Nitroimidazole-sulfonamides as carbonic anhydrase IX and XII inhibitors targeting tumor hypoxia: Design, synthesis, molecular docking and molecular dynamics simulation

Abstract

In the present investigation, we focused on the development of dual drugs able to inhibit carbonic anhydrase enzyme (CA) by harboring sulfonamide group and to increase the sensitivity of hypoxic tumors to radio and chemotherapies by incorporating 5-nitroimidazole scaffold. The synthesized compounds were evaluated as cytotoxic agents under oxic and hypoxic conditions against three cell lines including human colorectal carcinoma (HCT116), epithelioid carcinoma (Hela), and mammary gland carcinoma (MCF-7) cells. Compounds 13a and 15a,b exhibited the highest cytotoxic activity against the three cell lines under both oxic (IC50 = 6.18 - 23.06 µM) and hypoxic (IC50 = 5.63 - 19.78 µM) conditions. The capability of compounds 13a and 15b to augment the lethal effect of ɤ-irradiation was evaluated. Both compounds increased the sensitivity of cancerous HCT116 cells to the cell-killing effect of ionizing radiation (IC50 = 4.18 and 2.53 µM, respectively). Sulfonamide derivatives 13a,b, 15a,b, and 17a,b were evaluated for their inhibitory effect against the tumor-associated hCA IX and XII isoforms in comparison to acetazolamide. Molecular docking and molecular dynamics simulation were performed for some sulfonamides on isoforms hCA IX and XII to understand the elements governing the inhibitory effect and the stability of interaction under dynamic conditions.