Some New 1,2,4-triazole Derivatives Bearing the Pyrimidine Moiety as Potential Antimycobacterial Agents: Synthesis and Docking Analysis

Background: Pyrimidine and 1,2,4-triazole heterocycles have been linked to a variety of biological and pharmacological properties such as effective bactericides, fungicides, vermicides, insecticides, anticancer and antiviral agents. Accordingly, the synthetic derivatives and analogs of these molecules have attracted attention as potential pharmacological agents. Objective: A novel set of heterocyclic derivatives comprising 1,2,4-triazole, pyrimidine moieties was developed, synthesized, and assessed for their antimicrobial activity. Methods: In this study, we performed ligand-based pharmacophore modeling as a promising design strategy for the design of substituted triazolyl-pyrimidine derivatives as antitubercular agents. The designed compounds were synthesized and characterized by proton, carbon nuclear magnetic resonance spectroscopy, infrared, and mass spectroscopy. Synthesized compounds were screened for anti-TB activity using the agar micro dilution method against M. tuberculosis H37Rv strain. Results: Our results revealed that the target 1,2,4-triazoles 7d, 7e, 7c have potent potency against Gram- (+ve) bacteria S. epidermidis (MICs: 1.7, 3.7, 16.4 μg/mL), whereas final pyrimidines 7c, 7e, 7f, have the strongest antibacterial activity against Gram-(-ve) strain P. aeruginosa (MICs: 3.5, 6.4, 8.4 μg/mL). Among all tested compounds, 7a, 7e, and 7h revealed an outstanding antitubercular activity against M. tuberculosis H37Rv strain with MICs of 3.24, 8.93, and 4.70 μg/mL, respectively. The most active ligand 7b reveals highest hydrophobic binding modes with ThrA:127 [2.194 ŝ, LysA:103 [3.103, 2.164 ŝ, GlyA:102 [1.713 ŝ, ArgA:238 [1.713 ŝ, ValA:101 [2.113 ŝ (hydrogen bondings), AspA:129, GluA:201 [Pi-anion], AlaA:246, LeuA:180 [Pi-alkyl] and HisA:179 [3.104 ŝ [Pi-Pi], respectively. Conclusion: In this communication, our aim has been verified by the synthesis of 3-methoxy-10,12- dimethyl-8-phenyl-6,7,8,12-tetrahydrobenzo[2,3]oxepino[4,5-d][1,2,4]triazolo[4,3-a] pyrimidine derivatives 7 in which 1,2,4-triazole and pyrimidine moieties with benzoxepine in a single molecular framework were found. After all the above findings, it can be concluded that these molecules become lead molecules for further synthetic and biological evaluation.