Synthesis, characterization, DFT and in silico anti-ulcer activities of novel sulphonamide derivatives.

Peptic ulcer disease (PUD) is a major gastrointestinal disorder associated with Helicobacter pylori infection and long-term use of non-steroidal anti-inflammatory drugs (NSAIDs). Current treatment strategies face limitations due to drug resistance, recurrence, and adverse effects, highlighting the need for novel therapeutic scaffolds. In this study, four newly designed sulfonamide derivatives (CPD-1 to CPD-4) were synthesized, characterized using state-of-the art instruments, and evaluated for anti-ulcer activities through a comprehensive computational chemistry approach. Density functional theory (DFT) optimizations with B3LYP, ωB97XD, and M06-2X functionals confirmed molecular stability and reactivity. Frontier molecular orbital (FMO) analysis revealed small HOMO–LUMO gaps, with CPD-1 exhibiting the lowest energy (3.71 eV), suggesting high chemical reactivity. Natural bond orbital (NBO) analysis indicated strong intramolecular charge transfer and stabilization, while molecular electrostatic potential (MESP) maps identified regions favorable for electrophilic and nucleophilic interactions. Non-covalent interaction (NCI) plots further supported stabilization through hydrogen bonding and van der Waals interactions. Docking studies against H. pylori CagI protein (PDB ID: 8AK1) showed CPD-1 had the strongest binding affinity (− 7.2 kcal/mol), stabilized by five hydrogen bonds, surpassing the reference drug DB00338. ADMET predictions revealed that CPD-2 had the most favorable pharmacokinetic and safety profile, with acceptable clearance, moderate plasma protein binding, and compliance with Lipinski’s rules. Collectively, these results suggest that CPD-1, CPD-2, and CPD-3 are promising candidates for further development as anti-ulcer agents. This integrative approach demonstrates the power of combining DFT, docking, and ADMET modeling for the rational design of novel therapeutics targeting H. pylori.