ChloroquineV1, Istex, Corpus, bibRecord, 000904

Antiplasmodial Activity and Cytotoxicity of Bis-, Tris-, and Tetraquinolines with Linear or Cyclic Amino Linkers

Identifieur interne : 000904 ( Istex/Corpus ); précédent : 000903; suivant : 000905

Antiplasmodial Activity and Cytotoxicity of Bis-, Tris-, and Tetraquinolines with Linear or Cyclic Amino Linkers

Auteurs : Sophie Girault ; Philippe Grellier ; Amaya Berecibar ; Louis Maes ; Pascal Lemière ; Elisabeth Mouray ; Elisabeth Davioud-Charvet ; Christian Sergheraert

Source :

Journal of Medicinal Chemistry [ 0022-2623 ] ; 2001.

RBID : ISTEX:0A2A8BD78C7DDE4E4D3F300108747C1BA26F1032

Abstract

Bisquinoline heteroalkanediamines were structurally modified in order to study the effects of enhanced bulkiness and rigidity on both their activity on strains of Plasmodium falciparum expressing different degrees of chloroquine (CQ) resistance and their cytotoxicity toward mammalian cells. While cyclization yielded molecules of greater rigidity that were not more active than their linear counterparts, they were characterized by an absence of cytotoxicity. Alternatively, dimerization of these compounds led to tetraquinolines that are very potent for CQ-resistant strains and noncytotoxic.

Url:

