Carbamoyl Triazoles,Known Serine Protease Inhibitors,Are a Potent New Class of Antimalarials.

Screeningof the GSK corporate collection, some 1.9 million compounds,against Plasmodium falciparum(Pf), revealed almost 14000 active hits that are now knownas the Tres Cantos Antimalarial Set (TCAMS). Followup work by Calderonet al. clustered and computationally filtered the TCAMS through avariety of criteria and reported 47 series containing a total of 522compounds. From this enhanced set, we identified the carbamoyl triazoleTCMDC-134379 (1), a known serine protease inhibitor,as an excellent starting point for SAR profiling. Lead optimizationof 1led to several molecules with improved antimalarialpotency, metabolic stabilities in mouse and human liver microsomes,along with acceptable cytotoxicity profiles. Analogue 44displayed potent in vitro activity (IC50= 10 nM) andoral activity in a SCID mouse model of Pfinfectionwith an ED50of 100 and ED90of between 100and 150 mg kg−1, respectively. The results presentedencourage further investigations to identify the target of these highlyactive compounds. [ABSTRACT FROM AUTHOR]