11k</bold> (80) <sup>b</sup></td></tr></tbody></table><table-wrap-foot><fn><p><sup>a</sup> yield of pure isomer, <sup>b</sup> yield of pure mixture of <italic>cis</italic>- and <italic>trans</italic>-isomers.</p></fn></table-wrap-foot></table-wrap><table-wrap id="molecules-23-01889-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">molecules-23-01889-t002_Table 2</object-id><label>Table 2</label><caption><p>Antiviral activity and cytotoxicity against varicella-zoster virus (VZV) in HEL cell cultures.</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">Compound</th><th rowspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">R</th><th colspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">Antiviral Activity EC<sub>50</sub> (μM) <sup>a</sup></th><th colspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">Cytotoxicity (μM)</th></tr><tr><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TK<sup>+</sup> VZV Strain (OKA)</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TK<sup>−</sup> VZV Strain (07-1)</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cell Morphology MCC <sup>b</sup></th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cell Growth CC<sub>50</sub><sup>c</sup></th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>cis</italic>-<bold>11a</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">H</td><td align="center" valign="middle" rowspan="1" colspan="1">>100</td><td align="center" valign="middle" rowspan="1" colspan="1">>100</td><td align="center" valign="middle" rowspan="1" colspan="1">>100</td><td align="center" valign="middle" rowspan="1" colspan="1">n.d.</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11a</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">H</td><td align="center" valign="middle" rowspan="1" colspan="1">>100</td><td align="center" valign="middle" rowspan="1" colspan="1">66.87</td><td align="center" valign="middle" rowspan="1" colspan="1">>100</td><td align="center" valign="middle" rowspan="1" colspan="1">n.d.</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11b</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">C<sub>6</sub>H<sub>5</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">13.5 ± 7.1</td><td align="center" valign="middle" rowspan="1" colspan="1">13.6 ± 9.1</td><td align="center" valign="middle" rowspan="1" colspan="1">100</td><td align="center" valign="middle" rowspan="1" colspan="1">42.3 ± 0.3</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11c</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">2-NO<sub>2</sub>-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">10.3 ± 1.1</td><td align="center" valign="middle" rowspan="1" colspan="1">5.4 ± 1.0</td><td align="center" valign="middle" rowspan="1" colspan="1">100</td><td align="center" valign="middle" rowspan="1" colspan="1">9.4 ± 0.4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11d</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">3-NO<sub>2</sub>-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">8.3 ± 1.4</td><td align="center" valign="middle" rowspan="1" colspan="1">5.8 ± 1.4</td><td align="center" valign="middle" rowspan="1" colspan="1">100</td><td align="center" valign="middle" rowspan="1" colspan="1">37.0 ± 4.3</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11e</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">4-NO<sub>2</sub>-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">6.84</td><td align="center" valign="middle" rowspan="1" colspan="1">7.51</td><td align="center" valign="middle" rowspan="1" colspan="1">20</td><td align="center" valign="middle" rowspan="1" colspan="1">n.d.</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11f</bold>/<italic>cis</italic>-<bold>11f</bold> (95:5)</td><td align="center" valign="middle" rowspan="1" colspan="1">2-F-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">7.76</td><td align="center" valign="middle" rowspan="1" colspan="1">9.56</td><td align="center" valign="middle" rowspan="1" colspan="1">20</td><td align="center" valign="middle" rowspan="1" colspan="1">n.d.</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11g</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">3-F-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">11.6 ± 5.3</td><td align="center" valign="middle" rowspan="1" colspan="1">7.7 ± 6.2</td><td align="center" valign="middle" rowspan="1" colspan="1">>20</td><td align="center" valign="middle" rowspan="1" colspan="1">33.0 ± 3.5</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11h</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">4-F-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">12.6 ± 2.6</td><td align="center" valign="middle" rowspan="1" colspan="1">7.5 ± 5.4</td><td align="center" valign="middle" rowspan="1" colspan="1">>20</td><td align="center" valign="middle" rowspan="1" colspan="1">39.4 ± 5.2</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11i</bold>/<italic>cis</italic>-<bold>11i</bold> (92:8)</td><td align="center" valign="middle" rowspan="1" colspan="1">2,4-diF-C<sub>6</sub>H<sub>3</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">8.7 ± 3.2</td><td align="center" valign="middle" rowspan="1" colspan="1">10.5 ± 0.3</td><td align="center" valign="middle" rowspan="1" colspan="1">>20</td><td align="center" valign="middle" rowspan="1" colspan="1">15.6 ± 3.2</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11j</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">CH<sub>3</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">>4</td><td align="center" valign="middle" rowspan="1" colspan="1">>4</td><td align="center" valign="middle" rowspan="1" colspan="1">20</td><td align="center" valign="middle" rowspan="1" colspan="1">n.d.