2. Academic Validation
  3. Identification of isatin-triazole-benzenesulfonamide hybrids as dual hCA IX/XII and c-met inhibitors with hypoxia-mediated chemo-sensitizing activity

Identification of isatin-triazole-benzenesulfonamide hybrids as dual hCA IX/XII and c-met inhibitors with hypoxia-mediated chemo-sensitizing activity

  • Bioorg Chem. 2025 Nov:166:109071. doi: 10.1016/j.bioorg.2025.109071.
Wagdy M Eldehna 1,  Mohamed R Elnagar 2,  Simone Giovannuzzi 3,  Amr Tayel 4,  Maha-Hamadien Abdulla 5,  Noura S Alhassan 6,  Moataz A Shaldam 7,  Alessio Nocentini 3,  Claudiu T Supuran 3,  Haytham O Tawfik 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt. Electronic address: wagdy2000@gmail.com.
  • 2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11823, Egypt; Department of Pharmacology, College of Pharmacy, The Islamic University, Najaf 54001, Iraq.
  • 3 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
  • 4 Department of Chemistry, The American University in Cairo, AUC Avenue, New Cairo 11835, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alsalam University in Egypt, Tanta 31712, Egypt.
  • 5 Colorectal Research Chair, Department of Surgery, College of Medicine, King Saud University, Riyadh 11472, Saudi Arabia. Electronic address: mabdulla@ksu.edu.sa.
  • 6 Colorectal Research Chair, Department of Surgery, College of Medicine, King Saud University, Riyadh 11472, Saudi Arabia.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
  • 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt. Electronic address: haytham.omar.mahmoud@pharm.tanta.edu.eg.
PMID: 41075616 DOI: 10.1016/j.bioorg.2025.109071
Abstract

One of the main factors contributing to treatment resistance and a poor prognosis in colorectal Cancer is hypoxia. Eleven isatin-based hybrids comprising 1,2,3-triazole and benzenesulfonamide fragments (5a-f and 7a-e) were logically designed and synthesized in this study to investigate their dual inhibitory potential against carbonic anhydrases IX and XII (CA IX/XII) and receptor tyrosine kinase c-Met, two hypoxia-related targets. Strong nanomolar inhibition of CA IX/XII and sub-micromolar to low-micromolar inhibition of c-Met were shown by a number of drugs (5c, 5d, 5e, 5f, and 7e). Compound 5d had the highest activity (IC₅₀ = 1.57 μM under hypoxia vs. 9.57 μM under normoxia), according to a subsequent cytotoxicity assay in HCT-116 colorectal Cancer cells, which showed improved potency of all lead compounds under hypoxic conditions. In the cell lines HT-29 and SW-620, the better profile of 5d was further validated. Mechanistic investigations revealed that 5d triggered Apoptosis and caused G₂/M phase arrest, confirming its function in hypoxia-driven cytotoxicity. Additionally, in hypoxic conditions, 5d significantly increased the effectiveness of 5-fluorouracil (5-FU) and oxaliplatin (OXP), increasing its potency by more than 10 times. Positive pharmacokinetic and drug-like characteristics were validated through in silico ADME profiling. Molecular docking investigations revealed that 5d exhibited strong binding interactions within the c-Met and CA IX/XII active sites. Compound 5d could be a promising dual-targeting option for overcoming hypoxia-associated resistance in colorectal Cancer, as indicated by these data.

Keywords

Chemosensitization; Colon Cancer; Docking; Dual CA IX and c-met inhibitors; HIF-1α; Hypoxia.

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