title: 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.
authors: Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Jagadguru Sri Shivarathreeshwara University, Mysore, Karnataka, India.
authors: Bharathkumar
authors: B
authors: Inturi
authors: Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Jagadguru Sri Shivarathreeshwara University, Mysore, Karnataka, India. gvpujar@jssuni.edu.in.
authors: Gurubasavaraj V
authors: GV
authors: Pujar
authors: Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Jagadguru Sri Shivarathreeshwara University, Mysore, Karnataka, India.
authors: Madhusudhan N
authors: MN
authors: Purohit
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D010647:Phenyl Ethers; D011714:Pyrans; D011728:Pyridones; D011759:Pyrrolidines; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium
keywords: 4-Hydroxy-2-pyridones; Antituberculosis activity; Aryl amides; Diphenyl ethers; Mtb InhA