Synthesis, Antitubercular Activity and Molecular Docking Studies of Benzyl-modified 8-Hydroxyquinolines

Allan Patrick G. Macabeo, Mark Lester M. Mathias, Mark Tristan J. Quimque, Kirstin Rhys S. Pueblos, Mohd Tajudin Mohd Ali, Scott G. Franzblau


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 the currently administered front-line therapeutics. Quinoline-based natural products and synthetic derivatives have been extensively explored for antitubercular activity.

Objectives: The main goal of this study is 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.

Methods: The benzylated 8-hydroxyquinoline derivatives were synthesized using Williamson synthesis methods. Antitubercular activity was assessed against fast replicating M. tuberculosis H₃₇Rv 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 MIC '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: Our findings suggest a rationale for the further evolution of this promising series of antitubercular quinoline small molecules. Structure-activity analysis show that an 8-benzyl moiety with chlorine atom/s is/are important for improved activity against replicating and non-replicating M. tb. H₃₇Rv, which is also supported by our in silico studies.


Antitubercular; Mycobacterium tuberculosis; quinolines; molecular docking; enoyl-acyl carrier protein reductase

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