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

Abstract

SummarySignificance of type II fatty acid synthase pathway in the life cycle of malarial parasite has long been established. Enoyl acyl carrier protein (ACP) reductase of Plasmodium falciparum (PfENR) is the rate determining enzyme of its elongation module. Hence, PfENR has been a target for the development of antimalarials as well as vaccines. Towards this endeavour, we had recently identified rhodanine class of compounds as inhibitors of PfENR. Here, we report a number of new inhibitors belonging to this class. These inhibitors have been divided into two broad subclasses: rhodanine-furans and rhodanine-phenyls. The inhibitory activity of all compounds was determined against purified PfENR. IC 50 of these compounds were found to be in nanomolar to low-micromolar range. The structure-activity relationship of both the classes has been explored in detail for the first time. Separate 3D pharmacophore models for this enzyme have been generated for both rhodanine furans and phenyls. The pharmacophore model for rhodanine furan has a Hydrogen bond donor, two Hydrogen bond acceptors, two metal ligators, three hydrophobic, and two aromatic ring features, whereas the pharmacophore model for the phenyl subclass has two hydrogen bond donors, two hydrogen bond acceptor, a metal ligator, two hydrophobic, and two aromatic ring features. These models could be used for in silico screening of compound libraries for PfENR inhibitors.

Synthesis and Antimalarial Activity of Some New 3-Phenyl-2-Thioxothiazolidin-4-One Derivatives

“…The development of drug resistance has become a major health concern and has stimulated the search for alternative antimalarial agents. In this perspective rhodanine nucleus offers an alternative due to presence of wide spectrum of activities such as antibacterial [7], anti-inflammatory [8], antiviral [9,10], antidiabetic [11], anticancer [12], tyrosinase inhibitors [8] and antimalarial [13] and are frequently associated with low toxicity and they can be considered as a privileged scaffold and an ideal framework for the design of compounds that can interact with different targets as their inherent affinity for several biological targets [14]. In present work, a series of ten new 3-phenyl-2-thioxothiazolidin-4-one (MF1-MF10) derivatives were synthesized and evaluated for their invitro antimalarial activities against resistant strain of Plasmodium falciparum.…”

The Synthesis and Anti-Bacterial Activities of N-carboxymethyl Rhodanines

“…Rhodanines are fivemembered heterocyclic compounds, which have a sulfur atom at their 1-position, a thiocarbonyl group at their 2-position, a nitrogen atom at their 3-position, and a carbonyl group at their 4-position. These compounds belong to an interesting class of heterocyclic molecules, which have attracted considerable attention from chemists over the last 20 years because of their wide range of biological properties, including their antibacterial [4][5][6][7][8][9], antifungal [10][11][12][13], antidiabetic [14][15][16], antiinflammatory [17][18], antituberculosis [19], anticancer [20,21], anti-HIV [22,23], antiparasitic [24], hypnotic [25], and anthelmintic [26,27] activities.…”

X‐ray crystallographic analysis of the complexes of enoyl acyl carrier protein reductase of Plasmodium falciparum with triclosan variants to elucidate the importance of different functional groups in enzyme inhibition

“…1. In this context, several triclosan analogs were designed by our group (23)(24)(25) and we have also discovered that rhodanines are potent inhibitors of PfENR (26). Triclosan is also shown to be potent against Plasmodium berghei in vivo mice infections (3) and in vitro human cells (27).…”