Scaffold hybridization strategy towards potent hydroxamate-based inhibitors of Flaviviridae viruses and Trypanosoma species.
Identifieur interne : 000A96 ( Main/Exploration ); précédent : 000A95; suivant : 000A97Scaffold hybridization strategy towards potent hydroxamate-based inhibitors of Flaviviridae viruses and Trypanosoma species.
Auteurs : Erofili Giannakopoulou [Grèce] ; Vasiliki Pardali [Grèce] ; Efseveia Frakolaki [Grèce] ; Vasileios Siozos [Grèce] ; Vassilios Myrianthopoulos [Grèce] ; Emmanuel Mikros [Grèce] ; Martin C. Taylor [Royaume-Uni] ; John M. Kelly [Royaume-Uni] ; Niki Vassilaki [Grèce] ; Grigoris Zoidis [Grèce]Source :
- MedChemComm [ 2040-2511 ] ; 2019.
Abstract
Infections with Flaviviridae viruses, such as hepatitis C virus (HCV) and dengue virus (DENV) pose global health threats. Infected individuals are at risk of developing chronic liver failure or haemorrhagic fever respectively, often with a fatal outcome if left untreated. Diseases caused by tropical parasites of the Trypanosoma species, T. brucei and T. cruzi, constitute significant socioeconomic burden in sub-Saharan Africa and continental Latin America, yet drug development is under-funded. Anti-HCV chemotherapy is associated with severe side effects and high cost, while dengue has no clinically approved therapy and antiparasitic drugs are outdated and difficult to administer. Moreover, drug resistance is an emerging concern. Consequently, the need for new revolutionary chemotherapies is urgent. By utilizing a molecular framework combination approach, we combined two distinct chemical entities with proven antiviral and trypanocidal activity into a novel hybrid scaffold attached by an acetohydroxamic acid group (CH2CONHOH), aiming at derivatives with dual activity. The novel spiro-carbocyclic substituted hydantoin analogues were rationally designed, synthesized and evaluated for their potency against three HCV genotypes (1b, 3a, 4a), DENV and two Trypanosoma species (T. brucei, T. cruzi). They exhibited significant EC50 values and remarkable selectivity indices. Several modifications were undertaken to further explore the structure activity relationships (SARs) and confirm the pivotal role of the acetohydroxamic acid metal binding group.
DOI: 10.1039/c9md00200f
PubMed: 31303998
Affiliations:
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Sofias Avenue , GR-11521 , Athens </wicri:regionArea><wicri:noRegion>Athens </wicri:noRegion></affiliation></author><author><name sortKey="Myrianthopoulos, Vassilios" sort="Myrianthopoulos, Vassilios" uniqKey="Myrianthopoulos V" first="Vassilios" last="Myrianthopoulos">Vassilios Myrianthopoulos</name><affiliation wicri:level="1"><nlm:affiliation>School of Health Sciences , Faculty of Pharmacy , Department of Pharmaceutical Chemistry , National and Kapodistrian University of Athens , Panepistimiopolis-Zografou , GR-15771 Athens , Greece . Email: zoidis@pharm.uoa.gr.</nlm:affiliation><country wicri:rule="url">Grèce</country></affiliation></author><author><name sortKey="Mikros, Emmanuel" sort="Mikros, Emmanuel" uniqKey="Mikros E" first="Emmanuel" last="Mikros">Emmanuel Mikros</name><affiliation wicri:level="1"><nlm:affiliation>School of Health Sciences , Faculty of Pharmacy , Department of Pharmaceutical Chemistry , National and Kapodistrian University of Athens , Panepistimiopolis-Zografou , GR-15771 Athens , Greece . Email: zoidis@pharm.uoa.gr.</nlm:affiliation><country wicri:rule="url">Grèce</country></affiliation></author><author><name sortKey="Taylor, Martin C" sort="Taylor, Martin C" uniqKey="Taylor M" first="Martin C" last="Taylor">Martin C. Taylor</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathogen Molecular Biology , London School of Hygiene and Tropical Medicine , Keppel Street , London WC1E 7HT , UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pathogen Molecular Biology , London School of Hygiene and Tropical Medicine , Keppel Street , London WC1E 7HT </wicri:regionArea><wicri:noRegion>London WC1E 7HT </wicri:noRegion></affiliation></author><author><name sortKey="Kelly, John M" sort="Kelly, John M" uniqKey="Kelly J" first="John M" last="Kelly">John M. Kelly</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathogen Molecular Biology , London School of Hygiene and Tropical Medicine , Keppel Street , London WC1E 7HT , UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pathogen Molecular Biology , London School of Hygiene and Tropical Medicine , Keppel Street , London WC1E 7HT </wicri:regionArea><wicri:noRegion>London WC1E 7HT </wicri:noRegion></affiliation></author><author><name sortKey="Vassilaki, Niki" sort="Vassilaki, Niki" uniqKey="Vassilaki N" first="Niki" last="Vassilaki">Niki Vassilaki</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Virology Laboratory , Hellenic Pasteur Institute , Vas. Sofias Avenue , GR-11521 , Athens , Greece.