Synthesis and preliminary biological evaluation of novel N-(3-aryl-1,2,4-triazol-5-yl) cinnamamide derivatives as potential antimycobacterial agents: an operational Topliss Tree approach.

A series of novel N-(3-aryl-1,2,4-triazol-5-yl) cinnamamide derivatives were designed on basis of structural similarity to the known FAS II inhibitors. Topliss operational method was used to optimize the potency of molecules. The minimum inhibitory concentration (MIC) of all synthesized compounds was determined against Mycobacterium tuberculosis H(37)R(v) using resazurin microtitre assay (REMA) plate method. The synthesized compounds exhibit antimycobacterial activity in the range of 5-95µM with a good safety profile.

Design and Synthesis of a Focused Library of Diamino Triazines as Potential Mycobacterium tuberculosis DHFR Inhibitors.

We report design of a series of 2,4-diamino triazines as Mycobacterium tuberculosis (Mtb) dihydrofolate reductase inhibitors. The synthesized compounds were evaluated against Mtb (H37Rv and Dormant stage H37Ra), their cytotoxicity was assessed (HepG2 and A549 cell lines), and selectivity toward Mtb was evaluated by testing against other bacterial strains. Some derivatives showed promising activity along with low cytotoxicity. The most potent compound in the whole cell assay (MIC 0.325 µM against H37Rv) showed selectivity in the enzyme assay and exhibited synergy with second line anti-TB agent p-amino salicylic acid. This study therefore provides promising molecules for further development as antituberculosis DHFR inhibitors.

Rational drug design, synthesis and biological evaluation of dihydrofolate reductase inhibitors as antituberculosis agents.

BACKGROUND: A series of 2,4-diamino-s-triazines was designed, with potential for activity against Mycobacterium tuberculosis (Mtb) dihydrofolate reductase enzyme, on the basis of virtual screening results and structure-based drug design. RESULTS: The compounds were evaluated against Mtb (H37Rv) and their cytotoxicity was assessed using VERO cell lines. Of particular note, two compounds were found to have the most promising antituberculosis activity (6b minimum inhibitory concentration: 1.76 µM and 6i minimum inhibitory concentration: 1.57 µM) along with low cytotoxicity (CC50: >300 µM). The enzyme assay results of these two indicated significant inhibition of Mtb dihydrofolate reductase along with selectivity. Selected derivatives were tested against dormant tubercle bacilli in vivo and ex vivo indicating potential inhibition. CONCLUSION: This study provides promising antituberculosis dihydrofolate reductase inhibitors that can act as potential leads for further development.