Carbonic Anhydrase Inhibitors Developed Through ‘Click Tailing’

Abstract

In recent years there has been renewed activity in the literature concerning the 1,3-dipolar cycloaddition reaction (1,3-DCR) of organic azides (R-N₃) with alkynes (R'-C≡CH) to form 1,2,3-triazoles, i.e. the Huisgen synthesis. The use of catalytic Cu(I) leads to a dramatic rate enhancement (up to 10(7)-fold) and exclusive synthesis of the 1,4-disubstituted 1,2,3-triazole product. The reaction, now referred to as the copper-catalyzed azide-alkyne cycloaddition (CuAAC), meets the stringent criteria of a click-reaction in that it is modular, wide in scope, high yielding, has no byproducts, operates in water at ambient temperature, product purification is simple and the starting materials are readily available. The 1,3-DCR reaction has rapidly become the premier click chemistry reaction with applications spanning modern chemistry disciplines, including medicinal chemistry. Recently the 'tail' approach initiative for the development of carbonic anhydrase inhibitors (CAIs) has been combined with the synthetic versatility of click chemistry. This has proven a powerful combination leading to the synthesis of CAIs with useful biopharmaceutical properties and activities. This review will discuss complementary and contrasting applications that have utilized 'click tailing' for the development of CAIs. Applications encompass i) medicinal chemistry and drug discovery; ii) radiopharmaceutical development of positron emission topography (PET) chemical probes; and iii) in situ click chemistry.

Saccharin: A lead compound for structure-based drug design of carbonic anhydrase IX inhibitors

“…Specifically, compound 1 consists of the SAC pharmacophore as the ZBG, a 1,2,3-triazole linker group and a glucose tail moiety (Figure 2B). The use of this arrangement has been previously shown to selectively target CA IX via preferential inhibition and physiochemical attributes 12,19,22 .…”

Structural Mapping of Anion Inhibitors to β‐Carbonic Anhydrase psCA3 from Pseudomonas aeruginosa

“…This mapping of regions revealed a selective valley that could be targeted for the development of β‐CA selective inhibitors (Figure , inset). Based on the distances of this pocket, the tail approach could be used; which consists of a zinc‐binding group, a linker tail group, and a tail chemical moiety to extend and bind within the selective cleft. By using this method, the drugs developed would increase the specificity of inhibition toward psCA3 β‐CA and limit binding to β‐CAs that may be important to the bacteria flora of the human gut.…”

Inhibition studies on a panel of human carbonic anhydrases withN1-substituted secondary sulfonamides incorporating thiazolinone or imidazolone-indole tails

“…The previously accepted idea 8 that only primary sulfonamides may act as effective inhibitors has been shown to be incorrect, but only few modifications were carried out on the sulfonamide moiety 1 a, in comparison to the high number of tails appended at the aromatic ring incorporating this ZGB 6 , 3 , 9 , 10 . The rational of this choice could be that of not losing the ideal features of primary sulfonamides, i.e.…”