Recent Advances and Structural Features of Enoyl‐ACP Reductase Inhibitors of Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis enoyl-ACP reductase (InhA) has been validated as a promising target for antitubercular agents. Isoniazid (INH), the most prescribed drug to treat tuberculosis (TB), inhibits a NADH-dependent InhA that provides precursors of mycolic acids, which are components of the mycobacterial cell wall. It is a pro-drug that needs activation to form the inhibitory INH-NAD adduct by KatG coding for catalase-peroxidase. The INH resistance of M. tuberculosis is caused by mutations in KatG, which may lead to multidrug-resistant TB (MDR-TB). Hence, there is a need for new drugs that can combat MDR-TB. The rationale for the development of new drugs to combat MDR-TB strains is the design of InhA inhibitors that can bypass bioactivation by KatG. In the present review, special attention was paid to discuss the chemical nature and recent developments of direct InhA inhibitors. The InhA inhibitors reported here have significant inhibitory effects against Mtb InhA. The diphenyl ether derivatives have shown slow onset, a tight-binding mechanism, and high affinity at the InhA active site. However, some of the diphenyl ethers have significant in vitro efficacy, which fails to transform into in vivo efficacy. Among the InhA inhibitors, 4-hydroxy-2-pyridones have emerged as a new chemical class with significant InhA inhibitory activity and better pharmacokinetic parameters when compared to diphenyl ethers.

Protein targets in Mycobacterium tuberculosis and their inhibitors for therapeutic implications: A narrative review

“…Glucose-1-phosphate thymidyl transferase (RmlA), dTDP-d glucose 4,6-dehydratase (RmlB), dTDP-6-deoxy-d-xylo-4-hexulose 3,5-epimerase (RmlC) and dTDP-6-deoxyd-xylo-4hexulose reductase (RmlD) [30] Cell wall Mycolic Acid MmpL3 [4] Nitrobenzothiazinone (BTZ-043) inhibits replicating and nonreplicating Mtb by acting on DprE1. The catalytic pocket of DprE1 contains FADH 2 generated by the oxidation of the substrate.…”

Advances in Key Drug Target Identification and New Drug Development for Tuberculosis

“…Mtb has been reported to be resistant to triclosan, but the specific drug resistance mechanism is still unclear [10]. In addition, 3-nitropropanoic acid, gallic acid derivatives, pyrrolidone derivatives, tetrahydrofuran derivatives, 4-hydroxy-2-pyri-done analogs, aryl amides, and other inhA inhibitors have been reported [9,[11][12][13][14].…”

Benzoxazole Derivatives as Promising Antitubercular Agents

“…Mycobacterium tuberculosis enoyl acyl carrier protein reductase ( Mt InhA) is one of the most attractive enzymes to design and develop novel drugs for tuberculosis therapy and might be a promising target for novel inhibitors active against MDR and XDR MTB . Several benzoxazoles have been studied in respect to the Mt InhA inhibition .…”