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

Screening of the GSK corporate collection, some 1.9 million compounds, against Plasmodium falciparum (<i>Pf</i>), 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 (<b>1</b>), a known serine protease inhibitor, as an excellent starting point for SAR profiling. Lead optimization of <b>1</b> led to several molecules with improved antimalarial potency, metabolic stabilities in mouse and human liver microsomes, along with acceptable cytotoxicity profiles. Analogue <b>44</b> displayed potent in vitro activity (IC₅₀ = 10 nM) and oral activity in a SCID mouse model of <i>Pf</i> 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

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

Screening of the GSK corporate collection, some 1.9 million compounds, against Plasmodium falciparum (<i>Pf</i>), 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 (<b>1</b>), a known serine protease inhibitor, as an excellent starting point for SAR profiling. Lead optimization of <b>1</b> led to several molecules with improved antimalarial potency, metabolic stabilities in mouse and human liver microsomes, along with acceptable cytotoxicity profiles. Analogue <b>44</b> displayed potent in vitro activity (IC₅₀ = 10 nM) and oral activity in a SCID mouse model of <i>Pf</i> 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