lunes, 19 de agosto de 2013

Evaluation of Structurally Related 3-Substituted 4-Amino-2- arylquinolines and 2-Aryl-4- methoxyquinolines for Potential Antimycobacterial Activity

Background: A series of structurally related 2-aryl-4-(amino/methoxy)quinoline derivatives were evaluated for potential antimycobacterial activity against Mycobacterium tuberculosis strain H37Rv. Methods: The chemical compounds were tested against a drug sensitive and drug-resistant strains of M. tuberculosis using rapid radiometric techniques. The selected derivatives were tested for their intracellular activity against TB- infected macrophages. Two 4-amino-2,3-diarylquinoline derivatives were investigated for their immune modulatory effect with regard to to Th1 and Th2-subset cytokines Results: A complete inhibition of a drug sensitive strain of M. tuberculosis was observed at 20.0 μg/mL for 4-amino-2-(4-chlorophenyl)quinoline 3b, 4-amino-3- iodo-2-(4-methoxyphenyl)quinoline 5d, 4-amino-2,3-diphenylquinoline 6a, 4-amino- 2-(4-fluorophenyl)-3-phenylquinoline 6b and 4-amino-2-(4-methoxyphenyl)-3- phenylquinoline 6d. These derivatives were further evaluated for activity against a multidrug resistant strain of M. tuberculosis. The minimum inhibitory concentration (MIC) against a two drug-resistant strain was found to be ≥5.0≤20.0 μg/mL. Systems 6a and 6b were, in turn, subjected to cytotoxicity assay using U937 human macrophages and their subsequent intracellular antimycobacterial activity was determined. Intracellular M. tuberculosis growth was inhibited with 64 and 61% by compounds 6a and 6b, at concentrations of 18.00 and 14.00 μg/mL, respectively. Moreover, these two 4-amino-2,3-diarylquinoline derivatives were also investigated for their immune modulatory effect according to Th1 and Th2-subset cytokines. System 6b indicated activity that stimulated multi-effector macrophages with a mixed Th1/Th2 cytokine profile. Conclusions: The presence of a primary amino group at C-4 and phenyl ring at C-3 and the accompanying increased basicity of the quinoline ring as well as electronic effect and lipophilicity of the substituent on the para position of the 2-phenyl ring seem to be critical for the antimycobacterial activity of the 2,3-diarylquinoline derivatives. Overall, the production of cytokines from this specific experiment gives an idea of the amount of individual cytokines produced daily instead of a cumulative response to the test samples during infection. Compound 6a holds potential to modulate the functionality of M. tuberculosis infected macrophages.

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