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 NH(2), NO(2) 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 IC(50) and inhibition constant (K(i)) 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 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.
National Institute of Immunology, Molecular Sciences Laboratory, New Delhi, India.
Neha
N
Kapoor
Tanushree
T
Banerjee
Ponnusamy
P
Babu
Koustav
K
Maity
Namita
N
Surolia
Avadhesha
A
Surolia
D000214:Acyl Coenzyme A / Q000378:metabolism; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry; D002733:Chlorophenols / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000201:enzymology; D013329:Structure-Activity Relationship; D014260:Triclosan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
C547398:5-chloro-2-(4-chloro-2-nitrophenoxy)phenol; D000214:Acyl Coenzyme A; D000962:Antimalarials; D002733:Chlorophenols; D004791:Enzyme Inhibitors; D010647:Phenyl Ethers; D014260:Triclosan; C010701:crotonyl-coenzyme A; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)