Development of Diaminoquinazoline Histone Lysine Methyltransferase Inhibitors as Potent Blood‐Stage Antimalarial Compounds
Identifieur interne : 000A26 ( Istex/Curation ); précédent : 000A25; suivant : 000A27Development of Diaminoquinazoline Histone Lysine Methyltransferase Inhibitors as Potent Blood‐Stage Antimalarial Compounds
Auteurs : Sandeep Sundriyal [Royaume-Uni] ; Nicholas A. Malmquist [France] ; Joachim Caron [Royaume-Uni] ; Scott Blundell [Australie] ; Feng Liu [États-Unis] ; Xin Chen [États-Unis] ; Nitipol Srimongkolpithak [Royaume-Uni] ; Jian Jin [États-Unis] ; Susan A. Charman [Australie] ; Artur Scherf [France] ; Matthew J. Fuchter [Royaume-Uni]Source :
- ChemMedChem [ 1860-7179 ] ; 2014-10.
Abstract
Modulating epigenetic mechanisms in malarial parasites is an emerging avenue for the discovery of novel antimalarial drugs. Previously we demonstrated the potent in vitro and in vivo antimalarial activity of (1‐benzyl‐4‐piperidyl)[6,7‐dimethoxy‐2‐(4‐methyl‐1,4‐diazepin‐1‐yl)‐4‐quinazolinyl]amine (BIX01294; 1), a known human G9a inhibitor, together with its dose‐dependent effects on histone methylation in the malarial parasite. This work describes our initial medicinal chemistry efforts to optimise the diaminoquinazoline chemotype for antimalarial activity. A variety of analogues were designed by substituting the 2 and 4 positions of the quinazoline core, and these molecules were tested against Plasmodium falciparum (3D7 strain). Several analogues with IC50 values as low as 18.5 nM and with low mammalian cell toxicity (HepG2) were identified. Certain pharmacophoric features required for antimalarial activity were found to be analogous to the previously published SAR of these analogues for G9a inhibition, thereby suggesting potential similarities between the malarial and human HKMT targets of this chemotype. Physiochemical, in vitro activity, and in vitro metabolism studies were also performed for a select set of potent analogues to evaluate their potential as antimalarial leads.
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DOI: 10.1002/cmdc.201402098
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Charman</name><affiliation wicri:level="1"><mods:affiliation>Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052 (Australia)</mods:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville</wicri:regionArea></affiliation></author><author><name sortKey="Scherf, Artur" sort="Scherf, Artur" uniqKey="Scherf A" first="Artur" last="Scherf">Artur Scherf</name><affiliation wicri:level="1"><mods:affiliation>Unité de Biologie des Interactions Hôte‐Parasite, Institut Pasteur, 75724 Paris CEDEX 15 (France)</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Unité de Biologie des Interactions Hôte‐Parasite, Institut Pasteur</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, 75724 Paris CEDEX 15 (France)</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581</wicri:regionArea></affiliation></author><author><name sortKey="Fuchter, Matthew J" sort="Fuchter, Matthew J" uniqKey="Fuchter M" first="Matthew J." last="Fuchter">Matthew J. Fuchter</name><affiliation wicri:level="1"><mods:affiliation>Department of Chemistry, Imperial College London, London SW7 2AZ (UK)</mods:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Chemistry, Imperial College London</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>E-mail: m.fuchter@imperial.ac.uk</mods:affiliation><country wicri:rule="url">Royaume-Uni</country></affiliation><affiliation wicri:level="1"><mods:affiliation>Correspondence address: Department of Chemistry, Imperial College London, London SW7 2AZ (UK)</mods:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Correspondence address: Department of Chemistry, Imperial College London</wicri:regionArea></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">ChemMedChem</title><title level="j" type="alt">CHEMMEDCHEM</title><idno type="ISSN">1860-7179</idno><idno type="eISSN">1860-7187</idno><imprint><biblScope unit="vol">9</biblScope><biblScope unit="issue">10</biblScope><biblScope unit="page" from="2360">2360</biblScope><biblScope unit="page" to="2373">2373</biblScope><biblScope unit="page-count">14</biblScope><publisher>WILEY‐VCH Verlag</publisher><pubPlace>Weinheim</pubPlace><date type="published" when="2014-10">2014-10</date></imprint><idno type="ISSN">1860-7179</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1860-7179</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Modulating epigenetic mechanisms in malarial parasites is an emerging avenue for the discovery of novel antimalarial drugs. Previously we demonstrated the potent in vitro and in vivo antimalarial activity of (1‐benzyl‐4‐piperidyl)[6,7‐dimethoxy‐2‐(4‐methyl‐1,4‐diazepin‐1‐yl)‐4‐quinazolinyl]amine (BIX01294; 1), a known human G9a inhibitor, together with its dose‐dependent effects on histone methylation in the malarial parasite. This work describes our initial medicinal chemistry efforts to optimise the diaminoquinazoline chemotype for antimalarial activity. A variety of analogues were designed by substituting the 2 and 4 positions of the quinazoline core, and these molecules were tested against Plasmodium falciparum (3D7 strain). Several analogues with IC50 values as low as 18.5 nM and with low mammalian cell toxicity (HepG2) were identified. Certain pharmacophoric features required for antimalarial activity were found to be analogous to the previously published SAR of these analogues for G9a inhibition, thereby suggesting potential similarities between the malarial and human HKMT targets of this chemotype. Physiochemical, in vitro activity, and in vitro metabolism studies were also performed for a select set of potent analogues to evaluate their potential as antimalarial leads.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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