https://api.istex.fr/ark:/67375/TPS-V78BD7W8-B/fulltext.pdf

DOI: 10.1021/jm001096a

Links to Exploration step

ISTEX:0A2A8BD78C7DDE4E4D3F300108747C1BA26F1032

Le document en format XML

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<front><div type="abstract">Bisquinoline heteroalkanediamines were structurally modified in order to study the effects of enhanced bulkiness and rigidity on both their activity on strains of Plasmodium falciparum expressing different degrees of chloroquine (CQ) resistance and their cytotoxicity toward mammalian cells. While cyclization yielded molecules of greater rigidity that were not more active than their linear counterparts, they were characterized by an absence of cytotoxicity. Alternatively, dimerization of these compounds led to tetraquinolines that are very potent for CQ-resistant strains and noncytotoxic.</div>
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<json:string>Muséum National d'Histoire Naturelle.</json:string>
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<json:item><name>DAVIOUD-CHARVET Elisabeth</name>
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<abstract>Bisquinoline heteroalkanediamines were structurally modified in order to study the effects of enhanced bulkiness and rigidity on both their activity on strains of Plasmodium falciparum expressing different degrees of chloroquine (CQ) resistance and their cytotoxicity toward mammalian cells. While cyclization yielded molecules of greater rigidity that were not more active than their linear counterparts, they were characterized by an absence of cytotoxicity. Alternatively, dimerization of these compounds led to tetraquinolines that are very potent for CQ-resistant strains and noncytotoxic.</abstract>
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with Linear or Cyclic Amino Linkers</title>
<author xml:id="author-0000"><persName><surname>Girault</surname>
<forename type="first">Sophie</forename>
</persName>
<affiliation>UMR CNRS 8525, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette,
B.P. 447, 59021 Lille Cedex, France, Laboratoire de Biologie Parasitaire, IFR CNRS 63, Muséum National d'Histoire
Naturelle, 61 rue Buffon, 75005 Paris, France, and Tibotec, B-32800 Mechelen, Belgium
</affiliation>
<note place="foot"><ref>†</ref>
<p>
 Institut de Biologie et Institut Pasteur de Lille.</p>
</note>
</author>
<author xml:id="author-0001"><persName><surname>Grellier</surname>
<forename type="first">Philippe</forename>
</persName>
<affiliation>UMR CNRS 8525, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette,
B.P. 447, 59021 Lille Cedex, France, Laboratoire de Biologie Parasitaire, IFR CNRS 63, Muséum National d'Histoire
Naturelle, 61 rue Buffon, 75005 Paris, France, and Tibotec, B-32800 Mechelen, Belgium
</affiliation>
<note place="foot"><ref>‡</ref>
<p>
 Muséum National d'Histoire Naturelle.</p>
</note>
</author>
<author xml:id="author-0002"><persName><surname>Berecibar</surname>
<forename type="first">Amaya</forename>
</persName>
<affiliation>UMR CNRS 8525, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette,
B.P. 447, 59021 Lille Cedex, France, Laboratoire de Biologie Parasitaire, IFR CNRS 63, Muséum National d'Histoire
Naturelle, 61 rue Buffon, 75005 Paris, France, and Tibotec, B-32800 Mechelen, Belgium
</affiliation>
<note place="foot"><ref>†</ref>
<p>
 Institut de Biologie et Institut Pasteur de Lille.</p>
</note>
<note place="foot"><ref>§</ref>
<p>
 Present address:  Pfizer Global Research and Development, 3-9
rue de la Loge, 94265 Fresnes Cedex, France.</p>
</note>
</author>
<author xml:id="author-0003"><persName><surname>Maes</surname>
<forename type="first">Louis</forename>
</persName>
<affiliation>UMR CNRS 8525, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette,
B.P. 447, 59021 Lille Cedex, France, Laboratoire de Biologie Parasitaire, IFR CNRS 63, Muséum National d'Histoire
Naturelle, 61 rue Buffon, 75005 Paris, France, and Tibotec, B-32800 Mechelen, Belgium
</affiliation>
<note place="foot"><ref>‖</ref>
<p>
 Tibotec.</p>
</note>
</author>
<author xml:id="author-0004"><persName><surname>Lemière</surname>
<forename type="first">Pascal</forename>
</persName>
<affiliation>UMR CNRS 8525, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette,
B.P. 447, 59021 Lille Cedex, France, Laboratoire de Biologie Parasitaire, IFR CNRS 63, Muséum National d'Histoire
Naturelle, 61 rue Buffon, 75005 Paris, France, and Tibotec, B-32800 Mechelen, Belgium
</affiliation>
<note place="foot"><ref>†</ref>
<p>
 Institut de Biologie et Institut Pasteur de Lille.</p>
</note>
</author>
<author xml:id="author-0005"><persName><surname>Mouray</surname>
<forename type="first">Elisabeth</forename>
</persName>
<affiliation>UMR CNRS 8525, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette,
B.P. 447, 59021 Lille Cedex, France, Laboratoire de Biologie Parasitaire, IFR CNRS 63, Muséum National d'Histoire
Naturelle, 61 rue Buffon, 75005 Paris, France, and Tibotec, B-32800 Mechelen, Belgium
</affiliation>
<note place="foot"><ref>‡</ref>
<p>
 Muséum National d'Histoire Naturelle.</p>
</note>
</author>
<author xml:id="author-0006"><persName><surname>Davioud-Charvet</surname>
<forename type="first">Elisabeth</forename>
</persName>
<affiliation>UMR CNRS 8525, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette,
B.P. 447, 59021 Lille Cedex, France, Laboratoire de Biologie Parasitaire, IFR CNRS 63, Muséum National d'Histoire
Naturelle, 61 rue Buffon, 75005 Paris, France, and Tibotec, B-32800 Mechelen, Belgium
</affiliation>
<note place="foot"><ref>†</ref>
<p>
 Institut de Biologie et Institut Pasteur de Lille.</p>
</note>
</author>
<author xml:id="author-0007" role="corresp"><persName><surname>Sergheraert</surname>
<forename type="first">Christian</forename>
</persName>
<affiliation>UMR CNRS 8525, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette,
B.P. 447, 59021 Lille Cedex, France, Laboratoire de Biologie Parasitaire, IFR CNRS 63, Muséum National d'Histoire
Naturelle, 61 rue Buffon, 75005 Paris, France, and Tibotec, B-32800 Mechelen, Belgium
</affiliation>
<note place="foot"><ref>†</ref>
<p>
 Institut de Biologie et Institut Pasteur de Lille.</p>
</note>
<affiliation role="corresp"> To whom correspondence should be addressed. Phone:  (33) 3 20 87 12 11. Fax:  (33) 3 20 87 12 33. E-mail:  christian.sergheraert@ pasteur-lille.fr.</affiliation>
</author>
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<profileDesc><abstract><graphic url="jm001096an00001.tif"></graphic>
<p>Bisquinoline heteroalkanediamines were structurally modified in order to study the effects of
enhanced bulkiness and rigidity on both their activity on strains of <hi rend="italic">Plasmodium falciparum</hi>
expressing different degrees of chloroquine (CQ) resistance and their cytotoxicity toward
mammalian cells. While cyclization yielded molecules of greater rigidity that were not more
active than their linear counterparts, they were characterized by an absence of cytotoxicity.
Alternatively, dimerization of these compounds led to tetraquinolines that are very potent for
CQ-resistant strains and noncytotoxic.
</p>
</abstract>
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<journal-id journal-id-type="coden">jmcmar</journal-id>
<journal-title-group><journal-title>Journal of Medicinal Chemistry</journal-title>
<abbrev-journal-title>J. Med. Chem.</abbrev-journal-title>
</journal-title-group>
<issn pub-type="ppub">0022-2623</issn>
<issn pub-type="epub">1520-4804</issn>
<publisher><publisher-name>American Chemical Society</publisher-name>
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<title-group><article-title>Antiplasmodial Activity and Cytotoxicity of Bis-, Tris-, and Tetraquinolines
with Linear or Cyclic Amino Linkers</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name name-style="western"><surname>Girault</surname>
<given-names>Sophie</given-names>
</name>
<xref rid="jm001096aAF2"><sup>†</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>Grellier</surname>
<given-names>Philippe</given-names>
</name>
<xref rid="jm001096aAF3"><sup>‡</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>Berecibar</surname>
<given-names>Amaya</given-names>
</name>
<xref rid="jm001096aAF2"><sup>†</sup>
</xref>
<xref rid="jm001096aAF4"><sup>§</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>Maes</surname>
<given-names>Louis</given-names>
</name>
<xref rid="jm001096aAF5"><sup>‖</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>Lemière</surname>
<given-names>Pascal</given-names>
</name>
<xref rid="jm001096aAF2"><sup>†</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>Mouray</surname>
<given-names>Elisabeth</given-names>
</name>
<xref rid="jm001096aAF3"><sup>‡</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>Davioud-Charvet</surname>
<given-names>Elisabeth</given-names>
</name>
<xref rid="jm001096aAF2"><sup>†</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name name-style="western"><surname>Sergheraert</surname>
<given-names>Christian</given-names>
</name>
<xref rid="jm001096aAF1">*</xref>
<xref rid="jm001096aAF2"><sup>†</sup>
</xref>
</contrib>
