Design, in silico study, synthesis and cytotoxic evaluation of new isatin-thiazole-sulfanilamide derivatives as potential carbonic anhydrase inhibitors

Abstract

One of the promising strategies in treatment of cancer is inhibiting the overexpression of carbonic anhydrase enzyme. This target represents a viable target for cancer therapy. In order to do this, four new compounds containing sulfonamide were prepared and manufactured utilizing different isatin derivatives. To choose the most appropriate compounds with the greatest S score prior to their production, docking research was carried out using MOE software (Molecular Operating Environment). Furthermore, the synthesis process involved the preparation of Schiff base derivatives by condensation of ketone (isatin and its derivatives) with 4-amino ethyl benzoate using Glacial acetic acid, then these derivatives combined with 4-aminobenzene sulfonamide to synthesize the final product (sulfonamide-containing isatin derivatives, compound A1-A3).
In order to evaluate how well the synthesized compounds could fight cancer, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test was used. The results of the assay revealed that the compound A2 demonstrated the greatest cytotoxic action against cancer cells within the group IC50=9.95 μM in MCF-7 and 135.18 μM in MCF10A. Whereas, compound A1 displayed the least amount of cytotoxicity IC50=16.30 μM in MCF-7 and 291.98 μM in MCF10A. In comparison with acetazolamide IC50=19.71 μM in MCF-7 and 67.53 μM in MCF10A, these results demonstrate that these chemicals' potential as subjects for additional research in the realm of cancer therapies.
As mentioned before, this study aimed to design and synthesis of new compounds A1-A3, which have isatin-thiazole-sulfanilamide derivatives and then evaluate the cytotoxic activity of these compunds. The synthesized compounds demonstrated significant inhibition of carbonic anhydrase IX activity through molecular docking and significant inhibition of cancer cell viability. Compounds A1-A3 have (IC50 16.30μM, 9.95 μM, 15.44 μM) respectively for MCF7 which is better than IC50 for acetazolamide which is 19.71 μM. Additionally they show higher selectivity toward cancer cells than normal cells. Additionally, compounds A1-A3 have S scores in docking studies higher than acetazolamide so they possess a higher affinity for binding to the receptor's active pocket. Flexibility and receptor interaction are enhanced by the substituted thiazole ring and isatin. In conclusion, the synthesized derivatives have a valuable cytotoxic activity against cancer cell, accordingly this enhance the ability to inhibit cancer growth.