The emergence of multidrug-resistant bacterial and fungal pathogens necessitates the development of novel antimicrobial agents. This study aimed to synthesize and evaluate a series of chlorophenylamino- s -triazine derivatives for antibacterial and antifungal activities. The compounds were tested in vitro against clinically relevant strains, and their target interactions were investigated by molecular docking. Derivatives bearing piperazine or 4-methylpiperazine substituents at the 4- and 6-positions of the s -triazine core exhibited enhanced activity. Among them, compound 2f showed the highest potency, with MIC values of 16 μg/mL against Staphylococcus aureus and 32 μg/mL against MRSA (methicillin-resistant S. aureus ), as well as antifungal activity against Candida albicans (32 μg/mL) and Aspergillus niger (128 μg/mL). Molecular docking demonstrated strong binding affinities toward DNA gyrase and 1,3- β -glucan synthase, supported by hydrophobic interactions. Structure-activity relationship analysis highlighted the importance of the diamine linker and halogenated phenyl moiety in enhancing activity. In silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis indicated favorable druglikeness and absorption, although potential toxicity risks require further optimization. Notably, this study introduces a new class of chlorophenylamino- s -triazine derivatives with dual antibacterial and antifungal activity. In conclusion, compound 2f represents a promising lead, providing a valuable framework for the development of next-generation antimicrobial agents. • Compound 2f emerged as a strong lead against MRSA and Candida albicans . • Compounds 2e and 3e emerged as a strong lead against Aspergillus niger . • Piperazine substitution at C4/C6 was critical for biological efficacy. • Dual-target action on DNA gyrase and 1,3- β -glucan synthase was revealed. • ADMET profiling supports lead optimization despite hERG and toxicity risks.
Pham et al. (Wed,) studied this question.