Introduction::With a projected mortality toll of 1.4 million in 2019, tuberculosis
(TB) continues to be a significant public health concern around the world. Studies of novel
treatments are required due to decreased bioavailability, increased toxicity, increased side effects,
and resistance of several first- and second-line TB therapies, including isoniazid and ethionamide.
Methods::This study reports the synthesis of oxindole-based hybrids as potent InhA inhibitors
targeting Mycobacterium tuberculosis. The synthesized compounds (5a-5e and 8a-8c) were
evaluated for their anti-mycobacterial activity against Mycobacterium tuberculosis and nontuberculous
mycobacteria (NTMs), viz. M. abscessus (ATCC 19977), M. fortuitum (ATCC 6841),
and M. chelonae (ATCC 35752) using the Microplate Alamar Blue Assay (MABA). Molecular
docking studies were performed using AutoDock Vina to explore the binding interactions of
these compounds with the InhA enzyme (PDB: 2NSD). Additionally, biochemical and histopathological
studies were conducted to assess the hepatotoxicity of the lead compounds. Insilico
molecular properties and ADMET properties of the synthesized compounds were predicted
using SwissADME and Deep-PK online tools to assess their drug-likeness.
Results::Among the tested compounds, 8b exhibited significant anti-mycobacterial activity with
a minimum inhibitory concentration (MIC = 1 μg/mL) comparable to the reference drug ethambutol.
Further, the compound demonstrated a binding affinity and orientation similar to the reference
inhibitor 4PI, indicating its potential as a potent InhA inhibitor, and was found to be stabilized
within the binding pocket of InhA through H-bonding, hydrophobic and van der Waal’s
interactions. Besides, the compounds hepatotoxicity assessment studies depicted that 8b showed
no significant liver dysfunction or damage to liver tissues. Additionally, 8b adhered to
Lipinski’s rule of five and Veber’s rule, displaying favourable pharmacokinetic and drug-like
properties, including high human intestinal absorption, distribution, and acceptable metabolic
stability and excretion.
Conclusion::Compound 8b emerged as a promising candidate for further optimization and development
as a therapeutic agent for tuberculosis, offering a new avenue for tackling tuberculosis.