Reactivity investigation of N-(phenylsulfonyl)acetamide derivatives with nitrogen nucleophiles to give the corresponding aminothiazole, aminooxazole, 2H-benzo[b][1,4]oxazin-3-yl, 2H-benzo[b][1,4]thiazin-3-yl, quinoxalin-2-yl, pyridin-4-ylamino, benzo[d]thiazol-2-ylthio and 1H-benzo[d]imidazol-2-ylthio derivatives; respectively. The sulphonamides were examined in vitro antimalarial activity and characterized their ADMET properties, with IC50 values of <30µ M. The synthesized sulfonamide had c-LogP values between 2 and (mean value 2.23) and MW(molecular weight) less than 400, and the common and didn’t exhibition cytotoxicity at the concentration confirmed. Sulphonamide 6a was equipped the excellent antimalarial activity through IC50=1.2µM with had the best selectivity index (9.0) due to the occurrence of quinoxaline moiety attached to the sulfonamide ring system. Additionally, the theoretical calculations of most active compounds 4a, 5c, and 6a exhibited that value of ∆ E so small which growth tendency of electron transfer from HOMO-LUMO energy gap due to existence of benzo[b][1,4]oxazin-3-yl,benzo[b][1,4]thiazin-3-yl and quinoxalin-2-yl rings attached to sulfonamide ring. Additionally, The molecular docking study of these synthesized compounds revealed small energy affinity against Plasmepsin-1 (PDBID:1j3i) and Plasmepsin-2 (PDBID:1n81) and shorter bond length. Also, the most active compounds 4a, 5c, and 6a were docked on main protease (SARS-CoV-2) (PDBID: 6lu7) and Spike Glycoprotein (SARS-CoV-2) (PDBID:6vxx) to calculate the binding energy of these fused heterocycles sulfonamides.