title: Development of diaminoquinazoline histone lysine methyltransferase inhibitors as potent blood-stage antimalarial compounds.
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.
authors.affiliation: Department of Chemistry, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Sundriyal
authors.affiliation: Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, F-75724 Paris CEDEX 15, France.|Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, F-75724 Paris CEDEX 15, France.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Malmquist
authors.affiliation: Department of Chemistry, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Joachim
authors.initials: J
authors.lastname: Caron
authors.affiliation: Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Scott
authors.initials: S
authors.lastname: Blundell
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 26 Chapel Hill, North Carolina 27599, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 26 Chapel Hill, North Carolina 27599, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Chemistry, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Nitipol
authors.initials: N
authors.lastname: Srimongkolpithak
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 26 Chapel Hill, North Carolina 27599, United States.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.affiliation: Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, F-75724 Paris CEDEX 15, France.|Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, F-75724 Paris CEDEX 15, France.
authors.forename: Artur
authors.initials: A
authors.lastname: Scherf
authors.affiliation: Department of Chemistry, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fuchter
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D011799:Quinazolines; D011495:Histone-Lysine N-Methyltransferase
keywords: diaminoquinazolines; drug design; histone methyltransferase; malaria; structure-activity relationships