Cytotoxicity of multicellular cancer spheroids, antibacterial, and antifungal of selected sulfonamide derivatives coupled with a salicylamide and/or anisamide scaffold

In an attempt to overcome the drawbacks of the cancer monolayers model (2D), the 3-dimensional (3D) multicellular cancer spheroids (MCS) have been developed. Nine of most active sulfonamide derivatives coupled with a salicylamide scaffold were screened for cytotoxicity on two human cancer cell line spheroids (MCF7 and HCT116) in addition to one human normal cell line spheroid (RPE-1). 5-Chloro-N-[(N-4-chlorophenyl) 4-sulfamoylbenzyl] salicylamide (9) was found to be the most active compound among all tested compounds. It showed 70% inhibition on HCT116 spheroids, almost double the activity of cisplatin, and higher activity than cisplatin on MCF7 spheroids. Also, 5-chloro-N-[(N-benzyl) 4-sulfamoylbenzyl] salicylamide (18) and 5-chloro-N-[(N-2-phenylethyl) 4-sulfamoylbenzyl] salicylamide (19) showed cytotoxicity against HCT116 slightly lower than that of cisplatin (32% and 31%, respectively) but with much lower cytotoxicity against the normal cell (4% and 10% vs. 39%, respectively). Based on in silico virtual screening against DHPS enzyme, some sulfonamide derivatives coupled with a salicylamide and/or anisamide scaffold were tested in vitro against four bacterial and fungal pathogens. 5-Chloro-N-[(N-2-nitro-4-methylphenyl) 4-sulfamoylbenzyl] salicylamide (17) and 5-chloro-N-[(N-2-nitro-4-methylphenyl) 4-sulfamoylbenzyl] anisamide (5) showed strong antifungal activity on the tested organism, while the first one (17) have the strongest antibacterial activity against the G +ve and G −ve bacterium. In vitro, dihydropterate synthase (DHPS) enzyme assay showed that, compounds 5 and 17 effectively inhibit dihydropterate synthase (DHPS) enzyme by 93.78% and 95.15%, respectively, while miconazole inhibit the enzyme with only 87.50%. In addition, their effect upon amylase, lipase and protease enzymes was reported. The most active compounds 5, 9, 17–19 could be subjected to in vivo investigation as new drugs.