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

Funding Sponsor

King Saud University

Fourth Author's Department

Chemistry Department

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https://doi.org/10.1016/j.bioorg.2025.109071

All Authors

Wagdy M. Eldehna Mohamed R. Elnagar Simone Giovannuzzi Amr Tayel Maha Hamadien Abdulla Noura S. Alhassan Moataz A. Shaldam Alessio Nocentini Claudiu T. Supuran Haytham O. Tawfik

Document Type

Research Article

Publication Title

Bioorganic Chemistry

Publication Date

11-1-2025

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.

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