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

Abstract

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.

An insight on medicinal attributes of 1,2,4-triazoles

“…McConville et al. used a rational approach to investigate carbamoyl triazoles 209 , known serine protease inhibitors, as promising antimalarial agents [ 185 ]. Among them, compound 209a exhibited potent in vitro antiplasmodial activity (IC 50 : 10 nM) against 3D7 strain of P. falciparum with in vivo oral efficacy in a SCID mouse model of P. falciparum infection with an ED 50 and ED 90 of about 100 and 150 mg/kg, respectively.…”

Public-Private Partnerships: Compound and Data Sharing in Drug Discovery and Development

“…TCAMS has been widely used across the malaria community with good success. [62][63][64][65][66][67][68][69] For example, a TCAMS screen identified 14 primary sulfonamides that inhibited the in vitro growth of Plasmodium falciparum asexual-stage malaria parasites within an IC 50 range of 0.16-0.89 µM. 70 Primary sulfonamides exist in a number of marketed drugs, as they are a common pharmacophore for carbonic anhydrase inhibition.…”

Structural Insights Into Key Plasmodium Proteases as Therapeutic Drug Targets

“…Owing to the dual role of SUB1 in hepatic as well as erythrocytic phases, it has been an attractive multi-stage target for antimalarial drug development (Suarez et al, 2013). In various studies, low molecular weight compounds and natural compounds effectively blocking PfSUB1 mediated egress and inhibiting erythrocyte invasion by merozoites have been identified (Yeoh et al, 2007; Calderon et al, 2011; Moneriz et al, 2011; McConville et al, 2015). “Pan-reactive” drug-like compounds such as peptidyl alpha-ketoamides have been developed based on the unusual characteristics of substrate binding cleft of SUB1.…”