2. Academic Validation
  3. Discovery of Novel Pyridazine-Tethered Sulfonamides as Carbonic Anhydrase II Inhibitors for the Management of Glaucoma

Discovery of Novel Pyridazine-Tethered Sulfonamides as Carbonic Anhydrase II Inhibitors for the Management of Glaucoma

  • J Med Chem. 2024 Jan 25;67(2):1611-1623. doi: 10.1021/acs.jmedchem.3c02279.
Haytham O Tawfik 1,  Mohamed M Saleh 1,  Andrea Ammara 2,  Eman F Khaleel 3,  Rehab Badi 3,  Yomna T T Khater 4,  Rabab A Rasheed 5,  Ahmed A Attia 6,  Salma M Hefny 1,  Eslam B Elkaeed 7 8,  Alessio Nocentini 2,  Claudiu T Supuran 2,  Wagdy M Eldehna 9,  Moataz A Shaldam 9
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
  • 2 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino 50019, Firenze, Italy.
  • 3 Department of Medical Physiology, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia.
  • 4 Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
  • 5 Department of Medical Histology and Cell Biology, Faculty of Medicine, King Salman International University, South Sinai 46511, Egypt.
  • 6 Mansoura Ophthalmic Center, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
  • 7 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
  • 8 Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh 13713, Saudi Arabia.
  • 9 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, P.O. Box 33516, Kafrelsheikh 33516, Egypt.
PMID: 38207099 DOI: 10.1021/acs.jmedchem.3c02279
Abstract

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 7c disclosed the most potent activity (IC50 = 0.63 nM) with high selectivity against CA II (605-fold than acetazolamide selectivity). Moreover, compound 7c also showed significant in vivo IOP-reducing properties in the in vivo model of glaucoma. Furthermore, the binding of compound 7c to CA II was assessed at the molecular level, exploiting the molecular docking approach.

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