Synthesis, molecular dynamics simulation and antimicrobial activity of novel s-triazine clubbed with three different hybrid pharmacophores

To address microbial infections and combat drug resistance, we designed, synthesized, and evaluated three novel s-triazine clubbed pharmacophores: 1-acetylpyrazoline (5a-e), 2-aminopyrimidine (6a-e), and 1,5-benzodiazepine (7a-e). These were derived from chalcone (4a-e), showing improved pharmacological profiles. The compounds underwent characterization by FTIR, NMR, and Mass Spectroscopy, and their antimicrobial activities, along with structure-activity relationships (SAR), were assessed using in silico and in vitro methods. Among the tested compounds, 5c, 5e, 6d, 7a, 7d, and 7e demonstrated significant antibacterial activities with MIC values between 50 and 62.5 μg/mL against Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, and Pseudomonas aeruginosa, which indicates their therapeutic potential. Similarly, 5b, 6a, 6c, 7b, and 7c exhibited vigorous antifungal activities against Candida albicans, Aspergillus niger, and Aspergillus clavatus, indicating their broad-spectrum antifungal efficacy. Moreover, the antitubercular potential of the compounds was evaluated against the Mycobacterium tuberculosis H37Rv strain, identifying 5c, 6a, 6d, 7a, and 7d as promising antimycobacterial agents. Molecular docking and molecular dynamics simulation analyses indicated excellent binding energies and stable complexes for 6c, 6e, 7a, and 7e against selected proteins from E. coli, Mycobacterium tuberculosis, and Candida albicans after 40 ns MD simulation. Compound 7a shows the best antimycobacterial activity, while 6c possessed significant antifungal properties in both in silico and in vitro analyses. Moreover, 7a and 7e exhibited desirable antibacterial activities in both experiment, indicating the synthesized compounds' broad-spectrum efficacy against various bacterial and fungal species.