Discovery of a Rhodanine Class of Compounds as Inhibitors of <i>Plasmodium falciparum</i> Enoyl-Acyl Carrier Protein Reductase

TLDR

Enoyl acyl carrier protein reductase, a key enzyme in the type II fatty acid biosynthesis pathway, is a validated target for developing new antimalarial drugs. The study aims to discover rhodanine‑based inhibitors of PfENR and to elucidate their structure–activity relationships. The authors employed rational compound selection, analogue searching, docking simulations, and lead optimization to identify these inhibitors. The lead compound shows an IC₅₀ of 35.6 nM against PfENR and 750 nM against parasite growth, while several other rhodanines inhibit PfENR at low nanomolar to micromolar levels, broadening the antimalarial drug pipeline.

Abstract

Enoyl acyl carrier protein (ACP) reductase, one of the enzymes of the type II fatty acid biosynthesis pathway, has been established as a promising target for the development of new drugs for malaria. Here we present the discovery of a rhodanine (2-thioxothiazolidin-4-one) class of compounds as inhibitors of this enzyme using a combined approach of rational selection of compounds for screening, analogue search, docking studies, and lead optimization. The most potent inhibitor exhibits an IC50 of 35.6 nM against Plasmodium falciparum enoyl ACP reductase (PfENR) and inhibits growth of the parasite in red blood cell cultures at an IC50 value of 750 nM. Many more compounds of this class were found to inhibit PfENR at low nanomolar to low micromolar concentrations, expanding the scope for developing new antimalarial drugs. The structure−activity relationship of these rhodanine compounds is discussed.