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HERDIN Record #: 108948-20012005010012 Submitted: 20 January 2020 Modified: 21 January 2020

Synthesis, Antitubercular Activity, and Molecular Docking Studies of Benzylmodified 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

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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 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 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. H₃₇Rv. This is also supported by our in silico studies.

Publication Type
Journal
Publication Sub Type
Journal Article, Original
Project Title
Support to Publication of the Philippine Journal of Health Research and Development (PJHRD)
Title
Philippine Journal of Health Research and Development
Frequency
Quarterly
Publication Date
July-September 2019
Volume
23
Issue
3
Page(s)
1-9
LocationLocation CodeAvailable FormatAvailability
PJHRD Office Fulltext Print Format
PJHRD Office Fulltext pdf (Download)