Design, synthesis, computational molecular docking studies of novel heterocyclics bearing 1,2,4–triazole, 1,3,4–oxadiazole conjugates as potent antibacterial and antitubercular agents

Abstract

Herein, we report the synthesis, and characterization of a new series of 1,3,4–oxadiazole and 1,2,4–triazole derivatives based on azaindole acetamides and assigned as potential antibacterial and antitubercular substances. The structures of these compounds were established by ¹H NMR, ¹³C NMR, and HRMS spectral analysis. In preliminary antibacterial studies, analogues 6b, 6d, and 6e were found to be most effective against S. aureus with MIC of 12.5, 6.25, and 12.5 μg/mL, whereas 8d displayed excellent activity against S. aureus, B. subtilis, E. coli bacterial strains with zones of inhibition 12.5, 25, and 12.5 μg/mL respectively. Particularly, the prepared scaffolds 8c, 8d, and 8e showed remarkable antifungal activity with MIC value 12.5, 12.5, and 6.25 μg/mL against A. flavus and 6d, 6c producing an increase in the activity against C. Albicans with zones of inhibition 12.5 and 12.5 μg/mL respectively. Also, through the antitubercular studies, we found that compounds 6e and 8b have a strong activity with M. tuberculosis H₃₇Rv with MICs 3.26, and 6.48 μg/mL, respectively. The protein stability, fluctuations of APO-Protein, and protein-ligand complexes were investigated through Molecular Dynamics (MD) simulations studies using Desmond Maestro 11.3, and potential lead molecules were identified. Our findings were further confirmed using molecular docking, revealing that azaindole based ligand 6e, 6f, and 8a has strong hydrophobic Tyr179, Trp183, Ile177, Ile445, and H–bondings interactions Arg151 and Arg454 through molecular dynamics simulation studies, making it potential biological compound. These compounds were further evaluated for their ADMET and physicochemical properties by using SwissADME.

Communicated by Ramaswamy H. Sarma

Keywords:

• 1,3,4–oxadiazoles
• 1,2,4–triazoles
• tuberculosis
• antibacterial activity
• antifungal activity
• docking analysis
• ADMET

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors thank the Department of Chemistry, GITAM Institute of Science, and GITAM University for providing the required facilities to complete the research work. We also extend our gratitude to Osmania University, Hyderabad, for providing Molecular Modelling studies. We gratefully acknowledge the financial support from the VGST, Bangalore, under Research Project. No. KSTePS/VGST/GRD-660/KFIST(L1)/2018 for sanctioning the research project to purchase the computing facility to perform molecular dynamics simulations and molecular modelling experiments.