</nlm:affiliation><country xml:lang="fr">Grèce</country><wicri:regionArea>Molecular Virology Laboratory , Hellenic Pasteur Institute , Vas. Sofias Avenue , GR-11521 , Athens </wicri:regionArea><wicri:noRegion>Athens </wicri:noRegion></affiliation></author><author><name sortKey="Zoidis, Grigoris" sort="Zoidis, Grigoris" uniqKey="Zoidis G" first="Grigoris" last="Zoidis">Grigoris Zoidis</name><affiliation wicri:level="1"><nlm:affiliation>School of Health Sciences , Faculty of Pharmacy , Department of Pharmaceutical Chemistry , National and Kapodistrian University of Athens , Panepistimiopolis-Zografou , GR-15771 Athens , Greece . Email: zoidis@pharm.uoa.gr.</nlm:affiliation><country wicri:rule="url">Grèce</country></affiliation></author></analytic><series><title level="j">MedChemComm</title><idno type="eISSN">2040-2511</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Infections with <i>Flaviviridae</i> viruses, such as hepatitis C virus (HCV) and dengue virus (DENV) pose global health threats. Infected individuals are at risk of developing chronic liver failure or haemorrhagic fever respectively, often with a fatal outcome if left untreated. Diseases caused by tropical parasites of the <i>Trypanosoma</i> species, <i>T. brucei</i> and <i>T. cruzi</i>, constitute significant socioeconomic burden in sub-Saharan Africa and continental Latin America, yet drug development is under-funded. Anti-HCV chemotherapy is associated with severe side effects and high cost, while dengue has no clinically approved therapy and antiparasitic drugs are outdated and difficult to administer. Moreover, drug resistance is an emerging concern. Consequently, the need for new revolutionary chemotherapies is urgent. By utilizing a molecular framework combination approach, we combined two distinct chemical entities with proven antiviral and trypanocidal activity into a novel hybrid scaffold attached by an acetohydroxamic acid group (CH<sub>2</sub>CONHOH), aiming at derivatives with dual activity. The novel spiro-carbocyclic substituted hydantoin analogues were rationally designed, synthesized and evaluated for their potency against three HCV genotypes (1b, 3a, 4a), DENV and two <i>Trypanosoma</i> species (<i>T. brucei</i>, <i>T. cruzi</i>). They exhibited significant EC<sub>50</sub> values and remarkable selectivity indices. Several modifications were undertaken to further explore the structure activity relationships (SARs) and confirm the pivotal role of the acetohydroxamic acid metal binding group.</div></front></TEI><affiliations><list><country><li>Grèce</li><li>Royaume-Uni</li></country></list><tree><country name="Grèce"><noRegion><name sortKey="Giannakopoulou, Erofili" sort="Giannakopoulou, Erofili" uniqKey="Giannakopoulou E" first="Erofili" last="Giannakopoulou">Erofili Giannakopoulou</name></noRegion><name sortKey="Frakolaki, Efseveia" sort="Frakolaki, Efseveia" uniqKey="Frakolaki E" first="Efseveia" last="Frakolaki">Efseveia Frakolaki</name><name sortKey="Mikros, Emmanuel" sort="Mikros, Emmanuel" uniqKey="Mikros E" first="Emmanuel" last="Mikros">Emmanuel Mikros</name><name sortKey="Myrianthopoulos, Vassilios" sort="Myrianthopoulos, Vassilios" uniqKey="Myrianthopoulos V" first="Vassilios" last="Myrianthopoulos">Vassilios Myrianthopoulos</name><name sortKey="Pardali, Vasiliki" sort="Pardali, Vasiliki" uniqKey="Pardali V" first="Vasiliki" last="Pardali">Vasiliki Pardali</name><name sortKey="Siozos, Vasileios" sort="Siozos, Vasileios" uniqKey="Siozos V" first="Vasileios" last="Siozos">Vasileios Siozos</name><name sortKey="Vassilaki, Niki" sort="Vassilaki, Niki" uniqKey="Vassilaki N" first="Niki" last="Vassilaki">Niki Vassilaki</name><name sortKey="Zoidis, Grigoris" sort="Zoidis, Grigoris" uniqKey="Zoidis G" first="Grigoris" last="Zoidis">Grigoris Zoidis</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Taylor, Martin C" sort="Taylor, Martin C" uniqKey="Taylor M" first="Martin C" last="Taylor">Martin C. Taylor</name></noRegion><name sortKey="Kelly, John M" sort="Kelly, John M" uniqKey="Kelly J" first="John M" last="Kelly">John M. Kelly</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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