Carbonic Anhydrase Inhibitors With Strong Topical Antiglaucoma Properties Incorporating a 4-(2-amino-pyrimidin-4-yl-amino)-benzenesulfonamide Scaffold

Abstract

Reaction of 4-(2-amino-pyrimidin-4-yl-amino)-benzenesulfonamide with alkyl/aryl-sulfonyl halides, acyl halides or arysulfonyl isocyanates afforded a series of derivatives which were tested for inhibition of three carbonic anhydrase (CA) isozymes. These compounds were designed in such a way as to (i) strongly inhibit several CA isozymes involved in aqueous humor secretion within the eye (such as CA II and CA IV), and (ii) to possess a pharmacological profile that allows easy penetration through the cornea, when administered as eye drops in solution or suspension, constituting thus a valuable therapeutic approach for glaucoma. Several of the obtained inhibitors showed low nanomolar affinities for the two isozymes involved in aqueous humor secretion, CA II and CA IV. Furthermore, in normotensive and hypertensive rabbits, some of them showed an effective and prolonged intraocular pressure (IOP) lowering when administered topically, as 2% suspensions/solutions.

Purification of carbonic anhydrase-II from sheep liver and inhibitory effects of some heavy metals on enzyme activity

“…Inhibition effects of many substances such as medical drugs, various metals, anions and pesticides have been reported in the literature 20,22,35,36 . Many chemicals affect metabolism by changing normal enzyme activity, particularly inhibition of a specific enzyme 36,37 and the effects can be dramatic and systemic 38 . Hence, heavy metals have various toxicological effects on living organisms.…”

Investigation of the carbonic anhydrase inhibitory activity of benzenesulfonamides incorporating substituted fused‐pyrimidine tails

“…[ 32 ] Also, compound II (Figure 1) was reported to have potent CA II inhibitory activity ( K i = 1.0 nM) with promising antiglaucoma activity. [ 29 ] In addition, another series of quinazoline‐benzenesulfonamide conjugates was displayed as anticancer agents by targeting CA IX and CA XII. Compound III demonstrated a reduction in the expression level of CA XI and CA XII selectively in HT‐29 cells giving a potential antiproliferative effect.…”

“…[23][24][25][26][27][28] Therefore, they were selected to be hybridized with the classical benzenesulfonamides aiming at affording potent and selective CAIs. [29][30][31][32][33] For instance, a novel scaffold of CAIs as anticancer agents was designed based on a molecular hybridization between 5-fluorouracil which is a well-known thymidylate synthase inhibitor with the classical benzenesulfonamide moiety. [32] Compound I (Figure 1) is an example of the designed and synthesized compounds, it displayed potent CA IX inhibitory activity (K i of 1.90 nM).…”

Novel benzenesulfonamide‐thiouracil conjugates with a flexible N‐ethyl acetamide linker as selective CA IX and CA XII inhibitors

“…In this context, several studies reported the beneficial application of structural hybridization between the benzenesulfonamides as ZBGs and thiopyrimidine as a tail for the design and synthesis of novel selective CAIs. [25][26][27][28][29][30] For example, the authors recently adapted the molecular hybridization concept for the rational design of a series of selective CA II inhibitors based on benzenesulfonamide-thiopyrimidine scaffold. [31] Screening of the synthesized series against hCA I, hCA II, hCA IX, and hCA XII isozymes showed that the hybrids I and II exhibited potent and selective inhibition toward hCA II (K i = 40 nM) over the other isozymes with selectivity index (SI) up to 980 (Figure 1).…”