1. Novel 3-substituted coumarins as selective human carbonic anhydrase IX and XII inhibitors: Synthesis, biological and molecular dynamics analysis.
- Author
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Abdelrahman MA, Ibrahim HS, Nocentini A, Eldehna WM, Bonardi A, Abdel-Aziz HA, Gratteri P, Abou-Seri SM, and Supuran CT
- Subjects
- Carbonic Anhydrase IX antagonists & inhibitors, Humans, Molecular Docking Simulation, Molecular Dynamics Simulation, Structure-Activity Relationship, Antigens, Neoplasm metabolism, Carbonic Anhydrase IX metabolism, Carbonic Anhydrase Inhibitors chemistry, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrases metabolism, Coumarins chemistry, Coumarins pharmacology
- Abstract
In this study, diverse series of coumarin derivatives were developed as potential carbonic anhydrase inhibitors (CAIs). A "tail" approach was adopted by selecting the coumarin motif as a tail that is connected to the ZBG benzenesulfonamide moiety via a hydrazine (4a,b) or hydrazide (5a,b) linker. Thereafter, an aryl sulfone tail was incorporated to afford the dual tailed coumarin-sulfonamide arylsulfonehydrazones (13a-d) and hydrazides (14a,b). Then, the ZBG were removed from compounds 13 and 14 to furnish coumarin arylsulfonehydrazones (11a-d) and hydrazides (12a,b). Coumarin-sulfonamides 4 and 5 emerged as non-selective CAIs as they displayed good inhibitory activities toward all the examined CA isozymes (I, II, IX and XII) in the nanomolar ranges. Interestingly, the "dual-tail" approach (compounds 13 and 14) succeeded in achieving a good activity and selectivity toward CA IX/XII over the physiologically dominant CA I/II. In particular, compounds 13d and 14a were the most selective coumarin-sulfonamide counterparts. Concerning non-sulfonamide coumarin derivatives, coumarins 8 exhibited excellent activity and selectivity profiles against the target hCA IX/XII, whereas, coumarins 11 and 12 reported excellent selectivity profile, but they barely inhibited hCA IX/XII with K
I s spanning in the micromolar ranges. Furthermore, molecular modelling studies were applied to get a deep focus about the feasible affinities and binding interactions for target coumarin-sulfonamides 4, 5, 13 and 14 with the active site for CA II, IX and XII isoforms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)- Published
- 2021
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