Carbamoyl triazoles, known serine protease inhibitors, are a potent new class of antimalarials
Authors listMatthew McConville Jorge Fernández Íñigo Angulo-Barturen Noemi Bahamontes-Rosa Lluis Ballell-Pages Pablo Castañeda Cristina de Cózar Benigno Crespo Laura Guijarro María Belén Jiménez-Díaz Maria S Martínez-Martínez Jaime de Mercado Ángel Santos-Villajero Laura M Sanz Micol Frigerio Gina Washbourn Stepen A Ward Gemma L Nixon Giancarlo A Biagini Neil G Berry Michael Blackman Félix Calderón Paul M O'Neill
Screening of the GSK corporate collection, some 1.9 million compounds, against Plasmodium falciparum (Pf), revealed almost 14000 active hits that are now known as the Tres Cantos Antimalarial Set (TCAMS). Followup work by Calderon et al. clustered and computationally filtered the TCAMS through a variety of criteria and reported 47 series containing a total of 522 compounds. From this enhanced set, we identified the carbamoyl triazole TCMDC-134379 (1), a known serine protease inhibitor, as an excellent starting point for SAR profiling. Lead optimization of 1 led to several molecules with improved antimalarial potency, metabolic stabilities in mouse and human liver microsomes, along with acceptable cytotoxicity profiles. Analogue 44 displayed potent in vitro activity (IC50 = 10 nM) and oral activity in a SCID mouse model of Pf infection with an ED50 of 100 and ED90 of between 100 and 150 mg kg(-1), respectively. The results presented encourage further investigations to identify the target of these highly active compounds.
Journal Journal of Medicinal Chemistry
Issue number 16