Abstract
A novel series of tri-aryl imidazole derivatives 5a–n carrying benzene sulfonamide moiety has been designed for their selective inhibitory against hCA IX and XII activity. Six compounds were found to be potent and selective CA IX inhibitors with the order of 5g > 5b > 5d > 5e > 5g > 5n (Ki = 0.3–1.3 μM, and selectivity ratio for hCA IX over hCA XII = 5–12) relative to acetazolamide (Ki = 0.03 μM, and selectivity ratio for hCA IX over hCA XII = 0.20). The previous sixth inhibitors have been further investigated for their anti-proliferative activity against four different cancer cell lines using MTT assay. Compounds 5g and 5b demonstrated higher antiproliferative activity than other tested compounds (with GI50 = 2.3 and 2.8 M, respectively) in comparison to doxorubicin (GI50 = 1.1 M). Docking studies of these two compounds adopted orientation and binding interactions with a higher liability to enter the active side pocket CA-IX selectively similar to that of ligand 9FK. Molecular modelling simulation showed good agreement with the acquired biological evaluation.
Highlights
Carbonic anhydrases (CAs) are metalloenzymes that catalyze the reversible hydration of CO2 into protons and bicarbonate [1]
In the 1H NMR spectra of chemical 5i (Ar = 3,4-dimethoxyphenyl), two singlet signals were common for methoxy groups: one at 3.52 ppm (OCH3) and the second at 3.76 ppm (OCH3) protons, as well as a doublet signal at 7.77–7.79 of 2H associated to NH2 of the sulfonamide moiety
Results displayed that our targets 5a–n had selective inhibition of hCA IX and XII in comparable with hCA I and II in the micromolar range
Summary
Carbonic anhydrases (CAs) are metalloenzymes that catalyze the reversible hydration of CO2 into protons and bicarbonate [1]. There are 16 different mammalian—CA isoforms recognized, including human isoforms [4] These CAs. Molecules 2021, 26, 4718 diseases such as glaucoma, obesity, osteoporosis, and cancer [2,3]. The aryl imidazole scaffold has gained recognition as a helpful and promising scaffold for the design and development of effective CA inhibitors. Molecules 2021, 26, 4718 In recent years, the aryl imidazole scaffold has gained recognition as a helpful and promising scaffold for the design and development of effective CA inhibitors. The synthesis and biological evaluation of novel 4-phenyl-imidazol-2(3H)-one derivatives as CA inhibitors were described by Congiu et al [17], (Compound I, Figure 1). The inhibitory activities of the newly synthesized 5a–n against hCAs could serve as a preliminary study for future biological studies on these new scaffolds
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