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

<i>N</i>‑Aryl-2-aminobenzimidazoles: Novel, Efficacious, Antimalarial Lead Compounds

From the phenotypic screening of the AstraZeneca corporate compound collection, <i>N</i>-aryl-2-aminobenzimidazoles have emerged as novel hits against the asexual blood stage of <i>Plasmodium falciparum</i> (<i>Pf</i>). Medicinal chemistry optimization of the potency against <i>Pf</i> and ADME properties resulted in the identification of <b>12</b> as a lead molecule. Compound <b>12</b> was efficacious in the <i>P. berghei</i> (<i>Pb</i>) model of malaria. This compound displayed an excellent pharmacokinetic profile with a long half-life (19 h) in rat blood. This profile led to an extended survival of animals for over 30 days following a dose of 50 mg/kg in the <i>Pb</i> malaria model. Compound <b>12</b> retains its potency against a panel of <i>Pf</i> isolates with known mechanisms of resistance. The fast killing observed in the <i>in vitro</i> parasite reduction ratio (PRR) assay coupled with the extended survival highlights the promise of this novel chemical class for the treatment of malaria

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