Carbonic Anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide involved in several biological processes. They show a wide diversity in tissue distribution and their subcellular localization. Twenty-two novel phthalazine derivatives were designed, synthesized, and evaluated against four human isoforms: hCA I, hCA II, hCA IX, and hCA XII. Compounds appeared to be very active mostly against hCA IX (7) and hCA I (6) isoforms being more potent than reference drug acetazolamide (AAZ). Some compounds appeared to be very selective with a selectivity index up to 13.8. Furthermore, docking was performed for some of these compounds on all isoforms to understand the possible interactions with the active site. Additionally, the most active compounds against hCA IX were subjected to cell viability assay. The anticancer activity of the compounds (3 a-d, 5 d, 5 i, and 5 m) was investigated using two human breast cancer cell lines, i. e. MCF-7 and MDA-MB-231 cells, and the normal counterpart, namely MCF10-A cells.
Keywords: carbonic anhydrase; docking; drug-likeness; sulfonamides; triazolophthalazines.
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