DABCO-mediated synthesis of novel pyrimidine and uracil sulfonamide analogues as potential therapeutic agents: multifaceted experimental and computational study

A series of novel pyrimidine- and uracil-based sulfonamide analogues 3(a–g) were synthesized in excellent yields (85–93%) using diazabicyclo[2.2.2]octane (DABCO) as an efficient, nontoxic, and economical organo-base catalyst. In vitro antioxidant activity was evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and H2O2 free radical assays. Compounds 3a and 3f displayed promising radical scavenging activity with inhibition percentages of 88.32 ± 0.71, 81.25 ± 0.26, 87.45 ± 0.75, and 84.24 ± 0.21 at 100 µg/mL when compared with ascorbic acid standard. Compound 3a exhibited the highest docking score (−3.183 kcal/mol) and maximum hydrogen-bond interactions with PrxV (PDB: 1HD2). MD simulations confirmed stable binding, comparable to benzoic acid (BA), indicating stable binding modes. MM-GBSA binding energies were −35.46 kcal/mol for compound 3a and −42.27 kcal/mol for compound 3f. Density functional theory (DFT) calculations demonstrated lower energy gaps of −3.51 and −3.2 eV for 3a and 3f compounds. NBO analysis indicated efficient charge transfer, with hyperconjuagation energies at 195.51 and 211.37 kcal/mol for compounds 3a and 3f. FMO and hyperpolarizability studies confirmed the excellent electronic stability and optical properties. This study provides an integrated experimental–computational framework for developing sulfonamides for identifying lead scaffolds for antioxidant drug discovery.