Exploration of quinoxaline triazoles as antimycobacterial agents: design, synthesis and biological evaluation

Abstract

In this work, novel 2-substituted-3-((1-substituted-1H-1,2,3-triazol-4-yl) methoxy) quinoxaline analogues were designed, synthesized, and various analytical techniques, viz., 1H NMR, 13C NMR, and Mass spectrometry, were deployed in the structure confirmation of the final compounds. Synthesized derivatives were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis (Mtb) H37Rv. Target molecules mainly consist of methyl substituent in the second position of quinoxaline moiety (QM series) or phenyl substituent in the second position (QP series). Among the forty-two compounds synthesized and evaluated for anti-mycobacterial activity, the MIC values ranged between 5.58 μg/mL to >100 μg/mL. Among QM series compounds, QM7, with MIC 5.58 μg /mL, was the most active compound. Among the QP series derivatives, the intermediate QP-Acy with MIC 23.39 μg /mL was the most promising. Most of the analogues tested in the QP series are less potent than the QM series. All the synthesized molecules showed good drug-likeness when evaluated using the SWISS ADME tool. QM7 was evaluated for docking studies using the crystal structure of enoyl-acyl carrier (INH-A) enzyme PDB: 4TZK, and it showed significant docking scores and interactions. MD simulations were carried out to assess the stability of the protein QM7 complex. Single crystals were grown for QM1, QM6, and QPb from these forty-two compounds, and their structures were solved using OLEX. The corresponding CCDC numbers for these compounds are 2,388,310, 2,388,309, and 2,388,291, respectively.