Rational drug design, synthesis, and biological evaluation of novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamides as potential antimalarial, antifungal, and antibacterial agents

Sulfanilamide, sulfadiazine, and dapsone were the first sulfonamides to be used to treat malaria by disrupting the folate biosynthesis process, which is essential for parasite survival. Therefore, we aimed to synthesize novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives through a rational drug design approach. All compounds were synthesized by the conventional method, and the products were characterized by spectral analysis ( 1 H NMR and mass spectrometry). The progression of the reaction was monitored using thin-layer chromatography (TLC). All the derivatives were analyzed for their effective binding mode in the allosteric site of the plasmodium cysteine protease falcipain-2. Antibacterial and antifungal activities were determined using the broth dilution method. S6 (N-(2-thiazol-4yl)-acetyl-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide and S9 (N-(1H-benzo[d]imidazol-2-yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide formed five hydrogen bonds; S8 (N-(2-1H-imidazol-2yl)aminophenyl) - 2,3-diphenylquinoxaline-6-sulfonamide and S10 (N-(1H-benzo[d]imidazol-5-yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide formed four hydrogen bonds with the allosteric site of the enzyme. Considering the docking scores and formation of hydrogen bonds with the target enzyme, the novel derivatives were processed for wet lab synthesis. All the newly synthesized derivatives were subjected to in vitro antimalarial, antifungal, and antibacterial activities. All the derivatives exhibited sufficient sensitivity to the Plasmodium falciparum strain compared to the standards. Moreover, compounds S9 and S10 showed the most potent dual antimicrobial and antimalarial activities. They also exhibited powerful molecular interactions in molecular docking studies. Based on the above results, it was concluded that N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives have excellent biological potential to act as antimalarial, antifungal, and antibacterial agents.