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 (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.