</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11k</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">CH<sub>3</sub>CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">>20</td><td align="center" valign="middle" rowspan="1" colspan="1">>20</td><td align="center" valign="middle" rowspan="1" colspan="1">100</td><td align="center" valign="middle" rowspan="1" colspan="1">n.d.</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>Acyclovir</bold></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">1.55 ± 1.0</td><td align="center" valign="middle" rowspan="1" colspan="1">39.2 ± 3.6</td><td align="center" valign="middle" rowspan="1" colspan="1">>440</td><td align="center" valign="middle" rowspan="1" colspan="1">>350</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Brivudin</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.023 ± 0.008</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">31.9 ± 16.1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">>300</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">>300</td></tr></tbody></table><table-wrap-foot><fn><p><sup>a</sup> Effective concentration required to reduce virus plaque formation by 50%. Virus input was 100 plaque forming units (PFU), <sup>b</sup> Minimum cytotoxic concentration that causes a microscopically detectable alternation of cell morphology, <sup>c</sup> Cytotoxic concentrations required to reduce cell growth by 50%, n.d.—not determined.</p></fn></table-wrap-foot></table-wrap><table-wrap id="molecules-23-01889-t003" orientation="portrait" position="float"><object-id pub-id-type="pii">molecules-23-01889-t003_Table 3</object-id><label>Table 3</label><caption><p>Antiviral activity and cytotoxicity against human cytomegalovirus in HEL cell cultures.</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">Compound</th><th rowspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">R</th><th colspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">Antiviral Activity EC<sub>50</sub> (μM) <sup>a</sup></th><th colspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">Cytotoxicity (μM)</th></tr><tr><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AD-169 Strain</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Davis Strain</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cell Morphology MCC <sup>b</sup></th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cell Growth CC<sub>50</sub><sup>c</sup></th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>cis</italic>-<bold>11a</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">H</td><td align="center" valign="middle" rowspan="1" colspan="1">>100</td><td align="center" valign="middle" rowspan="1" colspan="1">100</td><td align="center" valign="middle" rowspan="1" colspan="1">20</td><td align="center" valign="middle" rowspan="1" colspan="1">n.d.</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11a</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">H</td><td align="center" valign="middle" rowspan="1" colspan="1">>100</td><td align="center" valign="middle" rowspan="1" colspan="1">>100</td><td align="center" valign="middle" rowspan="1" colspan="1">100</td><td align="center" valign="middle" rowspan="1" colspan="1">n.d.</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11b</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">C<sub>6</sub>H<sub>5</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">20</td><td align="center" valign="middle" rowspan="1" colspan="1">20</td><td align="center" valign="middle" rowspan="1" colspan="1">20</td><td align="center" valign="middle" rowspan="1" colspan="1">n.d.</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11c</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">2-NO<sub>2</sub>-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">>20</td><td align="center" valign="middle" rowspan="1" colspan="1">15.29</td><td align="center" valign="middle" rowspan="1" colspan="1">100</td><td align="center" valign="middle" rowspan="1" colspan="1">n.d.</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11d</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">3-NO<sub>2</sub>-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">10.4 ± 0.8</td><td align="center" valign="middle" rowspan="1" colspan="1">11.6 ± 2.5</td><td align="center" valign="middle" rowspan="1" colspan="1">100</td><td align="center" valign="middle" rowspan="1" colspan="1">37.0 ± 4.3</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11e</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">4-NO<sub>2</sub>-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">>20</td><td align="center" valign="middle" rowspan="1" colspan="1">>20</td><td align="center" valign="middle" rowspan="1" colspan="1">100</td><td align="center" valign="middle" rowspan="1" colspan="1">n.d.