Development of Diaminoquinazoline Histone Lysine Methyltransferase Inhibitors as Potent Blood-stage Anti-Malarial Compounds

• Published in: ChemMedChem Vol. 9; no. 10; pp. 2360 - 2373
• Main Authors: Sundriyal, Sandeep, Malmquist, Nicholas A., Caron, Joachim, Blundell, Scott, Liu, Feng, Chen, Xin, Srimongkolpithak, Nitipol, Jin, Jian, Charman, Susan A., Scherf, Artur, Fuchter, Matthew J.
• Format: Journal Article
• Language: English
• Published: 09.07.2014
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201402098

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 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 optimize 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 IC 50 values as low as 18.5 nM and with low mammalian cell toxicity (HepG2) were identified. Certain pharmacophoric features required for the 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 the 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 anti-malarial leads.