Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy

The antiplasmodial activity, DMPK
properties, and efficacy of a series of quinoline-4-carboxamides are
described. This series was identified from a phenotypic screen against
the blood stage of Plasmodium falciparum (3D7) and
displayed moderate potency but with suboptimal physicochemical properties
and poor microsomal stability. The screening hit (1,
EC50 = 120 nM) was optimized to lead molecules with low
nanomolar in vitro potency. Improvement of the pharmacokinetic profile
led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values
below 1 mg/kg when dosed orally for 4 days. The favorable potency,
selectivity, DMPK properties, and efficacy coupled with a novel mechanism
of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498)
to preclinical development.