</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11f</bold>/<italic>cis</italic>-<bold>11f</bold> (95:5)</td><td align="center" valign="middle" rowspan="1" colspan="1">2-F-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">8.94</td><td align="center" valign="middle" rowspan="1" colspan="1">8.94</td><td align="center" valign="middle" rowspan="1" colspan="1">20</td><td align="center" valign="middle" rowspan="1" colspan="1">n.d.</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11g</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">3-F-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">10.5 ± 2.2</td><td align="center" valign="middle" rowspan="1" colspan="1">8.94 ± 0</td><td align="center" valign="middle" rowspan="1" colspan="1">100</td><td align="center" valign="middle" rowspan="1" colspan="1">33.0 ± 3.5</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11h</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">4-F-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">12.5 ± 3.9</td><td align="center" valign="middle" rowspan="1" colspan="1">11.2 ± 3.1</td><td align="center" valign="middle" rowspan="1" colspan="1">100</td><td align="center" valign="middle" rowspan="1" colspan="1">39.4 ± 5.2</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11i</bold>/<italic>cis</italic>-<bold>11i</bold> (92:8)</td><td align="center" valign="middle" rowspan="1" colspan="1">2,4-diF-C<sub>6</sub>H<sub>3</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">9.4 ± 0.46</td><td align="center" valign="middle" rowspan="1" colspan="1">9.7 ± 1.1</td><td align="center" valign="middle" rowspan="1" colspan="1">>20</td><td align="center" valign="middle" rowspan="1" colspan="1">15.6 ± 3.2</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11j</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">CH<sub>3</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">>20</td><td align="center" valign="middle" rowspan="1" colspan="1">>100</td><td align="center" valign="middle" rowspan="1" colspan="1">20</td><td align="center" valign="middle" rowspan="1" colspan="1">n.d.</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11k</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">CH<sub>3</sub>CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">>20</td><td align="center" valign="middle" rowspan="1" colspan="1">44.72</td><td align="center" valign="middle" rowspan="1" colspan="1">20</td><td align="center" valign="middle" rowspan="1" colspan="1">n.d.</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>Ganciclovir</bold></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">16.9 ± 6.9</td><td align="center" valign="middle" rowspan="1" colspan="1">7.7 ± 0.9</td><td align="center" valign="middle" rowspan="1" colspan="1">>350</td><td align="center" valign="middle" rowspan="1" colspan="1">>350</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Cidofovir</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.5 ± 0.2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.7 ± 0.4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">>300</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">>300</td></tr></tbody></table><table-wrap-foot><fn><p><sup>a</sup> Effective concentration required to reduce virus plaque formation by 50%. Virus input was 100 plaque forming units (PFU), <sup>b</sup> Minimum cytotoxic concentration that causes a microscopically detectable alternation of cell morphology, <sup>c</sup> Cytotoxic concentrations required to reduce cell growth by 50%, n.d.—not determined.</p></fn></table-wrap-foot></table-wrap><table-wrap id="molecules-23-01889-t004" orientation="portrait" position="float"><object-id pub-id-type="pii">molecules-23-01889-t004_Table 4</object-id><label>Table 4</label><caption><p>Inhibitory effect of the tested compounds against the proliferation of murine leukemia (L1210), human T-lymphocyte (CEM), human cervix carcinoma (HeLa), and immortalized human dermal microvascular endothelial cells (HMEC-1).</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">Compound</th><th rowspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">R</th><th colspan="4" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">IC<sub>50</sub><sup>a</sup> (μM)</th></tr><tr><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">L1210</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CEM</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HeLa</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HMEC-1</th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>cis</italic>-<bold>11a</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">H</td><td align="center" valign="middle" rowspan="1" colspan="1">>250</td><td align="center" valign="middle" rowspan="1" colspan="1">242 ± 7</td><td align="center" valign="middle" rowspan="1" colspan="1">>250</td><td align="center" valign="middle" rowspan="1" colspan="1">140 ± 54</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11a</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">H</td><td