Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Tri-Aryl Imidazole-Benzene Sulfonamide Hybrids as Promising Selective Carbonic Anhydrase IX and XII Inhibitors
oleh: Lamya H. Al-Wahaibi, Bahaa G. M. Youssif, Ehab S. Taher, Ahmed H. Abdelazeem, Antar A. Abdelhamid, Adel A. Marzouk
| Format: | Article |
|---|---|
| Diterbitkan: | MDPI AG 2021-08-01 |
Deskripsi
A novel series of tri-aryl imidazole derivatives <b>5a</b>–<b>n</b> carrying benzene sulfonamide moiety has been designed for their selective inhibitory against hCA <b>IX</b> and <b>XII</b> activity. Six compounds were found to be potent and selective CA IX inhibitors with the order of <b>5g</b> > <b>5b</b> > <b>5d</b> > <b>5e</b> > <b>5g</b> > <b>5n</b> (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 <b>5g</b> and <b>5b</b> demonstrated higher antiproliferative activity than other tested compounds (with GI<sub>50</sub> = 2.3 and 2.8 M, respectively) in comparison to doxorubicin (GI<sub>50</sub> = 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 <b>9FK</b>. Molecular modelling simulation showed good agreement with the acquired biological evaluation.