Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides.

Article Details

Citation

Copy to clipboard

He X, Alian A, Ortiz de Montellano PR

Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides.

Bioorg Med Chem. 2007 Nov 1;15(21):6649-58. Epub 2007 Aug 15.

PubMed ID

17723305 [ View in PubMed

]

Abstract

InhA, the enoyl acyl carrier protein reductase (ENR) from Mycobacterium tuberculosis, is one of the key enzymes involved in the type II fatty acid biosynthesis pathway of M. tuberculosis. We report here the discovery, through high-throughput screening, of a series of arylamides as a novel class of potent InhA inhibitors. These direct InhA inhibitors require no mycobacterial enzymatic activation and thus circumvent the resistance mechanism to antitubercular prodrugs such as INH and ETA that is most commonly observed in drug-resistant clinical isolates. The crystal structure of InhA complexed with one representative inhibitor reveals the binding mode of the inhibitor within the InhA active site. Further optimization through a microtiter synthesis strategy followed by in situ activity screening led to the discovery of a potent InhA inhibitor with in vitro IC(50)=90 nM, representing a 34-fold potency improvement over the lead compound.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Enoyl-[acyl-carrier-protein] reductase [NADH]	P9WGR1	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Genz-10850	Enoyl-[acyl-carrier-protein] reductase [NADH]	IC 50 (nM)	200	6.8	23	Details
N-(4-METHYLBENZOYL)-4-BENZYLPIPERIDINE	Enoyl-[acyl-carrier-protein] reductase [NADH]	IC 50 (nM)	5160	6.8	23	Details