<aff>UMR CNRS 8525, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette,
B.P. 447, 59021 Lille Cedex, France, Laboratoire de Biologie Parasitaire, IFR CNRS 63, Muséum National d'Histoire
Naturelle, 61 rue Buffon, 75005 Paris, France, and Tibotec, B-32800 Mechelen, Belgium
</aff>
</contrib-group>
<author-notes><fn id="jm001096aAF2"><label>†</label>
<p>
 Institut de Biologie et Institut Pasteur de Lille.</p>
</fn>
<fn id="jm001096aAF3"><label>‡</label>
<p>
 Muséum National d'Histoire Naturelle.</p>
</fn>
<fn id="jm001096aAF4"><label>§</label>
<p>
 Present address:  Pfizer Global Research and Development, 3-9
rue de la Loge, 94265 Fresnes Cedex, France.</p>
</fn>
<fn id="jm001096aAF5"><label>‖</label>
<p>
 Tibotec.</p>
</fn>
<corresp id="jm001096aAF1">
 To whom correspondence should be addressed. Phone:  (33) 3 20
87 12 11. Fax:  (33) 3 20 87 12 33. E-mail:  christian.sergheraert@
pasteur-lille.fr.</corresp>
</author-notes>
<pub-date pub-type="epub"><day>27</day>
<month>04</month>
<year>2001</year>
</pub-date>
<pub-date pub-type="ppub"><day>24</day>
<month>05</month>
<year>2001</year>
</pub-date>
<volume>44</volume>
<issue>11</issue>
<fpage>1658</fpage>
<lpage>1665</lpage>
<supplementary-material xlink:href="jm001096a_s.pdf" orientation="portrait" position="float"></supplementary-material>
<history><date date-type="received"><day>10</day>
<month>10</month>
<year>2000</year>
</date>
<date date-type="asap"><day>27</day>
<month>04</month>
<year>2001</year>
</date>
<date date-type="issue-pub"><day>24</day>
<month>05</month>
<year>2001</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2001 American Chemical Society</copyright-statement>
<copyright-year>2001</copyright-year>
<copyright-holder>American Chemical Society</copyright-holder>
</permissions>
<abstract><graphic content-type="abstract-graphic" xlink:href="jm001096an00001.tif" orientation="portrait" position="float"></graphic>
<p>Bisquinoline heteroalkanediamines were structurally modified in order to study the effects of
enhanced bulkiness and rigidity on both their activity on strains of <italic toggle="yes">Plasmodium falciparum</italic>
expressing different degrees of chloroquine (CQ) resistance and their cytotoxicity toward
mammalian cells. While cyclization yielded molecules of greater rigidity that were not more
active than their linear counterparts, they were characterized by an absence of cytotoxicity.
Alternatively, dimerization of these compounds led to tetraquinolines that are very potent for
CQ-resistant strains and noncytotoxic.
</p>
</abstract>
<custom-meta-group><custom-meta><meta-name>document-id-old-9</meta-name>
<meta-value>jm001096a</meta-value>
</custom-meta>
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</front>
<body><sec id="d7e203"><title>Introduction</title>
<p>Fifty years after its discovery, chloroquine (CQ, <bold>1</bold>,
Chart <xref rid="jm001096ac00001"></xref>) is still a mainstream drug in the fight against
malaria, but its efficacy is being eroded by the emergence of resistant parasites.<named-content content-type="bibref-group"><xref rid="jm001096ab00001" ref-type="bibr"></xref>
,<xref rid="jm001096ab00002" ref-type="bibr"></xref>
</named-content> CQ is believed to exert
its activity by inhibiting haemozoin formation in the
digestive vacuole of the malaria carrying the parasite
<italic toggle="yes">Plasmodium</italic>
.<named-content content-type="bibref-group"><xref rid="jm001096ab00003" ref-type="bibr"></xref>
,<xref rid="jm001096ab00004" ref-type="bibr"></xref>
</named-content> Discussion of the exclusivity of this
mechanism has recently been renewed by Ginsburg and
co-workers who have proposed that inhibition of ferriprotoporphyrin IX degradation by glutathione-dependent redox processes could be an additional mode of
action of CQ.<xref rid="jm001096ab00005" ref-type="bibr"></xref> Biochemical studies have indicated that
isolates of the CQ-resistant parasites accumulate less
drug content than their more sensitive counterparts;
however, a mechanistic explanation for this observation
remains the subject of continuing debate.<named-content content-type="bibref-group"><xref rid="jm001096ab00006" ref-type="bibr"></xref>
−<xref rid="jm001096ab00007" specific-use="suppress-in-print" ref-type="bibr"></xref>
<xref rid="jm001096ab00008" specific-use="suppress-in-print" ref-type="bibr"></xref>
<xref rid="jm001096ab00009" ref-type="bibr"></xref>
</named-content> Although
CQ resistance may involve several mechanisms, its
reversal by molecules such as verapamil, desipramine,
and chlorpromazine suggests that an enhanced CQ
efflux by a multidrug-resistant mechanism may be
implicated.<named-content content-type="bibref-group"><xref rid="jm001096ab00006" ref-type="bibr"></xref>
,<xref rid="jm001096ab00010" ref-type="bibr"></xref>
</named-content> A strategy having the potential to overcome this mechanism is the design of quinoline-based
drugs that will not be recognized by the proteins
involved in drug efflux. In this regard, bulky bisquinolines <bold>2</bold>
<bold>−</bold>
<bold>4</bold>
 (Chart <xref rid="jm001096ac00001"></xref>) likely to be extruded with difficulty
by a proteinaceous transporter<xref rid="jm001096ab00011" ref-type="bibr"></xref> have been synthesized
and were discovered to inhibit the growth of both CQ-sensitive and CQ-resistant parasites with similar
efficacy.<named-content content-type="bibref-group"><xref rid="jm001096ab00011" ref-type="bibr"></xref>
−<xref rid="jm001096ab00012" specific-use="suppress-in-print" ref-type="bibr"></xref>
<xref rid="jm001096ab00013" ref-type="bibr"></xref>
</named-content> However, further development of the most
promising molecule, <bold>4</bold>
 (Ro 47-7737),<xref rid="jm001096ab00013" ref-type="bibr"></xref> as well as that of
other bisquinolines such as piperaquine, hydroxypiperaquine, and dichloroquinazine,<xref rid="jm001096ab00014" ref-type="bibr"></xref> has been suspended for
reasons of toxicity. Compared with the numerous bisquinolines above, Ro 47-7737 differed by the absence of
a proton-accepting side chain and by a greater rigidity
likely to reduce its efflux from the parasite while
favoring its affinity for ferriprotoporphyrin IX by a
decrease in the cost of entropy. With the aim of
maintaining both steric hindrance and a reduction of
the degrees of freedom while introducing proton-accepting and/or substitution sites, we have designed new bis-,
tris-, and tetraquinolines whose 4-amino group belongs
to tri- and tetraazamacrocycles (cyclams) (A, C, and D
series of Charts <xref rid="jm001096ac00002"></xref>
 and <xref rid="jm001096ac00003"></xref>). Series B was synthesized as
a linear counterpart (Chart <xref rid="jm001096ac00002"></xref>).
<fig id="jm001096ac00001" position="float" fig-type="chart" orientation="portrait"><label>1</label>
<caption><p>Chloroquine (<bold>1</bold>
, CQ) and Biologically Active Bisquinolines <bold>2</bold>
−<bold>4</bold>
<sup>11-13</sup>
</p>
</caption>
<graphic xlink:href="jm001096ac00001.tif" position="float" orientation="portrait"></graphic>
</fig>
<fig id="jm001096ac00002" position="float" fig-type="chart" orientation="portrait"><label>2</label>
<caption><p>Compounds<bold>5</bold>
−<bold>14</bold>
 (A and B Series)<italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
</p>
<p><fn id="d7e299"><p><italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
 ClQ:  7-chloroquinol-4-yl. Q:  quinol-4-yl.</p>
</fn>
</p>
</caption>
<graphic xlink:href="jm001096ac00002.tif" position="float" orientation="portrait"></graphic>
</fig>
<fig id="jm001096ac00003" position="float" fig-type="chart" orientation="portrait"><label>3</label>
<caption><p>Compounds<bold>15</bold>
−<bold>37</bold>
 (C and D Series), <bold>38</bold>
, and <bold>39</bold>
</p>
</caption>
<graphic xlink:href="jm001096ac00003.tif" position="float" orientation="portrait"></graphic>
</fig>
</p>
<p>We report here the synthesis and the antiparasitic
activities on <italic toggle="yes">Plasmodium </italic>
<italic toggle="yes">falciparum</italic> of these new bis-,
tris-, and tetraquinolines. Cytotoxic effects upon human
MRC-5 cells (diploid embryonic lung cell line) and mouse
peritoneal macrophages are also discussed.
</p>
</sec>
<sec id="d7e335"><title>Chemistry</title>
<p>New bis- and trisquinolines were obtained by reacting
polyamines with 5 equiv of 4,7-dichloroquinoline in
DMF at reflux in the presence of an inorganic base
potassium carbonate (Scheme <xref rid="jm001096ah00001"></xref>). Thick-layer chromatography was used for purification. 1,4,8,11-Tetraazacyclotetradecane was reacted as described above, and
after purification, it afforded trisubstituted and disubstituted compounds <bold>5</bold>
 and <bold>6</bold>
 (A series of Chart <xref rid="jm001096ac00002"></xref>).
Forcing conditions and a greater excess of 4,7-dichloroquinoline did not yield the tetrasubstituted variant.
1,4,7-Triazacyclononane afforded compound <bold>7</bold>
, the disubstituted analogue of <bold>6</bold>, and the monosubstituted
compound<bold> 8 </bold>
(A series of Chart <xref rid="jm001096ac00002"></xref>) but not the trisubstituted derivative. This may have been the result of steric

