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Sulfonamide-based carboxamide drugs have multiple active sites that confers them with a variety of chemical and pharmacological activities. The combination of structural functionalities has been established to be vital in the drug discovery process. The synthesis of novel, nontoxic, cheap and effective anti-parasitic analogues is a trending aspect of pharmaceutical and medicinal chemistry research. In this research, the synthesis, characterization, and density functional theory (DFT) investigation of the reactivity and anti-trypanosomal simulation of benzenesulphonamide-based carboxamide derivatives was carried out for 2-[N-(benzenesulfonyl)-1-phenylformamido]-N-(4-nitrophenyl)acetamide(BPNA), 2-[N-(benzenesulfonyl)-1-phenylformamido]-N-(4-nitrophenyl)-3-phenylpropanamide (BPNPP), 2-[N-(benzenesulfonyl)-1-phenylformamido]-3-(1H-indol-2-yl)-N-(4-nitrophenyl)propenamide (BPINP) and 2-[N-(benzenesulfonyl)-1-phenylformamido]-4-methyl-N-(4-nitrophenyl)pentanamide (BPMNP) following an environmentally friendly zinc chloride catalyst mediated synthesis. The lower value of the HOMO-LUMO energy gap (2.9756 eV) observed for BPMNP indicated its higher chemical and biological activity. The global electrophilicity index (ω), which is related to chemical hardness and chemical potential in line with other global descriptors showed that the order of reactivity is BPMNP > BPINP > BPNPP > BPNA. The NBO analysis showed that σ → σ*, σ* →π*, π → π*, and π* → π* transitions were observed in all the compounds while σ → σ* and π* → π* showed the lowest and the highest stabilization energy, respectively. From the molecular docking analysis, BPMNP again, showed the most stable binding energy of − 9.6 kcal/mol and bond length of 1.99 Å, evidently performing better than the standard drug with binding energy and bond length of −7.6 kcal/mol and 2.89 Å, respectively. The binding energy obtained was observed to follow a decreasing order as thus; BPMNP > BPINP > BPNA > BPNPP which strongly indicates alkane-substituted benzenesulphonamide carboxamides especially BPINP and BPMNP possess potent curative properties against trypanosomiasis. [ABSTRACT FROM AUTHOR]