Synthesis, antitubercular activity, and molecular docking studies of Benzyl-modified 8-hydroxyquinolines

@#<p><strong>Background:</strong> 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.<br /><strong>Objective:</strong> 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.<br /><strong>Methodology:</strong> The benzylated 8-hydroxyquinoline derivatives were synthesized using Williamson synthesis methods. Antitubercular activity was assessed against fast replicating M. tuberculosis H??Rv 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).<br /><strong>Results:</strong> 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 ?M. Molecular docking against InhA showed modest 90 binding energies for compounds 4 (-8.5 kcal/mol) and 5 (-8.6 kcal/mol).<br /><strong>Conclusion:</strong> 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??Rv. This is also supported by our in silico studies.</p>

Antitubercular activity of the semi-polar extractives of Uvaria rufa

OBJECTIVE@#To investigate the inhibitory activity of the chloroform extract, petroleum ether and chloroform sub-extracts, lead-acetate treated chloroform extract, fractions and secondary metabolites of Uvaria rufa (U. rufa) against Mycobacterium tuberculosis (M. tuberculosis) H(37)Rv.@*METHODS@#The antituberculosis susceptibility assay was carried out using the colorimetric Microplate Alamar blue assay (MABA). In addition, the cytotoxicity of the most active fraction was evaluated using the VERO cell toxicity assay.@*RESULTS@#The in vitro inhibitory activity against M. tuberculosis H(37)Rv increased as purification progressed to fractionation (MIC up to 23 μg/mL). The chloroform extract and its sub-extracts showed moderate toxicity while the most active fraction from chloroform sub-extract exhibited no cytotoxicity against VERO cells. Meanwhile, the lead acetate-treated crude chloroform extract and its fractions showed complete inhibitions (100%) with MIC values up to 8 μg/mL. Phytochemical screening of the most active fraction showed, in general, the presence of terpenoids, steroids and phenolic compounds. Evaluation of the antimycobacterial activity of known secondary metabolites isolated showed no promising inhibitory activity against the test organism.@*CONCLUSIONS@#The present results demonstrate the potential of U. rufa as a phytomedicinal source of compounds that may exhibit promising antituberculosis activity. In addition, elimination of polar pigments revealed enhanced inhibition against M. tuberculosis H(37)Rv. While several compounds known for this plant did not show antimycobacterial activity, the obtained results are considered sufficient reason for further study to isolate the metabolites from U. rufa responsible for the antitubercular activity.