Synthesis, docking study and biological evaluation of some new thiourea derivatives bearing benzenesulfonamide moiety

Background: A series of novel N-(2, 6-dimethoxypyrimidin-4-yl)-4-(3-(aryl) thioureido) benzenesulfonamides 3a-t was synthesized by the addition of N-(2,6-dimethoxypyrimidin-4-yl)-4-isothiocyanatobenzenesulfonamide 2 to the appropriate aromatic amine. The structures of the synthesized compounds were inspired from the second line antituberculosis pro-drugs. Results: Most of the new compounds were screened for their activity against Mycobacterium tuberculosis. The results of the antimycobacterial assay showed that compound 3i exerted the highest activity (MIC = 3.13 mu g/mL), followed by compound 3s (MIC = 6.25 mu g/mL). Conclusion: The structure-activity relationship (SAR) analysis revealed that the introduction of the benzo[1,3] dioxol moiety in 3i and the 4-morpholinyl-4-phenyl moiety in 3s has proven to give the most potent compounds in this study. Docking of the promising compounds inside the active site of M. tuberculosis enoyl reductase InhA was performed in order to emphasize the results. The compounds showed a similar orientation to that of GSK 625 inside the active site of 5JFO and bind to Met 98 in a way similar to that of the co-crystallized ligand.