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Design, development, synthesis, and docking analysis of 2′‐substituted triclosan analogs as inhibitors for Plasmodium falciparum Enoyl‐ACP reductase
Author(s) -
Kapoor Neha,
Banerjee Tanushree,
Babu Ponnusamy,
Maity Koustav,
Surolia Namita,
Surolia Avadhesha
Publication year - 2009
Publication title -
iubmb life
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.132
H-Index - 113
eISSN - 1521-6551
pISSN - 1521-6543
DOI - 10.1002/iub.258
Subject(s) - triclosan , autodock , chemistry , plasmodium falciparum , stereochemistry , uncompetitive inhibitor , docking (animal) , reductase , phenol , naphthoquinone , non competitive inhibition , lead compound , enzyme , biochemistry , organic chemistry , biology , in vitro , in silico , medicine , nursing , pathology , malaria , immunology , gene
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 NH 2 , NO 2 and their inhibitory potencies against Pf ENR 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 IC 50 and inhibition constant (K i ) of 2′ substituted analogs of triclosan were determined against purified Pf ENR. 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 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. © 2009 IUBMB IUBMB Life, 61(11): 1083–1091, 2009