hindrance or of the greater rigidity provided by the ring.
Under the same conditions, linear amines diethylenetriamine, <italic toggle="yes">N</italic>-(3-aminopropyl)-1,3-propanediamine, and
spermidine were only substituted on primary amino
groups, yielding, respectively, amines <bold>9</bold>
,<bold> 10</bold>
, and <bold>11</bold> (B
series of Chart <xref rid="jm001096ac00002"></xref>
). Compounds <bold>12</bold>
 and <bold>13 </bold>
(Chart <xref rid="jm001096ac00002"></xref>) were
prepared by di- or trisubstitution of tris(2-aminoethyl)amine, while addition of a third quinoline moiety to
compound <bold>9</bold>
 by reductive amination with 4-quinolinecarboxaldehyde (Scheme <xref rid="jm001096ah00001"></xref>
) afforded trisubstituted compound <bold>14</bold>
 (Chart <xref rid="jm001096ac00002"></xref>
). Use of <italic toggle="yes">N</italic>-methylpyrrolidinone
(NMP) at reflux as solvent had been previously recommended for the obtention of bisquinolines via a displacement reaction with 4,7-dichloroquinoline, alkane-
or heteroalkanediamines, and triethylamine.<named-content content-type="bibref-group"><xref rid="jm001096ab00011" ref-type="bibr"></xref>
,<xref rid="jm001096ab00015" ref-type="bibr"></xref>
</named-content> Bisquinolines were then isolated by the addition of water
and diethyl ether or ethyl acetate to the cooled reaction
mixtures, which initiated product precipitation. Under
these conditions, yields ranged from 49 to 87% for
alkanediamines and only from 12 to 86% for heteroalkanediamines. This decrease explained the low yields
that we obtained with linear polyamines and a fortiori
with cyclic polyamines, especially since product precipitation in NMP, as with our series of compounds, was
not observed. In general, whatever the choice of the
solvent (DMF or NMP), it was very difficult to know
the fate of polyamines.
<fig id="jm001096ah00001" position="float" fig-type="scheme" orientation="portrait"><label>1</label>
<caption><p>Synthesis of Compounds<bold>5</bold>
−<bold>14</bold>
<italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
</p>
<p><fn id="d7e407"><p><italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
 Reagents:  (a) K<sub>2</sub>
CO<sub>3</sub>
, DMF; (b) 4-quinolinecarboxaldehyde, molecular sieves, absolute EtOH, then NaBH<sub>4</sub>
, absolute EtOH.</p>
</fn>
</p>
</caption>
<graphic xlink:href="jm001096ah00001.tif" position="float" orientation="portrait"></graphic>
</fig>
</p>
<p>Acids <bold>15</bold>
 and <bold>16 </bold>were synthesized, as described in
Scheme <xref rid="jm001096ah00002"></xref>
, by reaction of compound <bold>7</bold> with succinic and
glutaric anhydride, respectively, while the amide derivative <bold>17 </bold>
of acid <bold>15</bold> was prepared by treatment with
ammonium hydrogen carbonate. In the case of compounds <bold>18</bold>
, <bold>20</bold>
, <bold>21</bold>
, and <bold>25</bold>, the side chain was introduced
by coupling various carboxylic acids with the free,
secondary amino group of compound <bold>7</bold>
, using bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBroP) as coupling reagent (Scheme <xref rid="jm001096ah00002"></xref>
).<named-content content-type="bibref-group"><xref rid="jm001096ab00016" ref-type="bibr"></xref>
,<xref rid="jm001096ab00017" ref-type="bibr"></xref>
</named-content>
 For compounds <bold>26</bold>
<bold>−</bold>
<bold>28</bold>, transformation to the amino side chain
was achieved in two steps:  reaction of secondary amino
compound <bold>7</bold> with the appropriate bromo acid followed
by substitution of the remaining bromo group by piperidine (Scheme <xref rid="jm001096ah00002"></xref>). The benzylhydroxyl protecting group

was removed from compound <bold>18</bold> by treatment with
ammonium formate and Pd/C to give alcohol <bold>19</bold> (Scheme
<xref rid="jm001096ah00002"></xref>
). <italic toggle="yes">N</italic>
-Boc-amino protecting groups of compounds <bold>20</bold> and
<bold>21 </bold>were removed by treatment with a 1:1 mixture of
TFA/CH<sub>2</sub>
Cl<sub>2</sub>
 to give deprotected analogues <bold>22</bold>
 and <bold>23</bold>,
respectively (Scheme <xref rid="jm001096ah00002"></xref>
). The guanidinium derivative <bold>24</bold>
was synthesized by treating primary amino compound
<bold>23</bold> with 3,5-dimethylpyrazole-1-carboxamide, employing
sodium hydrogen carbonate as base (Scheme <xref rid="jm001096ah00002"></xref>
).<xref rid="jm001096ab00018" ref-type="bibr"></xref>
Compound <bold>29</bold>
 was synthesized in two steps:  (i) formation of the acyl chloride corresponding to acid <bold>16</bold> and
(ii) reaction of this latter with compound <bold>9</bold>
 (Scheme <xref rid="jm001096ah00002"></xref>).
<fig id="jm001096ah00002" position="float" fig-type="scheme" orientation="portrait"><label>2</label>
<caption><p>Synthesis of Compounds<bold>15</bold>
−<bold>29</bold>
<italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
</p>
<p><fn id="d7e542"><p><italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
 Reagents:  (a) anhydride, pyridine; (b) Boc<sub>2</sub>
O, NH<sub>4</sub>
HCO<sub>3</sub>
, pyridine, DMF; (c) acid, PyBroP, DIEA, DMF for compounds<bold> 18</bold>
,<bold> 20</bold>
,<bold> 21</bold>, and
<bold>25</bold>
; (d) (i) bromo acid, PyBroP, DIEA, DMF, (ii) piperidine, 1-pentanol for compounds <bold>26</bold>
<bold>−</bold>
<bold>28</bold>; (e) ammonium formate, Pd/C, MeOH; (f)
TFA/CH<sub>2</sub>
Cl<sub>2</sub>
 (1:1); (g) 3,5-dimethylpyrazole-1-carboxamide, NaHCO<sub>3</sub>
, EtOH; (h) (1) oxalyl chloride, Et<sub>3</sub>
N, dry CH<sub>2</sub>
Cl<sub>2</sub>
, (2) compound <bold>9</bold>,
dry CH<sub>2</sub>
Cl<sub>2</sub>
.</p>
</fn>
</p>
</caption>
<graphic xlink:href="jm001096ah00002.tif" position="float" orientation="portrait"></graphic>
</fig>
</p>
<p>Bis derivatives of 1,4,7-triazacyclononane and compounds <bold>30</bold>
 and <bold>32</bold>
<bold>−</bold>
<bold>35</bold>, were synthesized as described
in Scheme <xref rid="jm001096ah00003"></xref> by coupling various diacids with the free,
secondary amino group of compound <bold>7</bold>, using the
method displayed in Scheme <xref rid="jm001096ah00002"></xref>
. Compound <bold>31</bold> was
prepared by coupling acid <bold>15</bold>
 and amine <bold>7</bold>
 (Scheme <xref rid="jm001096ah00003"></xref>).
In the case of compound <bold>36</bold>, the synthesis required four
steps:  (i) reaction of the anhydride, obtained by treatment with DCC<xref rid="jm001096ab00019" ref-type="bibr"></xref>
 of <italic toggle="yes">N</italic>
-(<italic toggle="yes">tert</italic>
-butoxycarbonyl)iminodiacetic acid, with compound <bold>7</bold>
,<xref rid="jm001096ab00019" ref-type="bibr"></xref> (ii) formation of the
corresponding acyl fluoride by treating acid with cyanuric fluoride,<xref rid="jm001096ab00017" ref-type="bibr"></xref> (iii) reaction of the latter with a second

