Targeting InhA for Tuberculosis Therapy: A Review of Recent Advancesin Enzyme Inhibition and Drug Development

Mycobacterium Tuberculosis (Mtb) is developing resistance to available antibiotics, posing new challenges and making first-line drugs (Isoniazid, ethambutol, pyrazinamide) ineffective. Second-line medications are also losing effectiveness due to their high toxicity and limited availability, necessitating more advanced treatment in modern drug discovery and development. Tiliacorinine, 2'-nortiliacorinine, and griselimycin, derived from natural sources, paved the way for the development of compounds and approved drugs, such as bedaquiline, delamanid, pyrifazimine, proteomandid, and telacebec, which are currently under review for use. The primary outcome of this worldwide endeavour is the breakthrough of the late-stage T.B. medication pipeline into the clinics. Fundamental research must be supported to maintain a robust pipeline of T.B. drugs, and early-stage discovery work must be pursued. Understanding pathophysiology, enzyme structure, and function helps identify novel therapeutic targets and associated therapeutic approaches. A comprehensive literature search was conducted across PubMed Central, MEDLINE, Scopus, and Embase. A total of 893 studies have been retrieved from the databases. Out of which 150 duplicates were removed. The studies were included based on InhA targeted in TB, "in-silico" studies, which performed biological activity on the molecules published from 2015 to date. The futuristic approach to treating tuberculosis on the ground level could be identifying potential targets and their pharmacophores. We selected an enzyme called InhA because InhA (enoyl acyl carrier protein reductase) plays a crucial role in metabolism, and its sequence is conserved across numerous bacterial species. This review provides a brief on the design, synthesis, protein, activity, and pharmacophore moieties and their substitutions that cause the inhibition of this versatile target. We verified publications from 2013 that explore the same topic and reviewed chemistry-related research from Elsevier and other publishers, including future directions and targets that have been available.