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

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Abstract

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.

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Acknowledgements

We are grateful for Professor Stig Linder, Karolinska Institute, Sweden, for kindly providing us with HCT116, MCF7, and RPE1 cell lines.

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  1. Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, 33 El Bohouth St. (former El Tahir St.)—Dokki, Giza, P.O. 12622, Egypt

    Alaaeldin M. F. Galal & Atef G. Hanna

  2. Drug Bioassay-Cell Culture Laboratory, Pharmacognosy Department, National Research Centre, Dokki, Giza, 12622, Egypt

    Walid Fayad

  3. Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, 33 El Bohouth St. (former El Tahir St.)—Dokki, Giza, P.O. 12622, Egypt

    Walaa S. A. Mettwally, Sanaa K. Gomaa & Heba A. El-Refai

  4. Confirmatory Diagnostic Unit, Vacsera, Giza, Egypt

    Esam R. Ahmed

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Galal, A.M.F., Fayad, W., Mettwally, W.S.A. et al. Cytotoxicity of multicellular cancer spheroids, antibacterial, and antifungal of selected sulfonamide derivatives coupled with a salicylamide and/or anisamide scaffold. Med Chem Res 28, 1425–1440 (2019). https://doi.org/10.1007/s00044-019-02382-w

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