molecule of <bold>7</bold>
, and (iv) deprotection of the <italic toggle="yes">N</italic>-Boc-amino
protecting group by treatment with a 1:1 mixture of
TFA/CH<sub>2</sub>
Cl<sub>2</sub>
 to give deprotected derivative <bold>36</bold> (Scheme
<xref rid="jm001096ah00003"></xref>
). The phenyl linker of compound <bold>37</bold> was introduced
by reaction of terephthaloyl chloride with compound <bold>7</bold>,
using diisopropylethylamine as a base (Scheme <xref rid="jm001096ah00003"></xref>).
Compounds <bold>38</bold>
 and <bold>39</bold> were synthesized by coupling
acid <bold>16</bold>
 with 1,4,7-triazacyclononane and its monoquinoline derivative <bold>8</bold>, respectively, using PyBroP as
coupling reagent (Scheme <xref rid="jm001096ah00003"></xref>).
<fig id="jm001096ah00003" position="float" fig-type="scheme" orientation="portrait"><label>3</label>
<caption><p>Synthesis of Compounds<bold>30</bold>
−<bold>39</bold>
<italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
</p>
<p><fn id="d7e712"><p><italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
 Reagents:  (a) diacid, PyBroP, DIEA, DMF; (b) (1) <italic toggle="yes">tert</italic>-butyl-2,6-dioxo-4-morpholinecarboxylate, dry THF, (2) cyanuric fluoride,
pyridine, dry CH<sub>2</sub>
Cl<sub>2</sub>
, (3) compound <bold>7</bold>
, pyridine, dry CH<sub>2</sub>
Cl<sub>2</sub>, (4)
TFA/CH<sub>2</sub>
Cl<sub>2</sub>
 (1:1); (c) terephthaloyl chloride, DIEA, dry CH<sub>2</sub>
Cl<sub>2</sub>;
(d) compound <bold>7</bold>, PyBroP, DIEA, DMF; (e) 1,4,7-triazacyclononane,
PyBroP, DIEA, DMF; (f) 1-(7-chloroquinol-4-yl)-1,4,7-triazacyclononane, PyBroP, DIEA, DMF.</p>
</fn>
</p>
</caption>
<graphic xlink:href="jm001096ah00003.tif" position="float" orientation="portrait"></graphic>
</fig>
</p>
</sec>
<sec id="d7e757"><title>Biological Results</title>
<p>All of the compounds were first tested for their
antimalarial activity upon the CQ-resistant strain
FcB1R (Tables <xref rid="jm001096at00001"></xref>
 and <xref rid="jm001096at00002"></xref>
, IC<sub>50</sub> = 110 nM for CQ) and for
their cytotoxicity toward human MRC-5 cells and mouse
peritoneal macrophages (Tables <xref rid="jm001096at00003"></xref>
 and <xref rid="jm001096at00004"></xref>). Bisquinoline
derived from 1,4,7-triazacyclononane, compound <bold>7</bold>
, displayed an activity similar to CQ (IC<sub>50</sub> = 112.8 nM),
while its monosubstituted derivative (compound <bold>8</bold>) and
the di- and trisubstituted 1,4,8,11-tetrazacyclotetradecane derivatives (compounds <bold>6 </bold>
and <bold>5</bold>
) yielded IC<sub>50</sub>
values greater than 1 μM. While its activity was similar
to that of CQ, compound <bold>7</bold> was found to inhibit haem
polymerization to a lesser extent (IC<sub>50</sub> = 170 μM) than
CQ (IC<sub>50</sub> = 65 μM). Among the bisquinolines derived
from linear amines (compounds <bold>9</bold>
<bold>−</bold>
<bold>11</bold>
), compounds <bold>10</bold>
and <bold>11</bold>
 were more active than compound <bold>7 </bold>but displayed
a high toxicity toward both human MRC-5 cells and
mouse peritoneal macrophages while no cytotoxicity was
observed for compound <bold>7</bold>
 (Table <xref rid="jm001096at00003"></xref>
). Compound <bold>11</bold>
inhibited haem polymerization in the same range as CQ
(IC<sub>50</sub>
 = 83 μM). Compounds <bold>12</bold>
−<bold>14</bold>, corresponding to
compound <bold>9</bold> substituted at the central nitrogen atom
of the linker, were less active than the parent molecule
itself (IC<sub>50</sub> was 605.7 nM, >1 μM, and >1 μM, respectively). Acylation of the remaining cyclic nitrogen of
compound <bold>7</bold> led to a comparative weakening in the
antimalarial activity (IC<sub>50</sub> values mostly about 1 μM)
irrespective of the nature of the terminal group:  the
free carboxylic group (compounds <bold>15</bold>
 and <bold>16</bold>
) or carboxamide group (compound <bold>17</bold>
), benzyl-protected (compound <bold>18</bold>
) or free alcohol group (compound <bold>19</bold>
), <italic toggle="yes">N</italic>
-Boc-protected (compounds <bold>20</bold>
 and <bold>21</bold>) or free amino group
(compounds <bold>22</bold>
 and <bold>23</bold>
), and guanidinium group (compound <bold>24</bold>). Alternatively, the presence of a terminal
piperidine proved favorable to activity independent of
the chain length (compounds <bold>25</bold>
<bold>−</bold>
<bold>28</bold>
, IC<sub>50</sub> between 38
and 132 nM), yet cytotoxic effects toward human MRC-5
cells and mouse peritoneal macrophages were observed
from a concentration of 8 μM.
<table-wrap id="jm001096at00001" position="float" orientation="portrait"><label>1</label>
<caption><p>In Vitro Sensitivity of<italic toggle="yes">P. </italic>
<italic toggle="yes">f</italic>
<italic toggle="yes">alciparum</italic> FcB1R Strain to
Compounds <bold>5</bold>
−<bold>29</bold>
 (A−C Series)</p>
</caption>
<oasis:table colsep="2" rowsep="2"><oasis:tgroup cols="6"><oasis:colspec colnum="1" colname="1"></oasis:colspec>
<oasis:colspec colnum="2" colname="2"></oasis:colspec>
<oasis:colspec colnum="3" colname="3"></oasis:colspec>
<oasis:colspec colnum="4" colname="4"></oasis:colspec>
<oasis:colspec colnum="5" colname="5"></oasis:colspec>
<oasis:colspec colnum="6" colname="6"></oasis:colspec>
<oasis:tbody><oasis:row><oasis:entry namest="1" nameend="1">compd</oasis:entry>
<oasis:entry namest="2" nameend="2">series</oasis:entry>
<oasis:entry namest="3" nameend="3"><italic toggle="yes">n</italic>
</oasis:entry>
<oasis:entry namest="4" nameend="4"><italic toggle="yes">n</italic>
‘</oasis:entry>
<oasis:entry namest="5" nameend="5">X<italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
</oasis:entry>
<oasis:entry namest="6" nameend="6">IC<sub>50</sub>
 <italic toggle="yes"><sup>b</sup>
</italic>
<sup></sup> (nM)
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>5</bold>
</oasis:entry>
<oasis:entry colname="2">A
</oasis:entry>
<oasis:entry colname="3"></oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5"></oasis:entry>
<oasis:entry colname="6">>1000<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>6</bold>
</oasis:entry>
<oasis:entry colname="2">A
</oasis:entry>
<oasis:entry colname="3"></oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5"></oasis:entry>
<oasis:entry colname="6">>1000<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>7</bold>
</oasis:entry>
<oasis:entry colname="2">A
</oasis:entry>
<oasis:entry colname="3"></oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5"></oasis:entry>
<oasis:entry colname="6">112.8 ± 24.9<italic toggle="yes"><sup>d</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>8</bold>
</oasis:entry>
<oasis:entry colname="2">A
</oasis:entry>
<oasis:entry colname="3"></oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5"></oasis:entry>
<oasis:entry colname="6">>1000<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>9</bold>
</oasis:entry>
<oasis:entry colname="2">B
</oasis:entry>
<oasis:entry colname="3">2
</oasis:entry>
<oasis:entry colname="4">2
</oasis:entry>
<oasis:entry colname="5">NH
</oasis:entry>
<oasis:entry colname="6">142.1 ± 10.2<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>10</bold>
</oasis:entry>
<oasis:entry colname="2">B
</oasis:entry>
<oasis:entry colname="3">3
</oasis:entry>
<oasis:entry colname="4">3
</oasis:entry>
<oasis:entry colname="5">NH
</oasis:entry>
<oasis:entry colname="6">75.4 ± 22.6<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>11</bold>
</oasis:entry>
<oasis:entry colname="2">B
</oasis:entry>
<oasis:entry colname="3">3
</oasis:entry>
<oasis:entry colname="4">4
</oasis:entry>
<oasis:entry colname="5">NH
</oasis:entry>
<oasis:entry colname="6">57 ± 6<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>12</bold>
</oasis:entry>
<oasis:entry colname="2">B
</oasis:entry>
<oasis:entry colname="3">2
</oasis:entry>
<oasis:entry colname="4">2
</oasis:entry>
<oasis:entry colname="5">N−CH<sub>2</sub>
−CH<sub>2</sub>
−NH<sub>2</sub>
</oasis:entry>
<oasis:entry colname="6">605.7 ± 22.7<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>13</bold>
</oasis:entry>
<oasis:entry colname="2">B
</oasis:entry>
<oasis:entry colname="3">2
</oasis:entry>
<oasis:entry colname="4">2
</oasis:entry>
<oasis:entry colname="5">N−CH<sub>2</sub>
−CH<sub>2</sub>−NH−ClQ
</oasis:entry>
<oasis:entry colname="6">>1000<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>14</bold>
</oasis:entry>
<oasis:entry colname="2">B
</oasis:entry>
<oasis:entry colname="3">2
</oasis:entry>
<oasis:entry colname="4">2
</oasis:entry>
<oasis:entry colname="5">N−CH<sub>2</sub>−Q
</oasis:entry>
<oasis:entry colname="6">>1000<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>15</bold>
</oasis:entry>
<oasis:entry colname="2">C
</oasis:entry>
<oasis:entry colname="3">2
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">COOH
</oasis:entry>
<oasis:entry colname="6">>1000<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>16</bold>
</oasis:entry>
<oasis:entry colname="2">C
</oasis:entry>
<oasis:entry colname="3">3
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">COOH
</oasis:entry>
<oasis:entry colname="6">940<italic toggle="yes"><sup>e</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>17</bold>
</oasis:entry>
<oasis:entry colname="2">C
</oasis:entry>
<oasis:entry colname="3">2
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">CONH<sub>2</sub>
</oasis:entry>
<oasis:entry colname="6">980<italic toggle="yes"><sup>e</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>18</bold>
</oasis:entry>
<oasis:entry colname="2">C
</oasis:entry>
<oasis:entry colname="3">3
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">O−CH<sub>2</sub>
−C<sub>6</sub>
H<sub>5</sub>
</oasis:entry>
<oasis:entry colname="6">1000<italic toggle="yes"><sup>e</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>19</bold>
</oasis:entry>
<oasis:entry colname="2">C
</oasis:entry>
<oasis:entry colname="3">3
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">OH
</oasis:entry>
<oasis:entry colname="6">930<italic toggle="yes"><sup>e</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>20</bold>
</oasis:entry>
<oasis:entry colname="2">C
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">CH(CH<sub>3</sub>)−NHBoc
</oasis:entry>
<oasis:entry colname="6">462.6 ± 41.7<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>21</bold>
</oasis:entry>
<oasis:entry colname="2">C
</oasis:entry>
<oasis:entry colname="3">2
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">NHBoc
</oasis:entry>
<oasis:entry colname="6">> 1000<italic toggle="yes"><sup>e</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>22</bold>
</oasis:entry>
<oasis:entry colname="2">C
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">CH(CH<sub>3</sub>
)−NH<sub>2</sub>
</oasis:entry>
<oasis:entry colname="6">228.3 ± 33.1<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>23</bold>
</oasis:entry>
<oasis:entry colname="2">C
</oasis:entry>
<oasis:entry colname="3">2
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">NH<sub>2</sub>
</oasis:entry>
<oasis:entry colname="6">> 1000<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>24</bold>
</oasis:entry>
<oasis:entry colname="2">C
</oasis:entry>
<oasis:entry colname="3">2
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">NH−C(NH<sub>2</sub>)NH
</oasis:entry>
<oasis:entry colname="6">> 1000<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>25</bold>
</oasis:entry>
<oasis:entry colname="2">C
</oasis:entry>
<oasis:entry colname="3">2
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">piperidine
</oasis:entry>
<oasis:entry colname="6">38.6 ± 17.7<italic toggle="yes"><sup>f</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>26</bold>
</oasis:entry>
<oasis:entry colname="2">C
</oasis:entry>
<oasis:entry colname="3">4
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">piperidine
</oasis:entry>
<oasis:entry colname="6">132.2 ± 68.0<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>27</bold>
</oasis:entry>
<oasis:entry colname="2">C
</oasis:entry>
<oasis:entry colname="3">7
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">piperidine
</oasis:entry>
<oasis:entry colname="6">81.1 ± 24.1<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>28</bold>
</oasis:entry>
<oasis:entry colname="2">C
</oasis:entry>
<oasis:entry colname="3">11
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">piperidine
</oasis:entry>
<oasis:entry colname="6">108.8 ± 69.8<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>29</bold>
</oasis:entry>
<oasis:entry colname="2">C
</oasis:entry>
<oasis:entry colname="3">3
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">C(O)-N((CH<sub>2</sub>
)<sub>2</sub>
-NH−ClQ)<sub>2</sub>
</oasis:entry>
<oasis:entry colname="6">152.2 ± 9.2<italic toggle="yes"><sup>g</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
</oasis:tbody>
</oasis:tgroup>
</oasis:table>
<table-wrap-foot><p><italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
 ClQ:  7-chloroquinol-4-yl. Q:  quinol-4-yl.<italic toggle="yes"><sup>b</sup>
</italic>
<sup></sup>
 IC<sub>50</sub> = 110 nM for
CQ.<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
 Number of expts <italic toggle="yes">n</italic>
 = 3.<italic toggle="yes"><sup>d</sup>
</italic>
<sup></sup>
 Number of experiements <italic toggle="yes">n</italic>
 = 5.<italic toggle="yes"><sup>e</sup>
</italic>
<sup></sup>
 Number of experiements <italic toggle="yes">n</italic>
 = 2.<italic toggle="yes"><sup>f</sup>
</italic>
<sup></sup>
 Number of experiements <italic toggle="yes">n</italic> =
6.<italic toggle="yes"><sup>g</sup>
</italic>
<sup></sup>