align="center" valign="middle" rowspan="1" colspan="1">126 ± 19</td><td align="center" valign="middle" rowspan="1" colspan="1">148 ± 2</td><td align="center" valign="middle" rowspan="1" colspan="1">196 ± 20</td><td align="center" valign="middle" rowspan="1" colspan="1">85 ± 13</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11b</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">C<sub>6</sub>H<sub>5</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">20 ± 2</td><td align="center" valign="middle" rowspan="1" colspan="1">16 ± 3</td><td align="center" valign="middle" rowspan="1" colspan="1">26 ± 7</td><td align="center" valign="middle" rowspan="1" colspan="1">30 ± 0</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11c</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">2-NO<sub>2</sub>-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">19 ± 3</td><td align="center" valign="middle" rowspan="1" colspan="1">14 ± 4</td><td align="center" valign="middle" rowspan="1" colspan="1">22 ± 11</td><td align="center" valign="middle" rowspan="1" colspan="1">30 ± 0</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11d</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">3-NO<sub>2</sub>-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">26 ± 1</td><td align="center" valign="middle" rowspan="1" colspan="1">33 ± 25</td><td align="center" valign="middle" rowspan="1" colspan="1">24 ± 9</td><td align="center" valign="middle" rowspan="1" colspan="1">30 ± 0</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11e</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">4-NO<sub>2</sub>-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">18 ± 76</td><td align="center" valign="middle" rowspan="1" colspan="1">17 ± 12</td><td align="center" valign="middle" rowspan="1" colspan="1">24 ± 9</td><td align="center" valign="middle" rowspan="1" colspan="1">26 ± 6</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11f</bold>/<italic>cis</italic>-<bold>11f</bold> (95:5)</td><td align="center" valign="middle" rowspan="1" colspan="1">2-F-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">17 ± 2</td><td align="center" valign="middle" rowspan="1" colspan="1">13 ± 1</td><td align="center" valign="middle" rowspan="1" colspan="1">25 ± 7</td><td align="center" valign="middle" rowspan="1" colspan="1">30 ± 0</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11g</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">3-F-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">16 ± 2</td><td align="center" valign="middle" rowspan="1" colspan="1">10 ± 0</td><td align="center" valign="middle" rowspan="1" colspan="1">25 ± 7</td><td align="center" valign="middle" rowspan="1" colspan="1">30 ± 0</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11h</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">4-F-C<sub>6</sub>H<sub>4</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">16 ± 0</td><td align="center" valign="middle" rowspan="1" colspan="1">9.6 ± 2.2</td><td align="center" valign="middle" rowspan="1" colspan="1">25 ± 7</td><td align="center" valign="middle" rowspan="1" colspan="1">29 ± 1</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11i</bold>/<italic>cis</italic>-<bold>11i</bold> (92:8)</td><td align="center" valign="middle" rowspan="1" colspan="1">2,4-diF-C<sub>6</sub>H<sub>3</sub>-CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">16 ± 1</td><td align="center" valign="middle" rowspan="1" colspan="1">9.8 ± 4.8</td><td align="center" valign="middle" rowspan="1" colspan="1">22 ± 6</td><td align="center" valign="middle" rowspan="1" colspan="1">30 ± 0</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11j</bold></td><td align="center" valign="middle" rowspan="1" colspan="1">CH<sub>3</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">138 ± 19</td><td align="center" valign="middle" rowspan="1" colspan="1">128 ± 21</td><td align="center" valign="middle" rowspan="1" colspan="1">175 ± 105</td><td align="center" valign="middle" rowspan="1" colspan="1">>250</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>trans</italic>-<bold>11k</bold>/<italic>cis</italic>-<bold>11k</bold> (97:3)</td><td align="center" valign="middle" rowspan="1" colspan="1">CH<sub>3</sub>CH<sub>2</sub></td><td align="center" valign="middle" rowspan="1" colspan="1">102 ± 14</td><td align="center" valign="middle" rowspan="1" colspan="1">44 ± 18</td><td align="center" valign="middle" rowspan="1" colspan="1">113 ± 44</td><td align="center" valign="middle" rowspan="1" colspan="1">121 ± 41</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>5-Fluorouracil</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.33 ± 0.17</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">18 ± 5</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.54 ± 0.12</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">n.d.</td></tr></tbody></table><table-wrap-foot><fn><p><sup>a</sup> 50% Inhibitory concentration or compound concentration required to inhibit tumor cell proliferation by 50%, n.d.—not determined.</p></fn></table-wrap-foot></table-wrap></sec></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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