A holistic molecular modelling approach to design novel indole-2-carboxamide derivatives as potential inhibitors of MmpL3.

Tuberculosis is an infectious air-borne disease and one of the leading causes of death globally among all infectious diseases. There is an urgent need to develop antitubercular drugs that would be highly efficient and less toxic than the presently available marketed drugs. Mycobacterium membrane protein large 3 (MmpL3) is an emerging drug target in tuberculosis with various classes of molecules that have been known to inhibit it. In this study, a dataset of indole-2-carboxamides showing antitubercular activity by inhibiting MmpL3 was utilized. Initially, a chimera-based homology model was developed and docking was performed with the filtered dataset to analyse the interactions. Thereafter, molecular dynamics simulations were run with representative molecules to gain a better insight on the binding patterns. To attain a more quantitative correlation, an atom-based 3D QSAR model was developed which complemented the results from the previous models. A library of novel indole-2-carboxamides was then generated using core hopping-based ligand enumeration and upon screening on our workflow model it predicted three molecules as potent antitubercular compounds. This work not only helps to gain new insights on the interactions at the MmpL3 binding site but also provides novel indole-2-carboxamides having the potential to become antitubercular drugs in future.

Synthesis and in-vitro antimicrobial activity of new 1,2,4-triazoles.

We have described the synthesis of new 1,2,4-triazoles and have evaluated their antimicrobial profile. Antitubercular activity was determined in triplicate using the Lowenstein-Jensen medium. A loopful of Mycobacterium tuberculosis suspension was inoculated on the surface of each Lowenstein-Jensen media containing the test compounds (100, 10 or 1 microg mL(-1)). To evaluate in-vitro antibacterial activity, compounds (50, 5 or 0.5 microg) were evaluated against B. subtilis, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus typhi by the disc diffusion method. To evaluate antifungal activity Sabourauds Dextrose agar medium was used. Some of the compounds (5, 0.5 or 0.05 microg mL(-1)) were screened for activity against Aspergillus niger 88 and Aspergillus niger 90 and others were screened for activity against T. rubrum TR1, T. rubrum R6, T. rubrum R7 and T. mentagrophyte M1, using the cup plate method. Our results show that the triazoles with a pyrazine moiety at position 3 were more active as antitubercular and antifungal agents compared with the triazoles which had a pyrazine moiety at position 4 of the molecule.