 Number of experiements <italic toggle="yes">n</italic>
 = 4.</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="jm001096at00002" position="float" orientation="portrait"><label>2</label>
<caption><p>In Vitro Sensitivity of<italic toggle="yes">P. </italic>
<italic toggle="yes">f</italic>
<italic toggle="yes">alciparum</italic> FcB1R Strain to
Compounds <bold>30</bold>
−<bold>37</bold>
 (D Series), <bold>38</bold>
, and <bold>39</bold>
</p>
</caption>
<oasis:table colsep="2" rowsep="2"><oasis:tgroup cols="6"><oasis:colspec colnum="1" colname="1"></oasis:colspec>
<oasis:colspec colnum="2" colname="2"></oasis:colspec>
<oasis:colspec colnum="3" colname="3"></oasis:colspec>
<oasis:colspec colnum="4" colname="4"></oasis:colspec>
<oasis:colspec colnum="5" colname="5"></oasis:colspec>
<oasis:colspec colnum="6" colname="6"></oasis:colspec>
<oasis:tbody><oasis:row><oasis:entry namest="1" nameend="1">compd</oasis:entry>
<oasis:entry namest="2" nameend="2">series</oasis:entry>
<oasis:entry namest="3" nameend="3"><italic toggle="yes">n</italic>
</oasis:entry>
<oasis:entry namest="4" nameend="4"><italic toggle="yes">n</italic>
‘</oasis:entry>
<oasis:entry namest="5" nameend="5">X</oasis:entry>
<oasis:entry namest="6" nameend="6">IC<sub>50</sub>
 <italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup> (nM)
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>30</bold>
</oasis:entry>
<oasis:entry colname="2">D
</oasis:entry>
<oasis:entry colname="3"></oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">CH<sub>2</sub>
−CH<sub>2</sub>−piperazine−
CH<sub>2</sub>
−CH<sub>2</sub>
</oasis:entry>
<oasis:entry colname="6">76.9 ± 9.4<italic toggle="yes"><sup>b</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>31</bold>
</oasis:entry>
<oasis:entry colname="2">D
</oasis:entry>
<oasis:entry colname="3"></oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">(CH<sub>2</sub>
)<sub>2</sub>
</oasis:entry>
<oasis:entry colname="6">38.1 ± 14.3<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>32</bold>
</oasis:entry>
<oasis:entry colname="2">D
</oasis:entry>
<oasis:entry colname="3"></oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">(CH<sub>2</sub>
)<sub>3</sub>
</oasis:entry>
<oasis:entry colname="6">18.3 ± 9.3<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>33</bold>
</oasis:entry>
<oasis:entry colname="2">D
</oasis:entry>
<oasis:entry colname="3"></oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">(CH<sub>2</sub>
)<sub>5</sub>
</oasis:entry>
<oasis:entry colname="6">32.7 ± 13.5<italic toggle="yes"><sup>b</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>34</bold>
</oasis:entry>
<oasis:entry colname="2">D
</oasis:entry>
<oasis:entry colname="3"></oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">(CH<sub>2</sub>
)<sub>7</sub>
</oasis:entry>
<oasis:entry colname="6">22.6 ± 7.2<italic toggle="yes"><sup>b</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>35</bold>
</oasis:entry>
<oasis:entry colname="2">D
</oasis:entry>
<oasis:entry colname="3"></oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">(CH<sub>2</sub>
)<sub>10</sub>
</oasis:entry>
<oasis:entry colname="6">79.1 ± 27.6<italic toggle="yes"><sup>b</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>36</bold>
</oasis:entry>
<oasis:entry colname="2">D
</oasis:entry>
<oasis:entry colname="3"></oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">CH<sub>2</sub>
−NH−CH<sub>2</sub>
</oasis:entry>
<oasis:entry colname="6">102.6 ± 20.1<italic toggle="yes"><sup>b</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>37</bold>
</oasis:entry>
<oasis:entry colname="2">D
</oasis:entry>
<oasis:entry colname="3"></oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5">phenyl (para)
</oasis:entry>
<oasis:entry colname="6">266.2 ± 30.1<italic toggle="yes"><sup>b</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>38</bold>
</oasis:entry>
<oasis:entry colname="2"></oasis:entry>
<oasis:entry colname="3">3
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5"></oasis:entry>
<oasis:entry colname="6">>1000<italic toggle="yes"><sup>d</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>39</bold>
</oasis:entry>
<oasis:entry colname="2"></oasis:entry>
<oasis:entry colname="3">3
</oasis:entry>
<oasis:entry colname="4"></oasis:entry>
<oasis:entry colname="5"></oasis:entry>
<oasis:entry colname="6">274.7 ± 32.7<italic toggle="yes"><sup>b</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
</oasis:tbody>
</oasis:tgroup>
</oasis:table>
<table-wrap-foot><p><italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
 IC<sub>50</sub>
 = 110 nM for CQ.<italic toggle="yes"><sup>b</sup>
</italic>
<sup></sup>
 Number of experiments <italic toggle="yes">n</italic>
 = 3.<italic toggle="yes"><sup>c</sup>
</italic>
<sup></sup>
 Number of experiments <italic toggle="yes">n</italic>
 = 6.<italic toggle="yes"><sup>d</sup>
</italic>
<sup></sup>
 Number of experiments <italic toggle="yes">n</italic>
 = 2.</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="jm001096at00003" position="float" orientation="portrait"><label>3</label>
<caption><p>In Vitro Cytotoxicity of Compounds<bold>5</bold>
−<bold>29</bold> on MRC-5
Cells and Mouse Peritoneal Macrophages</p>
</caption>
<oasis:table colsep="2" rowsep="2"><oasis:tgroup cols="8"><oasis:colspec colnum="1" colname="1"></oasis:colspec>
<oasis:colspec colnum="2" colname="2"></oasis:colspec>
<oasis:colspec colnum="3" colname="3"></oasis:colspec>
<oasis:colspec colnum="4" colname="4"></oasis:colspec>
<oasis:colspec colnum="5" colname="5"></oasis:colspec>
<oasis:colspec colnum="6" colname="6"></oasis:colspec>
<oasis:colspec colnum="7" colname="7"></oasis:colspec>
<oasis:colspec colnum="8" colname="8"></oasis:colspec>
<oasis:tbody><oasis:row><oasis:entry colname="1"></oasis:entry>
<oasis:entry namest="2" nameend="5">cytotoxicity on
MRC-5 cells (%)</oasis:entry>
<oasis:entry namest="6" nameend="8">cytotoxicity on
mouse  peritoneal
macrophages<italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry namest="1" nameend="1">compd</oasis:entry>
<oasis:entry namest="2" nameend="2">concn =
32 μM</oasis:entry>
<oasis:entry namest="3" nameend="3">concn =
8 μM</oasis:entry>
<oasis:entry namest="4" nameend="4">concn =
1 μM</oasis:entry>
<oasis:entry namest="5" nameend="5">concn =
0.5 μM</oasis:entry>
<oasis:entry namest="6" nameend="6">concn =
32 μM</oasis:entry>
<oasis:entry namest="7" nameend="7">concn =
8 μM</oasis:entry>
<oasis:entry namest="8" nameend="8">concn =
2 μM
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>5</bold>
</oasis:entry>
<oasis:entry colname="2">18
</oasis:entry>
<oasis:entry colname="3">13
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">T
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>6</bold>
</oasis:entry>
<oasis:entry colname="2">98
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">T
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>7</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>8</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>9</bold>
</oasis:entry>
<oasis:entry colname="2">81
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">T
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>10</bold>
</oasis:entry>
<oasis:entry colname="2">100
</oasis:entry>
<oasis:entry colname="3">98
</oasis:entry>
<oasis:entry colname="4">98
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">T
</oasis:entry>
<oasis:entry colname="7">T
</oasis:entry>
<oasis:entry colname="8">T
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>11</bold>
</oasis:entry>
<oasis:entry colname="2">100
</oasis:entry>
<oasis:entry colname="3">100
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">T
</oasis:entry>
<oasis:entry colname="7">T
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>12</bold>
</oasis:entry>
<oasis:entry colname="2">51
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>13</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>14</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>15</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">1
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>16</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>17</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>18</bold>
</oasis:entry>
<oasis:entry colname="2">14
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">T
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>19</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>20</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>21</bold>
</oasis:entry>
<oasis:entry colname="2">100
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">T
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>22</bold>
</oasis:entry>
<oasis:entry colname="2">88
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">T
</oasis:entry>
<oasis:entry colname="7">T
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>23</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>24</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>25</bold>
</oasis:entry>
<oasis:entry colname="2">91
</oasis:entry>
<oasis:entry colname="3">87
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">T
</oasis:entry>
<oasis:entry colname="7">T
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>26</bold>
</oasis:entry>
<oasis:entry colname="2">92
</oasis:entry>
<oasis:entry colname="3">92
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">T
</oasis:entry>
<oasis:entry colname="7">T
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>27</bold>
</oasis:entry>
<oasis:entry colname="2">91
</oasis:entry>
<oasis:entry colname="3">91
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">T
</oasis:entry>
<oasis:entry colname="7">T
</oasis:entry>
<oasis:entry colname="8">T
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>28</bold>
</oasis:entry>
<oasis:entry colname="2">89
</oasis:entry>
<oasis:entry colname="3">92
</oasis:entry>
<oasis:entry colname="4">11
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">T
</oasis:entry>
<oasis:entry colname="7">T
</oasis:entry>
<oasis:entry colname="8">T
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>29</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−</oasis:entry>
</oasis:row>
</oasis:tbody>
</oasis:tgroup>
</oasis:table>
<table-wrap-foot><p><italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup> The letter T means that the compound is toxic at this
concentration; − denotes no toxicity.</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="jm001096at00004" position="float" orientation="portrait"><label>4</label>
<caption><p>In Vitro Cytotoxicity of Compounds<bold>30</bold>
−<bold>39</bold> on MRC-5
Cells and Mouse Peritoneal Macrophages</p>
</caption>
<oasis:table colsep="2" rowsep="2"><oasis:tgroup cols="8"><oasis:colspec colnum="1" colname="1"></oasis:colspec>
<oasis:colspec colnum="2" colname="2"></oasis:colspec>
<oasis:colspec colnum="3" colname="3"></oasis:colspec>
<oasis:colspec colnum="4" colname="4"></oasis:colspec>
<oasis:colspec colnum="5" colname="5"></oasis:colspec>
<oasis:colspec colnum="6" colname="6"></oasis:colspec>
<oasis:colspec colnum="7" colname="7"></oasis:colspec>
<oasis:colspec colnum="8" colname="8"></oasis:colspec>
<oasis:tbody><oasis:row><oasis:entry colname="1"></oasis:entry>
<oasis:entry namest="2" nameend="5">cytotoxicity on
MRC-5 cells (%)</oasis:entry>
<oasis:entry namest="6" nameend="8">cytotoxicity on mouse
peritoneal
macrophages<italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry namest="1" nameend="1">compd</oasis:entry>
<oasis:entry namest="2" nameend="2">concn =
32 μM</oasis:entry>
<oasis:entry namest="3" nameend="3">concn =
8 μM</oasis:entry>
<oasis:entry namest="4" nameend="4">conc =
1 μM</oasis:entry>
<oasis:entry namest="5" nameend="5">concn =
0.5 μM</oasis:entry>
<oasis:entry namest="6" nameend="6">concn =
32 μM</oasis:entry>
<oasis:entry namest="7" nameend="7">concn =
8 μM</oasis:entry>
<oasis:entry namest="8" nameend="8">concn =
2 μM
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>30</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>31</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>32</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>33</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>34</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">T
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>35</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>36</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>37</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>38</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>39</bold>
</oasis:entry>
<oasis:entry colname="2">0
</oasis:entry>
<oasis:entry colname="3">0
</oasis:entry>
<oasis:entry colname="4">0
</oasis:entry>
<oasis:entry colname="5">0
</oasis:entry>
<oasis:entry colname="6">−
</oasis:entry>
<oasis:entry colname="7">−
</oasis:entry>
<oasis:entry colname="8">−</oasis:entry>
</oasis:row>
</oasis:tbody>
</oasis:tgroup>
</oasis:table>
<table-wrap-foot><p><italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup> The letter T means that the compound is toxic at this
concentration; − denotes no toxicity.</p>
</table-wrap-foot>
</table-wrap>
</p>
<p>Whatever the nature of the linker, the presence of an
additional chloroquinoline disubstituted 1,4,7-triazacyclononane (compounds <bold>30</bold>
<bold>−</bold>
<bold>37</bold>, D series) removed entirely any cytotoxic properties, except in the case of
compound <bold>34</bold>
, from a concentration of 32 μM (Table <xref rid="jm001096at00004"></xref>).
Antimalarial activity clearly depended on the length and
the nature of the linker; most of the compounds were

