Synthesis of new sulfonamides from sulfamethizole: in vitro antitubercular and antimicrobial activities supported by molecular docking, molecular dynamics, and ADME studies

The alarming increase in antimicrobial resistance and the persistence of diseases such as tuberculosis have created an urgent demand for novel agents with broad-spectrum antimicrobial potential. In this study, eleven new hybrid molecules (1–11) bearing sulfamethizole and benzamide scaffolds were synthesized using a molecular hybridization strategy. Structural elucidation was carried out via IR, ¹H-NMR, ¹³C-NMR, mass spectrometry, and elemental analysis. The synthesized compounds were evaluated for their biological activity against a diverse panel of microorganisms, including Gram-positive and Gram-negative bacteria, dermatophyte group mold-type fungi, yeast strains, and Mycobacterium species. Biological screening results revealed that several of the compounds exhibited notable antimicrobial activity, with certain derivatives showing enhanced efficacy against mycobacterial and fungal pathogens. Among them, compound 1 drew interest with its remarkable antifungal activity against Trichophyton rubrum and Microsporum gypseum (0.008 mM MIC for both), while compound 8 emerged as a potent antitubercular lead with a notable MIC of 0.031 mM against Mycobacterium intracellulare. Besides, according to the molecular docking studies performed on CYP51 enzyme, it showed the most promising binding in this group with a − 7.82 kcal/mol docking score, which is significantly better than the standard drug fluconazole (− 5.40 kcal/mol) and comparable to the co-crystallized ligand VT1 (− 9.36 kcal/mol), confirming its high binding affinity. Furthermore, 100 ns molecular dynamics simulations confirmed the structural stability of the enzyme-ligand complex through RMSD analysis, indicating a persistent binding mode. Complementary ADME predictions revealed that the compounds possess favorable pharmacokinetic properties and follow Lipinski’s Rule of Five. These findings highlight the potential of sulfamethizole-based benzamides as promising candidates for antimicrobial drug development through a successful correlation between in vitro and in silico data.