Novel Thiopyrano[2,3-d]thiazole-pyrazole Hybrids as Potential Nonsulfonamide Human Carbonic Anhydrase IX and XII Inhibitors: Design, Synthesis, and Biochemical Studies
Abstract
In recent years, molecular hybridization strategies have developed into a potent strategy for drug discovery. A series of novel thiopyrano[2,3-d]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-d]thiazole derivative 5a. The MTT assay was used to demonstrate the in vitro efficacy of compounds 5a–g and 7a–j on MCF-7 and HePG-2. The results showed that some cycloadducts such as bromophenyl-4-thioxo-2-thiazolidinone 3e, 4-methylphenyl derivative of thiopyrano[2,3-d]thiazole 5d, and 6-substituted-thiopyrano[2,3-d]thiazoles 7e–j displayed good to excellent IC50 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 3e, 5d, and 7e–j with IC50 ranging from 7.83 ± 2.1 to 25.95 ± 2.8 μM were chosen. Compound 7e exhibited an IC50 (0.067 ± 0.003 μM) similar to that of the standard drug AZA against CAIX (0.059 ± 0.003 μM)). For CAXII, the compound 7i had an IC50 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…
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