more active than both CQ and the starting molecule <bold>7</bold>
(IC<sub>50</sub> between 18 and 103 nM), while a phenyl ring
(compound <bold>37</bold>
, IC<sub>50</sub> = 266.2 nM) was found to be less
favorable. The presence of one (compound <bold>36</bold>) or two
proton-acceptor sites (compound <bold>30</bold>) in the linker, likely
to increase vacuolar pH, was also found to be unfavorable to antimalarial activity when compared with a
simple polymethylene chain (<italic toggle="yes">n</italic>
 = 2 to <italic toggle="yes">n</italic> = 10). The
partial or total absence of chloroquinoline moieties on
one of the cyclononanes led to a substantial decrease in
activity (compare compound <bold>32</bold>
, IC<sub>50</sub> = 18.3 nM, with
its analogues <bold>38</bold>
 and <bold>39</bold>
, IC<sub>50</sub>
 > 1000 nM and IC<sub>50</sub> =
274.7 nM, respectively). In addition, the presence of the
second triazacyclononane seems to be crucial for potent
antimalarial activity because compound <bold>29</bold>, a linear
analogue of compound <bold>32</bold>, displayed a much lower
activity (IC<sub>50</sub>
 = 152.2 nM) compared with compounds <bold>7</bold>
and <bold>9 </bold>
(see IC<sub>50</sub> values).
</p>
<p>The most active and least cytotoxic compounds of each
series (bis- and monoderivatives of 1,4,7-triazacyclononane <bold>7</bold>
, <bold>25</bold>
, and <bold>30</bold>
<bold>−</bold>
<bold>35</bold>) were subsequently evaluated for their capacity to inhibit the growth of other
strains expressing different degrees of CQ resistance
(Table <xref rid="jm001096at00005"></xref>
). With the exception of compound <bold>7</bold> they all
yielded similar IC<sub>50</sub> values whatever the CQ resistance
of a particular strain. Since a clear correlation between
the inhibition of parasite growth and that of haem
polymerization was found for many bisquinolines,<xref rid="jm001096ab00015" ref-type="bibr"></xref>
inhibition of haem polymerization was evaluated for CQ
and the two most active compounds <bold>25</bold> (C series) and
<bold>32</bold>
 (D series). When tested at 65 μM, the IC<sub>50</sub> value of
CQ in the haem polymerization assay of compounds <bold>25</bold>
and <bold>32</bold> displayed 70% and 66% inhibition, respectively.
<table-wrap id="jm001096at00005" position="float" orientation="portrait"><label>5</label>
<caption><p>Efficiency of Compounds<bold>7</bold>
, <bold>25</bold>
, and <bold>30</bold>
−<bold>35</bold> To Inhibit
Growth of Parasites Expressing Different Degrees of Resistance
to CQ</p>
</caption>
<oasis:table colsep="2" rowsep="2"><oasis:tgroup cols="5"><oasis:colspec colnum="1" colname="1"></oasis:colspec>
<oasis:colspec colnum="2" colname="2"></oasis:colspec>
<oasis:colspec colnum="3" colname="3"></oasis:colspec>
<oasis:colspec colnum="4" colname="4"></oasis:colspec>
<oasis:colspec colnum="5" colname="5"></oasis:colspec>
<oasis:tbody><oasis:row><oasis:entry colname="1"></oasis:entry>
<oasis:entry namest="2" nameend="5">IC<sub>50</sub>
 <italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup> (nM)
<italic toggle="yes">P. falciparum</italic>
 strain</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry namest="1" nameend="1">compd</oasis:entry>
<oasis:entry namest="2" nameend="2">W2</oasis:entry>
<oasis:entry namest="3" nameend="3">FcB1R</oasis:entry>
<oasis:entry namest="4" nameend="4">D6</oasis:entry>
<oasis:entry namest="5" nameend="5">F32
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">CQ
</oasis:entry>
<oasis:entry colname="2">175 ± 31
</oasis:entry>
<oasis:entry colname="3">110 ± 26
</oasis:entry>
<oasis:entry colname="4">54 ± 12
</oasis:entry>
<oasis:entry colname="5">19 ± 4
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>7</bold>
</oasis:entry>
<oasis:entry colname="2">170.1 ± 19.7
</oasis:entry>
<oasis:entry colname="3">112.8 ± 24.9
</oasis:entry>
<oasis:entry colname="4">74.5 ± 7.3
</oasis:entry>
<oasis:entry colname="5">64.6 ± 2.2
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>25</bold>
</oasis:entry>
<oasis:entry colname="2">50.2 ± 7.0
</oasis:entry>
<oasis:entry colname="3">38.6 ± 17.7
</oasis:entry>
<oasis:entry colname="4">18.9 ± 4.9
</oasis:entry>
<oasis:entry colname="5">16.1 ± 2.5
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>30</bold>
</oasis:entry>
<oasis:entry colname="2">111.9 ± 13.4
</oasis:entry>
<oasis:entry colname="3">76.9 ± 9.4
</oasis:entry>
<oasis:entry colname="4">59.7 ± 4.4
</oasis:entry>
<oasis:entry colname="5">68.3 ± 3.1
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>31</bold>
</oasis:entry>
<oasis:entry colname="2">29.5 ± 5.7
</oasis:entry>
<oasis:entry colname="3">38.1 ± 14.3
</oasis:entry>
<oasis:entry colname="4">21.9 ± 5.8
</oasis:entry>
<oasis:entry colname="5">23.7 ± 2.2
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>32</bold>
</oasis:entry>
<oasis:entry colname="2">29.2 ± 2.6
</oasis:entry>
<oasis:entry colname="3">18.3 ± 9.3
</oasis:entry>
<oasis:entry colname="4">18.5 ± 3.9
</oasis:entry>
<oasis:entry colname="5">17.9 ± 2.4
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>33</bold>
</oasis:entry>
<oasis:entry colname="2">47.8 ± 6.4
</oasis:entry>
<oasis:entry colname="3">32.7 ± 13.5
</oasis:entry>
<oasis:entry colname="4">29.3 ± 8.1
</oasis:entry>
<oasis:entry colname="5">34.5 ± 1.7
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>34</bold>
</oasis:entry>
<oasis:entry colname="2">67.2 ± 4.9
</oasis:entry>
<oasis:entry colname="3">22.6 ± 7.2
</oasis:entry>
<oasis:entry colname="4">41.7 ± 8.2
</oasis:entry>
<oasis:entry colname="5">46.3 ± 4.6
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>35</bold>
</oasis:entry>
<oasis:entry colname="2">179.9 ± 5.5
</oasis:entry>
<oasis:entry colname="3">79.1 ± 27.6
</oasis:entry>
<oasis:entry colname="4">123.2 ± 38.0
</oasis:entry>
<oasis:entry colname="5">132.6 ± 4.1</oasis:entry>
</oasis:row>
</oasis:tbody>
</oasis:tgroup>
</oasis:table>
<table-wrap-foot><p><italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
 Parasites were considered resistant to CQ for IC<sub>50</sub> > 100 nM.
IC<sub>50</sub>
 values are the mean ± standard deviation of three independent experiments except for the FcB1R strain (see Tables <xref rid="jm001096at00001"></xref> and
<xref rid="jm001096at00002"></xref>
).</p>
</table-wrap-foot>
</table-wrap>
</p>
</sec>
<sec id="d7e2930"><title>Discussion</title>
<p>Although the relationship between the P-glycoprotein
homologue 1 protein (Pgh1) of <italic toggle="yes">P.</italic>
 <italic toggle="yes">falciparum</italic> and
resistance to CQ and mefloquine (MF) remains debated,
there is now evidence that mutation occurring on Pgh1
can confer resistance to MF and can influence the
parasite resistance to CQ along with the structurally
unrelated compound artemisinin.<xref rid="jm001096ab00010" ref-type="bibr"></xref> Bisquinolines likely
to be extruded with difficulty by a proteinaceous transporter<sup>11</sup> were synthesized with the aim of avoiding CQ
resistance. New products were discovered that inhibit
the growth of CQ-sensitive and CQ-resistant parasites.
However, further development was suspended for 
reasons of toxicity, including that of the most potent
candidate, Ro 47-7737, unique for the steric hindrance
attributed to its cyclohexyl ring. Decreasing the degrees
of freedom of a drug is a well-known method of enhancing acutely its affinity for a target by reducing the loss
in entropy. Simultaneously, interactions with other
undesired targets responsible for certain levels in toxicity can be limited. We have therefore sought to augment
the rigidity of bisquinolines linked via short alkanediamines already reported as revealing a promising level
of activity.<xref rid="jm001096ab00011" ref-type="bibr"></xref> The new structures were obtained by
introducing chloroquinoline moieties to two azamacrocycles, retaining one or two amino groups for substitution. Bisquinoline obtained from the smallest cycle
(compound <bold>7</bold>), noncytotoxic at 32 μM, was found to be
more active than its tetraazamacrocycle homologue
(compound <bold>6</bold>) toward the CQ-resistant strain FcB1R and
was therefore selected for optimization. While compound
<bold>7</bold>
 inhibited haem polymerization (IC<sub>50</sub> = 170 μM) with
less potency than CQ, it revealed nonetheless a CQ-like
behavior because a correlation was observed between
the growth inhibition of 12 different strains of<italic toggle="yes"> P.
</italic>
<italic toggle="yes">falciparum</italic> and the degree of resistance to CQ (data not
shown). In the absence of a possible rational design,
acylation of the remaining amino group of compound <bold>7</bold>
by a number of different substituents with linkers of
varying length (C series) and the dimerization of the
resultant molecules (D series) were carried out, and the
impacts of these modifications were measured against
both CQ-resistant strains and haem polymerization. In
the C series, the presence of a terminal amino group
(compound <bold>23</bold>
) or a guanidino group (compound <bold>24</bold>),
which likely allows interaction with haem propionate
groups, greatly reduces antimalarial activity. The same
effect is observed with the other terminal groups,
whatever their nature, and in the presence of a protective group, except for that with a hydrogen bond
acceptor such as piperidine (compounds <bold>25</bold>
<bold>−</bold>
<bold>28</bold>). In the
latter case, the length of the linker proves to be
insignificant for antimalarial activity. However, these
derivatives are toxic on MRC-5 cells and mouse peritoneal macrophages at concentrations of 8 and 2 μM,
respectively. Molecular variations based on the dimerization of compound <bold>7</bold> (D series) led to an increase of
the antimalarial activity (6-fold for compound <bold>32</bold>) except
for the case of a rigid spacer (compound <bold>37</bold>). Furthermore, the absence of in vitro cytotoxic effects was noted.
The presence of one (compound <bold>36</bold>
) or two proton-acceptor sites (compound <bold>30</bold>) was found to be unfavorable for antimalarial activity when compared with a
simple polymethylene chain (<italic toggle="yes">n</italic>
 = 2 to <italic toggle="yes">n</italic> = 10). These
results confirm those previously reported, proving that
an increase in the alkalinity of the food vacuole by
quinoline drugs and alkylamines does not correlate well
with their antimalarial activity.<xref rid="jm001096ab00020" ref-type="bibr"></xref> The most active
compounds (<bold>30</bold>
<bold>−</bold>
<bold>35</bold>) inhibited, in the same range, the
growth of parasites expressing different degrees of
resistance to CQ and to MF, since the F32 and the W2
strains are respectively 10 and 5 times more resistant
to MF than to the FcB1R strain (data not shown). The
four isoquinoline moieties are vital for antimalarial
activity, as proved by the superior IC<sub>50</sub> values of
compounds <bold>39</bold>
 and <bold>38</bold> when compared with that of
compound <bold>32</bold>. The fact that the most active compounds
in the C and D series (compounds <bold>25</bold>
 and <bold>30</bold>
<bold>−</bold>
<bold>35</bold>)
displayed similar IC<sub>50</sub> values irrespective of the CQ

