1,5‐Benzodiazepines as a platform for the design of carbonic anhydrase inhibitors

Abstract

A series of novel N-triazolo-benzene sulfonamides-1,5-benzodiazepines 9a-d and 10dwere designed and prepared through the copper-catalyzed azide alkyne cycloaddition click chemistry procedure, reacting the N 1 -propargyl-1,5-benzodiazepine 2 and the N 1 ,N 5 -dipropargyl analog 6 with various benzene sulfonamide azides 8a-d. The synthesized compounds were found to show nanomolar affinity toward relevant isoforms of human carbonic anhydrase such as hCA I, II, IV, VII, IX, and XII. The divalent derivative 10d showed a particularly high inhibitory activity against all hCA isoforms when compared with acetazolamide, and showed potent multivalent effects, better than reported previously for divalent CA inhibitors.

Click chemistry approaches for developing carbonic anhydrase inhibitors and their applications

“…Ismail et al. described the synthesis of novel N ‐triazolo‐benzene sulphonamides‐1,5‐benzodiazepines 15, 16 ( Figure 3(A) ) via CuAAC reaction and investigated them against six human isoforms (hCA I, II, IV, VII, IX and XII) 26 . Interestingly, the divalent inhibitor 15 was found to be the most effective inhibitor against these six isoforms compared to the monovalent derivatives 16.…”

Bambus[4,6]urils as Dual Scaffolds for Multivalent Iminosugar Presentation and Ion Transport: Access to Unprecedented Glycosidase-Directed Anion Caging Agents

“…Multivalent drugs on nanoparticles also proved efficient for escaping efflux pumps [ 30 ]. Originally discovered with glycosidases [ 15 , 16 , 17 , 18 , 19 , 20 ], the inhibitory multivalent effect has been generalized to other enzymes such as glycosyltransferases and carbonic anhydrases [ 31 , 32 , 33 , 34 ]. In the case of enzyme inhibition, multivalent inhibitors may interact with enzymes by numerous mechanisms, such as the bind-and-recapture process, the chelate effect or receptor clustering [ 15 , 16 , 17 , 18 , 19 , 20 , 35 ].…”