Synthesis, Antitubercular Activity, and Molecular Docking Studies of Benzylmodified 8-hydroxyquinolines.

Background: Infection with Mycobacterium tuberculosis, the causative agent of TB, is responsible for one of the global epidemics. Thus, new drugs are needed that do not confer cross-resistance with currently administered front-line therapeutics. Quinoline-based natural products and synthetic derivatives have been extensively explored for antitubercular activity.
Objective: The main goal of this study was to prepare a collection of benzylated 8-hydroxyquinoline derivatives through synthesis and assess their antitubercular activity along with a molecular docking study to clarify their biological mechanism of action.
Methodology: The benzylated 8-hydroxyquinoline derivatives were synthesized using Williamson synthesis methods. Antitubercular activity was assessed against fast replicating M. tuberculosis H_₃₇Rv using Microplate Alamar Blue Assay (MABA) and non-replicating cultures using Low-Oxygen Recovery Assay (LORA). Molecular docking studies were carried out against enoyl-acyl carrier protein reductase (InhA).
Results: Five benzylated 8-hydroxyquinoline derivatives were synthesized in moderate yields and characterized using NMR spectroscopy. MABA and LORA assays indicate compounds 3-5 as the most inhibitory derivatives with MIC₉₀'s ranging from 6.38 to 54.28 μM. Molecular docking against InhA showed modest 90 binding energies for compounds 4 (-8.5 kcal/mol) and 5 (-8.6 kcal/mol).
Conclusion: Findings suggest a rationale for the further evolution of this promising series of antitubercular quinoline small molecules. Structure-activity analysis shows that an 8-benzyl moiety with chlorine atom/s is important for improved activity against replicating and non-replicating M. tb. H_₃₇Rv. This is also supported by our in silico studies.