resistance of the strain, while inhibiting haem polymerization in the same range as CQ (compounds <bold>25</bold> and
<bold>32</bold>), might suggest that their greater bulkiness results
in a weaker efflux by a parasite transporter, although
a mechanism of action differing from that of CQ should
not be excluded.
</p>
<p>In conclusion, an increase in rigidity by cyclization
yielded molecules that were not more active than their
linear counterparts but yet differed by an absence of
cytotoxic effects. Dimerization led to tetraquinolines
that are both very potent for CQ-resistant strains and
noncytotoxic.
</p>
</sec>
<sec id="d7e3054"><title>Materials and Methods</title>
<p><bold>Biological Evaluation. 1. In Vitro </bold>
<bold><italic toggle="yes">P. falciparum</italic>
</bold>
<bold> Culture and Drug Assays.</bold>
 <italic toggle="yes">P. falciparum</italic> strains were maintained continuously in culture on human erythrocytes as
described by Trager and Jensen.<xref rid="jm001096ab00021" ref-type="bibr"></xref> In vitro antiplasmodial
activity was determined using a modification of the semiautomated microdilution technique of Desjardins et al.<xref rid="jm001096ab00022" ref-type="bibr"></xref>
 <italic toggle="yes">P.
falciparum</italic> CQ-sensitive (F32/Tanzania and D6/Sierra-Leone)
and CQ-resistant (FcB1R/Colombia and W2/Indochina) strains
were used in sensitivity testing. FcB1R and F32 were strains
obtained by limit dilution. Stock solutions of chloroquine
diphosphate and test compounds were prepared in sterile,
distilled water and DMSO, respectively. Drug solutions were
serially diluted with culture medium and added to asynchronous parasite cultures (0.5% parasitemia and 1% final hematocrite) in 96-well plates for 24 h at 37 °C prior to the addition
of 0.5 μCi of [<sup>3</sup>H]hypoxanthine (1−5 Ci/mmol; Amersham, Les
Ulis, France) <italic toggle="yes">per</italic> well. The growth inhibition for each drug
concentration was determined by comparison of the radioactivity incorporated into the treated culture with that in the
control culture (without drug) maintained on the same plate.
The concentration causing 50% inhibition (IC<sub>50</sub>) was obtained
from the drug concentration−response curve, and the results
were expressed as the mean ± the standard deviations
determined from several independent experiments. The DMSO
concentration never exceeded 0.1% and did not inhibit the
parasite growth.
</p>
<p><bold>2. Haem Polymerization Assay. </bold>The drug effects on haem
polymerization were assessed according to Raynes et al.<xref rid="jm001096ab00023" ref-type="bibr"></xref> The
haemozoin content was determined using the procedure of
Chou and Fitch.<xref rid="jm001096ab00024" ref-type="bibr"></xref> Briefly, a 50 μL aliquot of insoluble trophozoite material of the FcB1R strain (approximately equivalent
to 4 × 10<sup>7</sup> parasites) was added to 900 μL of a haem/acetate
mixture (0.3 mM bovine haematin, 60 mM sodium acetate, pH
5). A total of 50 μL of drug solution at different concentrations
was mixed with the other components. Samples without drug
constituted controls. All of the samples contained the same
amount of DMSO (1%). After incubation for 4 h at 37 °C, the
samples were centrifuged at 27 000 <italic toggle="yes">g</italic> for 15 min at 4 °C. The
pellet was resuspended in 1 mL of buffer A (68 mM NaCl, 4.8
mM KCl, 1.2 mM MgSO<sub>4</sub>, 5 mM glucose, 50 mM sodium
phosphate, pH 7.4) and repelleted. This second pellet was
resuspended with 2.5% SDS in buffer A and sonicated for 10
min. The polymerized haem was collected by centrifugation
at 27 000 <italic toggle="yes">g</italic> for 30 min at 20 °C. The pellet was then washed
four times before being resuspended in 900 μL of 2.5% SDS in
buffer A, and 100 μL of 1 M NaOH was added to dissolve the
polymerized haem. After incubation for 1 h, the concentration
of haemozoin was determined by measuring the absorbance
at 404 nm.<xref rid="jm001096ab00025" ref-type="bibr"></xref> The amount of haemozoin formed during the
incubation period was corrected for the endogenous haemozoin
of the trophozoite preparation, and the concentration of drug
required to produce 50% inhibition of haem polymerization
(IC<sub>50</sub>) was determined. Data presented are the mean of two
independent experiments each performed in duplicate.
</p>
<p><bold>3. Cytotoxicity Test on MRC-5 Cells</bold>
 <bold>and Mouse Peritoneal Macrophages. </bold>A human diploid embryonic lung cell
line (MRC-5, Bio-Whittaker 72211D) and mouse primary
peritoneal macrophages were used to assess the cytotoxic
effects toward host cells. The peritoneal macrophages were
collected from the peritoneal cavity 48 h after stimulation with
potato starch and seeded in 96-well microplates at 30 000 cells
<italic toggle="yes">per</italic>
 well. MRC-5 cells were seeded at 5000 cells <italic toggle="yes">per</italic> well. After
24 h, the cells were washed and 2-fold dilutions of the drug
were added in 200 μL standard culture medium (RPMI + 5%
FCS). The final DMSO concentration in the culture remained
below 0.5%. The cultures were incubated with four concentrations of compounds (32, 8, 1, and 0.5 μM) at 37 °C in 5% CO<sub>2</sub>−95% air for 7 days. Untreated cultures were included as
controls. For MRC-5 cells, the cytotoxicity was determined
using the colorimetric MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (thiazolyl blue)) assay<xref rid="jm001096ab00026" ref-type="bibr"></xref> and
scored as a percent reduction of absorption at 540 nm of
treated cultures versus untreated control cultures. For macrophages, scoring was performed microscopically.
</p>
</sec>
</body>
<back><ack><title>Acknowledgments</title>
<p>We express our thanks to Gérard Montagne for NMR experiments and Dr Steve
Brooks for proof reading. This work was supported by
CNRS (GDR 1077, IFR CNRS 63, UMR CNRS 8525)
and Université de Lille II.
</p>
</ack>
<notes notes-type="si"><sec id="d7e3149"><title><ext-link xlink:href="/doi/suppl/10.1021%2Fjm001096a">Supporting Information Available</ext-link>
</title>
<p>Details of chemical
procedures and analytical data. This material is available free
of charge via the Internet at <uri xlink:href="http://pubs.acs.org">http://pubs.acs.org</uri>.
</p>
</sec>
</notes>
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<affiliation> Muséum National d'Histoire Naturelle.</affiliation>
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<affiliation> Institut de Biologie et Institut Pasteur de Lille.</affiliation>
<affiliation> Present address:  Pfizer Global Research and Development, 3-9rue de la Loge, 94265 Fresnes Cedex, France.</affiliation>
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<affiliation>UMR CNRS 8525, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette,B.P. 447, 59021 Lille Cedex, France, Laboratoire de Biologie Parasitaire, IFR CNRS 63, Muséum National d'HistoireNaturelle, 61 rue Buffon, 75005 Paris, France, and Tibotec, B-32800 Mechelen, Belgium</affiliation>
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<affiliation>UMR CNRS 8525, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette,B.P. 447, 59021 Lille Cedex, France, Laboratoire de Biologie Parasitaire, IFR CNRS 63, Muséum National d'HistoireNaturelle, 61 rue Buffon, 75005 Paris, France, and Tibotec, B-32800 Mechelen, Belgium</affiliation>
<affiliation> Institut de Biologie et Institut Pasteur de Lille.</affiliation>
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</role>
</name>
<name type="personal"><namePart type="family">MOURAY</namePart>
<namePart type="given">Elisabeth</namePart>
<affiliation>UMR CNRS 8525, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette,B.P. 447, 59021 Lille Cedex, France, Laboratoire de Biologie Parasitaire, IFR CNRS 63, Muséum National d'HistoireNaturelle, 61 rue Buffon, 75005 Paris, France, and Tibotec, B-32800 Mechelen, Belgium</affiliation>
<affiliation> Muséum National d'Histoire Naturelle.</affiliation>
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<affiliation>UMR CNRS 8525, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette,B.P. 447, 59021 Lille Cedex, France, Laboratoire de Biologie Parasitaire, IFR CNRS 63, Muséum National d'HistoireNaturelle, 61 rue Buffon, 75005 Paris, France, and Tibotec, B-32800 Mechelen, Belgium</affiliation>
<affiliation> Institut de Biologie et Institut Pasteur de Lille.</affiliation>
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<name type="personal" displayLabel="corresp"><namePart type="family">SERGHERAERT</namePart>
<namePart type="given">Christian</namePart>
<affiliation>UMR CNRS 8525, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette,B.P. 447, 59021 Lille Cedex, France, Laboratoire de Biologie Parasitaire, IFR CNRS 63, Muséum National d'HistoireNaturelle, 61 rue Buffon, 75005 Paris, France, and Tibotec, B-32800 Mechelen, Belgium</affiliation>
<affiliation> Institut de Biologie et Institut Pasteur de Lille.</affiliation>
<affiliation> To whom correspondence should be addressed. Phone:  (33) 3 2087 12 11. Fax:  (33) 3 20 87 12 33. E-mail:  christian.sergheraert@pasteur-lille.fr.</affiliation>
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<abstract>Bisquinoline heteroalkanediamines were structurally modified in order to study the effects of enhanced bulkiness and rigidity on both their activity on strains of Plasmodium falciparum expressing different degrees of chloroquine (CQ) resistance and their cytotoxicity toward mammalian cells. While cyclization yielded molecules of greater rigidity that were not more active than their linear counterparts, they were characterized by an absence of cytotoxicity. Alternatively, dimerization of these compounds led to tetraquinolines that are very potent for CQ-resistant strains and noncytotoxic.</abstract>
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Antiplasmodial Activity and Cytotoxicity of Bis-, Tris-, and Tetraquinolines with Linear or Cyclic Amino Linkers

Antiplasmodial Activity and Cytotoxicity of Bis-, Tris-, and Tetraquinolines with Linear or Cyclic Amino Linkers

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