2. Academic Validation
  3. 1,5-Diaryl-1,2,4-triazole Ureas as New SLC-0111 Analogues Endowed with Dual Carbonic Anhydrase and VEGFR-2 Inhibitory Activities

1,5-Diaryl-1,2,4-triazole Ureas as New SLC-0111 Analogues Endowed with Dual Carbonic Anhydrase and VEGFR-2 Inhibitory Activities

  • J Med Chem. 2023 Aug 10;66(15):10558-10578. doi: 10.1021/acs.jmedchem.3c00721.
Ahmed E Elsawi 1,  Mostafa M Elbadawi 1,  Alessio Nocentini 2,  Hadia Almahli 3,  Simone Giovannuzzi 2,  Moataz Shaldam 1,  Rofaida Salem 1,  Tamer M Ibrahim 1,  Hatem A Abdel-Aziz 4,  Claudiu T Supuran 2,  Wagdy M Eldehna 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
  • 2 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
  • 3 Department of Chemistry, University of Cambridge, Cambridge CB2 1TN, United Kingdom.
  • 4 Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt.
PMID: 37501287 DOI: 10.1021/acs.jmedchem.3c00721
Abstract

Presently, dual targeting by a single small molecule stands out as an effective cancer-fighting weapon. Carbonic Anhydrase (CA) and vascular-endothelial growth factor (VEGF) are hypoxia-activatable genes that are implicated in tumorigenesis and progression of hypoxic tumors at different levels. Herein, we designed and synthesized 30 1,5-diaryl-1,2,4-triazole-tethered sulfonamides (11a-f, 12a-l, 13a-f, 15a-f) as novel SLC-0111 analogues with dual CA IX/XII and VEGFR-2 inhibitory activities. The 4-fluorophenyl SLC-0111 tail was replaced by substituted 1,5-diaryl-1,2,4-triazoles. Changing the sulfamoyl motif position provided regioisomers 11a-f and 12a-l. Elongation of the ureido linker yielded derivatives 15a-f. Inhibitory evaluations included a panel of hCAs (hCA I, II, IX, and XII) and screening against 60 Cancer cell lines. Promising candidates were assessed for VEGFR-2 inhibition and selectivity and further evaluated on breast Cancer cell lines (MCF-7 and T-47D) and the non-tumorigenic (MCF-10A) cells. Molecular docking studies explored the binding modes of the sulfonamides against hCA IX/XII and VEGFR-2 kinase.

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