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

A structure‐based approach has been adopted to develop 2′‐substituted analogs of triclosan. The Cl at position 2′ in ring B of triclosan was chemically substituted with other functional groups like NH2, NO2 and their inhibitory potencies against PfENR were determined. The binding energies of the 2′...

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Bibliographic Details
Published in:IUBMB life 2009-11, Vol.61 (11), p.1083-1091
Main Authors: Kapoor, Neha, Banerjee, Tanushree, Babu, Ponnusamy, Maity, Koustav, Surolia, Namita, Surolia, Avadhesha
Format: Article
Language:English
Subjects:
Acyl Coenzyme A - metabolism
Antimalarials - chemical synthesis
Antimalarials - chemistry
Chlorophenols - chemical synthesis
Chlorophenols - pharmacology
Drug Design
Drug Evaluation, Preclinical
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - antagonists & inhibitors
Enoyl‐ACP reductase
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Inhibitory Concentration 50
Kinetics
Phenyl Ethers - chemical synthesis
Phenyl Ethers - pharmacology
Plasmodium falciparum
Plasmodium falciparum - enzymology
Structure-Activity Relationship
Triclosan
Triclosan - analogs & derivatives
Triclosan - chemical synthesis
Triclosan - chemistry
Triclosan analogs
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Summary:A structure‐based approach has been adopted to develop 2′‐substituted analogs of triclosan. The Cl at position 2′ in ring B of triclosan was chemically substituted with other functional groups like NH2, NO2 and their inhibitory potencies against PfENR were determined. The binding energies of the 2′ 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 IC50 and inhibition constant (Ki) of 2′ substituted analogs of triclosan were determined against purified PfENR. Among them, two compounds, 2‐(2′‐Amino‐4′‐chloro‐phenoxy)‐5‐chloro‐phenol (compound 4) and 5‐chloro‐2‐(4′‐chloro‐2′‐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 IC50 of 110 nM; inhibition constant was 104 nM with the substrate and 61 nM with the cofactor. IC50 of compound 5 was determined to be 229 nM. Compounds 4 and 5 showed significant inhibition of the parasite growth in P. falciparum culture. © 2009 IUBMB IUBMB Life, 61(11): 1083–1091, 2009
ISSN:1521-6543
1521-6551
DOI:10.1002/iub.258