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

摘要: 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 Tres Cantos Antimalarial Set (TCAMS). Followup work by Calderon et al. clustered and computationally filtered TCAMS through a variety criteria reported 47 series containing total 522 compounds. From this enhanced set, we identified carbamoyl triazole TCMDC-134379 (1), serine protease inhibitor, an excellent starting point for SAR profiling. Lead optimization 1 led to several molecules with improved antimalarial potency, metabolic stabilities in mouse human liver microsomes, along acceptable cytotoxicity profiles. Analogue 44 displayed potent vitro activity (IC50 = 10 nM) oral SCID model Pf infection ED50 100 ED90 between 150 mg kg(-1), respectively. The results presented encourage further investigations identify target these highly