Novel Antitubercular Agents: Design, Synthesis, Molecular Dynamic and Biological Studies of Pyrazole - 1,2,4-Triazole Conjugates

Abstract

Mycobacterium tuberculosis (Mtb) has numerous cell wall and non-cell wall mediated receptors for drug action, of which cell wall mediated targets were found to be more promising because of their pivotal role in bacterial protection and survival. Herein, we reported the design and synthesis of a series of pyrazole-linked triazoles based on the reported structural features of promising drug candidates that target DprE1 receptors through a Structure-based drug design (SBDD) approach (6a-6j and 7a-7j). The synthesized compounds were evaluated for their in-vitro antitubercular activity against virulent strains of Mtb H37Rv. In-silico studies revealed that most compounds exhibit binding interactions with crucial amino acids like Lys418, Tyr314, Tyr60, and Asp386 at DprE1. Furthermore, the protein-ligand (7j) shows appreciable stability compared to innate protein in a 100 ns molecular dynamic simulation study. In-vitro MAB assay revealed that 14 compounds exhibit significant antitubercular activity with minimum inhibitory concentration (MIC) of the 3.15-4.87 μM of the 20 compounds tested. An in-vitro cytotoxicity study on normal cell lines (MCF10) revealed safe compounds (IC₅₀ values:341.85 to 726.08 μM). Hence, the present study opens the development of new pyrazole-linked triazoles as probable DprE1 inhibitors.

Keywords: 1,2,4-triazoles; DprE1; Mtb; SBDD; molecular docking; molecular dynamic simulation.