Synthesis of bulky-tailed sulfonamides incorporating pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-1(5H)-yl) moieties and evaluation of their carbonic anhydrases I, II, IV and IX inhibitory effects

Authors

Mohamed Fares, University of Wollongong, Egyptian Russian UniversityFollow
Radwa A. Eladwy, Egyptian Russian University
Alessio Nocentini, Universita Degli Studi Di Firenze, University of Florence
Soha El Hadi, Egyptian Russian University
Hazem A. Ghabbour, King Saud University, University of Mansoura
Ashraf Mostafa Kamal Abdel-Megeed, Assiut UniversityFollow
Wagdy M. Eldehna, Kafrelsheikh University
Hatem A. Abdel-Aziz, National Research Center, Egypt
Claudiu Supuran, University of Florence

RIS ID

112822

Publication Details

Fares, M., Eladwy, R., Nocentini, A., El Hadi, S., Ghabbour, H., Abdel-Megeed, A., Eldehna, W., Abdel-Aziz, H. & Supuran, C. (2017). Synthesis of bulky-tailed sulfonamides incorporating pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-1(5H)-yl) moieties and evaluation of their carbonic anhydrases I, II, IV and IX inhibitory effects. Bioorganic and Medicinal Chemistry, 25 (7), 2210-2217.

Abstract

Using celecoxib as lead, two novel series of sulfonamides incorporating the pyridotriazolopyrimidine scaffold have been synthesized and evaluated in vitro as inhibitors against four relevant human (h) carbonic anhydrases (CAs, EC 4.2.1.1), the cytosolic and ubiquitous hCA I and II as well as the transmembrane hCA IV and hCA IX. Most of the reported sulfonamides acted as efficient, low micromolar inhibitors of hCAI, II and IV, whereas they displayed higher efficacy in inhibiting the tumor-associated isoform hCA IX. Many derivates herein reported showed better hCA IX versus hCA II selectivity ratios compared to celecoxib or acetazolamide. Considering isoform IX is a validated target for the diagnosis and treatment of hypoxic tumors, discovery of selective CA IX inhibitors represents a promising step to unveil more effective anticancer therapies.