Quantum chemical and in silico-driven structural refinement of sulfanilamide for improved efficacy and safety

Sulfanilamide (SN), a synthetic broad-spectrum antimicrobial that inhibits folic acid synthesis and suppresses bacterial growth. However, long-term use has caused allergic reactions, skin problems, crystalluria, nephrotoxicity, and other side effects. SN has developed resistance, and its associated side effects underscore the urgent need to discover safer alternatives with greater efficacy and reduced toxicity. In this study, we attempted to design new SN derivatives by incorporating various functional groups into their basic structure. Derivative structures were geometrically optimized utilizing density functional theory (DFT) and B3/LYP 6-31G+(d, p) basis set to calculate their physicochemical and spectrochemical properties. Molecular docking and molecular dynamics (MD) simulations were conducted against the dihydropteroate synthase (DHPS) protein (PDB ID: 1AJ2) to predict the binding affinities of analogs and stability at the active site. ADMET and PASS analyses evaluated toxicological and pharmacological profiles. Most of the derivatives showed lower energy gaps (5.14 eV to 5.30 eV) than SN (5.34 eV). All derivatives showed stronger binding affinities (-5.5 to -6.7 kcal mol^-1) compared to SN (-5.4 kcal mol^-1). ADMET results showed good pharmacokinetics, with some derivatives exhibiting higher GI absorption and most falling under toxicity class III. Overall, SN7 (-6.5 kcal/mol), SN17 (-6.6 kcal/mol), and SN18 (-6.7 kcal/mol) have exhibited better performance. Thus, our research reveals that the studied analogs can serve as novel alternatives to SN with superior quality. However, further experimental and biological studies are necessary to validate these theoretical findings and confirm their potential antibacterial efficacy.

The online version contains supplementary material available at 10.1007/s40203-025-00526-y.