Abstract
Dual-tail strategy has been successfully utilized in the development of novel carbonic anhydrase IX (CA IX) inhibitors. Herein we adopted this approach in the design and synthesis of a series of novel pyridine sulfonamide-pyrazole hybrid scaffold mimicking dual-tail inhibitors of CA IX. A library of 15 compounds was synthesized and assessed for their potential cytotoxic effects against colorectal cancer cells. Compounds 3, and 11 induced potential cytotoxic effects against the three cancer cell lines (HCT-116, HT-29, and SW-620) with IC50s' of 45.88, 28.27, and 16.57 uM, 25.01, 8.99, and 3.27 µM, respectively. Both compounds induced cellular apoptosis on HCT-116 and SW-620 cells, while compound 3 induced necrosis as well. In addition, both compounds induced cell cycle arrest on G0/G1, and S phases. Also, compound 11 showed potential autophagy induction on both colon cancer cell lines (HCT-116, and HT-29), and a little bit on metastatic type. Both compounds were less cytotoxic than the reference drug on normal epithelial cell. The migration rates of HCT-116 and the metastatic one SW-620 were reduced by both compounds. Finally, molecular docking of compounds 3 and 11 into the active site of CA IX confirmed in vitro inhibitory activity for both compounds.