Novel Triazolo[4,3-a]pyrazines as Potential MmpL3 Inhibitors: Design, Synthesis, Antitubercular Evaluation and Molecular Docking Studies

A series of biologically active novel triazolo[4,3-a]pyrazines (5a-f) were synthesized and characterized by spectroscopic techniques. The synthesized compounds 5a-f were evaluated for their in vitro anti-tubercular (anti-TB) activity against drug-sensitive Mtb H37Rv (ATCC 27294) strain as well as two drug-resistant Mtb strains viz. Mtb H37Rv ATCC 35822 (INH-resistant) and Mtb H37Rv ATCC 35837 (ETH-resistant). The synthesized compounds 5a-f displayed good to moderate anti-TB activity against drug-sensitive, INH-resistant and ETH-resistant Mtb H37Rv strains. Among all the compounds tested, compound 5c was found to be significantly potent. It inhibited the growth of drug-sensitive, INH-resistant and ETH-resistant Mtb H37Rv strains with MIC values 0.59 ± 0.11 µM, 20.83 ± 0.67 µM and 15.37 ± 0.14 µM, respectively. Moreover, compounds 5a-f were also tested for their cytotoxic efficacy against the mammalian Vero cell line at a maximum concentration of 50 µM. Molecular docking experiments of compounds 5a-f with the mycobacterial membrane protein large 3 (MmpL3) were performed to justify the biological activity and provide insight into the possible mechanism of action and binding mode of compounds. In silico predictions were used to validate compound toxicity descriptors, drug scores and drug-likeness properties.