Novel Azo Sulfonamide Derivatives of 5-Sulfosalicylic Acid: Synthesis, Biological Evaluation, and Computational Profiling

Abstract

The escalating crisis of multi-drug-resistant pathogens necessitates the development of novel therapeutic scaffolds with enhanced membrane permeability and multi-target inhibitory potential. This study describes the design, synthesis, and mechanistic evaluation of five novel azo-sulfonamide hybrids (4a–e) derived from a 5-sulfosalicylic acid scaffold. Structural integrity was elucidated via comprehensive spectroscopic techniques. Biological efficacy was evaluated against a diverse panel of clinical pathogens, including Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans, using standardized Clinical and Laboratory Standards Institute protocols for minimum inhibitory concentration and minimum microbicidal concentration determination alongside B3LYP/6-31G(d,p) DFT modeling and molecular docking. Molecular hybridization significantly enhanced biocidal potency, with lead compound 4d, incorporating a 4,6-dimethylpyrimidinyl moiety, exhibiting robust broad-spectrum activity (e.g., a zone of inhibition of 44 mm against Bacillus cereus), showing strong correlation with high electronic softness and a high binding affinity (ΔG = -9.7 kcal/mol) against lanosterol 14-α-demethylase. Density functional theory profiling revealed a direct correlation between high electronic softness and superior antimicrobial performance. Molecular docking validated these results, identifying 4d as a high-affinity inhibitor of Candida albicans lanosterol 14-α-demethylase through strategic pi–pi stacking and electrostatic salt bridges. These findings suggest that compound 4d represents a promising lead with favorable predicted pharmacokinetic and safety profiles, offering a potential platform for next-generation antimicrobial drug discovery.