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

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 IC(50) of 35.6 nM against Plasmodium falciparum enoyl ACP reductase (PfENR) and inhibits growth of the parasite in red blood cell cultures at an IC(50) 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.

X-ray Structural Analysis of Plasmodium falciparum Enoyl Acyl Carrier Protein Reductase as a Pathway toward the Optimization of Triclosan Antimalarial Efficacy

“…An independent study subsequently reported modest PfENR inhibition with a remarkably similar set of pyrazoles (57). These researchers also reported the discovery of a rhodanine class of small molecule binders to PfENR, with the most efficacious member of this class approximating the activity of triclosan (58). Building on initial investigations into plant polyphenols as antibacterial FAS-II inhibitors (59), other researchers have independently examined natural product inhibitors of PfENR where a common structural theme is the presence of one or more phenolic moieties (60,61).…”

Quinolines and structurally related heterocycles as antimalarials

“…While carrying out the microwave-assisted Friedländer synthesis of quinoline derivatives, Asís et al found that a series of substituted quinolines 107 possessed promising activities against P. falciparum and other parasites causative of leishmaniasis, sleeping sickness and Chagas disease [146]. Compounds 107a, and 107b were most active against P. falciparum with IC 50 docking and lead optimization to discover quinolines as inhibitor of PfENR, and most promising inhibitor 108 exhibited an IC 50 value of 50.0 mM [147]. Antimalarial chalcones and vinyl sulfones are believed to act against malarial cysteine proteases [148,149].…”

SAR and pharmacophore models for the rhodanine inhibitors of Plasmodium falciparum enoyl‐acyl carrier protein reductase

“…We had recently conducted a diversity-set screening against PfENR and identified a new scaffold-rhodanine with nanomo-lar inhibition constant (24). The mechanism of inhibition was probed and the inhibitors were found to be competitive with respect to the substrate and noncompetitive with respect to the cofactor NADH.…”