Novel Thiopyrano[2,3-]thiazole-pyrazole Hybrids as Potential Nonsulfonamide Human Carbonic Anhydrase IX and XII Inhibitors: Design, Synthesis, and Biochemical Studies.

In recent years, molecular hybridization strategies have developed into a potent strategy for drug discovery. A series of novel thiopyrano[2,3-]thiazoles linked to the pyrazole moiety was designed and developed as anticancer agents by a molecular hybridization. Target compounds were synthesized and characterized by spectroscopic tools as well as X-ray crystallography analysis as in the case of thiopyrano[2,3-]thiazole derivative . The MTT assay was used to demonstrate the efficacy of compounds - and - on MCF-7 and HePG-2. The results showed that some cycloadducts such as bromophenyl-4-thioxo-2-thiazolidinone , 4-methylphenyl derivative of thiopyrano[2,3-]thiazole , and 6-substituted-thiopyrano[2,3-]thiazoles - displayed good to excellent IC in the range of 10.08 ± 1.5 to 25.95 ± 2.8 μg/mL against the MCF-7 cell line and from 7.83 ±2.1 to 13.37 ± 1.2 μg/mL against the HePG-2 cell line. To explore the enzymatic tests for isozymes hCAIX and hCAXII, the most promising eight compounds , , and - with IC ranging from 7.83 ± 2.1 to 25.95 ± 2.8 μM were chosen. Compound exhibited an IC (0.067 ± 0.003 μM) similar to that of the standard drug AZA against CAIX (0.059 0.003 μM)). For CAXII, the compound had an IC equal to 0.123 ± 0.007 μM compared to that of AZA (0.083 0.005 μM). In addition, using flow cytometry, cell cycle analysis and apoptosis studies in HePG-2 were performed for the two potent anticancer and selective carbonic anhydrase agents ( and ). An enzymatic assay of these two compounds against caspase-9 was also examined. Interestingly, the molecular docking studies revealed that compounds and successfully embedded themselves in the active pockets of the CAIX and CAXII enzymes through different interactions. Overall, the novel thiopyrano[2,3-]thiazole-pyrazole hybrids ( and ) were suggested to be potent and selective inhibitors of CAIX and CAXII.