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Abstract #117002 Published in IGR 24-4
Discovery of Novel Pyridazine-Tethered Sulfonamides as Carbonic Anhydrase II Inhibitors for the Management of Glaucoma
Tawfik HO; Saleh MM; Ammara A; Khaleel EF; Badi R; Khater YTT; Rasheed RA; Attia AA; Hefny SM; Elkaeed EB; Nocentini A; Supuran CT; Eldehna WM; Shaldam MAJournal of Medicinal Chemistry 2024; 67: 1611-1623
As a progressive neuropathic condition, glaucoma can cause lifelong blindness if left untreated. Novel phenylpyridazine-tethered sulfonamides were designed as selective inhibitors for carbonic anhydrase (CA) isoform II to find effective therapeutic agents for glaucoma. Subsequently, the target inhibitors were synthesized and assessed for their inhibitory action against cytosolic CA I and II. Interestingly, the synthesized molecules poorly inhibited CA I while exhibiting low subnanomolar potency against CA II. Compound disclosed the most potent activity (IC = 0.63 nM) with high selectivity against CA II (605-fold than acetazolamide selectivity). Moreover, compound also showed significant in vivo IOP-reducing properties in the in vivo model of glaucoma. Furthermore, the binding of compound to CA II was assessed at the molecular level, exploiting the molecular docking approach.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
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