Synthesis, vibrational analysis, molecular property investigation, and molecular docking of new benzenesulphonamide-based carboxamide derivatives against Plasmodium falciparum

Abstract

Zinc chloride mediated synthesis, density functional theory (DFT) studies and molecular docking of new carboxamide derivatives containing sulphonamide functionality is reported. The synthesis of benzenesulphonamide (3a-d) was achieved from the reaction of benzenesulphonyl chlorides (1a) and amino acids (2a-d) and the yields were characterized using FT-IR and NMR spectroscopy. The reaction of compounds (3a-d) with benzoyl chloride (4) provided the N-benzoylated derivatives (5a-d) which upon reaction with 4-nitroaniline (6) using zinc chloride as a catalyst afforded the new carboxamides; 2-[N-(benzenesulfonyl)-1-phenylformamido]-3-methyl-N-(4-nitrophenyl)pentanamide (BSPFMNPP), 2-[N-(benzenesulfonyl)-1-phenylformamido]-3-methyl-N-(4-nitrophenyl)butanamide, (BSPFMNPB), 1-(benzenesulfonyl)-4-hydroxy-N-(4-nitrophenyl)pyrrolidine-2-carboxamide (BSHNPPC) and 1-(benzenesulfonyl)-N-(4-nitrophenyl)pyrrolidine-2-carboxamide (BSNPPC) in excellent yields. Theoretical calculations on the newly synthesized carboxamides were conducted at the B3LYP/6-311++G(d,p) level of theory to investigate the reactivity, stability, bonding nature, along with vibrational functional groups assignment and correlation with experimental values. From the docking result, the binding affinities obtained from the docking score were in the order; -7.3 > -7.2 > -6.1 > -5.8 kcal/mol for BSPFMNPB, BSPFMNPP, BSNPPC and BSHNPPC respectively while the standard drug, atovaquone scored -7.7 kcal/mol. There were no significant differences between the docking score by the standard drug and the studied compounds. However, results showed that the 2-[N-benzoylated]-alkane derivatives (pentanamide and butanamide); BSPFMNPB and BSPFMNPP are better anti-malaria drug candidates than their 1-[N-benzoylated]-pyrollidine derivatives; BSNPPC and BSHNPPC.