Triclosan inhibit the growth of the late liver‐stage of <i>Plasmodium</i>

Singh, Agam Prasad; Surolia, Namita; Surolia, Avadhesha

doi:10.1002/iub.237

Cited by 26 publications

(29 citation statements)

References 35 publications

(43 reference statements)

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“…The significance of type II FAS in the intraerythrocytic stages has been validated by various studies. Recently, several investigators have indicated that type II FAS is also important for the hepatic stage of malarial parasite (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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“…Two of these compounds approached the inhibitory activity of triclosan, exhibiting nanomolar inhibitory potency against purified PfENR as well as inhibition of the growth of blood stages of parasites in the low micromolar range. Given that triclosan also inhibits the liver stage parasite these derivatives hold promise of their elimination as well (29). The structure-activity relationship studies as analyzed here provides the basis for further exploration of diphenyl ether compounds for their antimalarial activity.…”

Section: Discussionmentioning

confidence: 90%

Design, development, synthesis, and docking analysis of 2′‐substituted triclosan analogs as inhibitors for Plasmodium falciparum Enoyl‐ACP reductase

et al. 2009

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SummaryA structure-based approach has been adopted to develop 2 0 -substituted analogs of triclosan. The Cl at position 2 0 in ring B of triclosan was chemically substituted with other functional groups like NH 2 , NO 2 and their inhibitory potencies against PfENR were determined. The binding energies of the 2 0 substituted analogs of triclosan for enoyl-acyl carrier protein reductase (ENR) of Plasmodium falciparum were determined using Autodock. Based on the autodock results, we synthesized the potential compounds. The IC 50 and inhibition constant (K i ) of 2 0 substituted analogs of triclosan were determined against purified PfENR. Among them, two compounds, 2-(2 0 -Amino-4 0 -chloro-phenoxy)-5-chloro-phenol (compound 4) and 5-chloro-2-(4 0 -chloro-2 0 -nitro-phenoxy)-phenol) (compound 5) exhibited good potencies. Compound 4 followed uncompetitive inhibition kinetics with crotonoyl CoA and competitive with NADH. It was shown to have an IC 50 of 110 nM; inhibition constant was 104 nM with the substrate and 61 nM with the cofactor. IC 50 of compound 5 was determined to be 229 nM. Compounds 4 and 5 showed significant inhibition of the parasite growth in P. falciparum culture.

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“…In the case of Plasmodium, de novo synthesis of fatty acids occurs by type II fatty acid synthase (FAS), which is fundamentally different from type I FAS system of humans (7)(8)(9)(10)(11). Using inhibitors (12) and type II FAS enzyme knock-out parasite lines (13), it has recently been shown to be indispensable for liver-stage parasite development which further strengthens its significance in the parasite biology.…”

Section: Introductionmentioning

confidence: 91%

Benzothiophene carboxamide derivatives as inhibitors of Plasmodium falciparum enoyl‐ACP reductase

et al. 2011

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SummaryBenzothiophene derivatives like benzothiophene sulphonamides, biphenyls, or carboxyls have been synthesized and have found wide pharmacological usage. Here we report, bromo-benzothiophene carboxamide derivatives as potent, slow tight binding inhibitors of Plasmodium enoyl-acyl carrier protein (ACP) reductase (PfENR). 3-Bromo-N-(4-fluorobenzyl)-benzo[b]thiophene-2-carboxamide (compound 6) is the most potent inhibitor with an IC 50 of 115 nM for purified PfENR. The inhibition constant (K i ) of compound 6 was 18 nM with respect to the cofactor and 91 nM with respect to crotonoyl-CoA. These inhibitors showed competitive kinetics with cofactor and uncompetitive kinetics with the substrate. Thus, these compounds hold promise for the development of potent antimalarials.

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Triclosan inhibit the growth of the late liver‐stage of Plasmodium

Cited by 26 publications

References 35 publications

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

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

Design, development, synthesis, and docking analysis of 2′‐substituted triclosan analogs as inhibitors for Plasmodium falciparum Enoyl‐ACP reductase

Benzothiophene carboxamide derivatives as inhibitors of Plasmodium falciparum enoyl‐ACP reductase

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