Click chemistry‐based synthesis of new benzenesulfonamide derivatives bearing triazole ring as selective carbonic anhydrase II inhibitors

Abstract

A series of 1,2,3‐triazol‐1‐ylbenzenesulfonamide derivatives was designed, synthesized and their ability to inhibit several carbonic anhydrase isoforms was evaluated. The basis of our design is to hybridize the benzenesulfonamide moiety widely used as a zinc‐binding group, a triazole ring as spacer with a tail of different substituted aryl moieties. The synthesis of these compounds was achieved using Cu(I)‐mediated click chemistry between the azide containing the benzenesulfonamide pharmacophore and various aryl acetylenes or 1,6‐heptadiyne through copper‐catalyzed [3+2] cycloaddition reaction. The ability the new derivatives to inhibit four human carbonic anhydrase isoforms hCA I, II, IX, and XII was evaluated. All the compounds exhibited good potency and high selectivity towards isoforms hCA I and II more than isoforms hCA IX and XII, especially for the derivatives 3c and 3j that displayed Ki of 2.8 and 3.8 nM against hCA II and a high hCA II selectivity ratio ranging from 77.6 to 3571.4 over other isoforms. All the compounds were docked in the active site of the downloaded hCA II active site and their binding pattern confirmed their significant activity by interacting of the sulfonamide moiety with zinc ion in the active site, in addition to its hydrogen bond interaction with Thr199 and Thr200. All the above‐mentioned findings pointed out towards the promising activity of the synthesized series that can be presented as a new scaffold to be further optimized as selective antiglaucoma drugs.

Selective carbonic anhydrase IX and XII inhibitors based around a functionalized coumarin scaffold

“…Catalyzed CO 2 hydration activity was evaluated using a photophysics stopped‐flow instrument using phenol red (0.2 mM) as an indicator and UV detection at 557 nm as previously described (Ewies et al, 2022). 4‐(2‐Hydroxyethyl)‐1‐piperazineethanesulfonic acid (20 mM, pH 7.5) was used as a buffer, and 20 mM Na 2 SO 4 to keep its ionic strength constant.…”

“…and UV detection at 557 nm as previously described (Ewies et al, 2022). 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid (20 mM, pH 7.5) was used as a buffer, and 20 mM Na 2 SO 4 to keep its ionic strength constant.…”

Click chemistry approaches for developing carbonic anhydrase inhibitors and their applications

“…Ewies et al. reported 10 exemples of 1,2,3‐triazol‐1‐yl-benzenesulfonamide derivatives ( Figure 3(B) ) with different aryl substitutions via CuAAC reaction, with all derivatives showing potent and selective inhibition towards the cytosolic hCA I and II compared to the tumour-associated hCA IX and XII 27 .…”

Dependence on linkers’ flexibility designed for benzenesulfonamides targeting discovery of novel hCA IX inhibitors as potent anticancer agents

“…The comprehensive procedures of in silico studies of the representative target sulphonamides Series I and II were presented in the Supplementary materials , including; molecular docking analysis 77 and MD simulations. 64 …”