2. Academic Validation
  3. Click-modifiable isatin hydrazones as COX-2, VEGFR-2, and carbonic anhydrase inhibitors: A multi-target approach to cancer therapy

Click-modifiable isatin hydrazones as COX-2, VEGFR-2, and carbonic anhydrase inhibitors: A multi-target approach to cancer therapy

  • Eur J Med Chem. 2026 Jan 15;302(Pt 1):118304. doi: 10.1016/j.ejmech.2025.118304.
Maryam A Z El-Attar 1,  Ola S Afifi 1,  Azza Ismail 1,  Yasmine N Kamel 2,  Hend A Yassin 2,  Hanan Mohamed Nomeir 2,  Hisham A Nematalla 3,  Andrea Angeli 4,  Hala F Labib 5,  Wagdy M Eldehna 6,  Claudiu T Supuran 7,  Ahmed S F Belal 8,  Perihan A Elzahhar 9,  Nayera W Hassan 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
  • 2 Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, 21131, Egypt.
  • 3 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, 22516, Egypt; Faculty of Pharmacy and the Research & Innovation Hub, Alamein International University, Alamein, 51718, Egypt.
  • 4 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, 50019, Firenze, Italy.
  • 5 Department of Pharmaceutical Chemistry, College of Pharmacy, Arab Academy for Science, Technology and Maritime Transport, Alamein, Egypt.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, P.O. Box 33516, Kafrelsheikh, Egypt. Electronic address: [email protected].
  • 7 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, 50019, Firenze, Italy. Electronic address: [email protected].
  • 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address: [email protected].
  • 9 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address: [email protected].
PMID: 41166765 DOI: 10.1016/j.ejmech.2025.118304
Abstract

In pursuit of novel therapeutic strategies for complex multifactorial diseases such as Cancer, a set of isatin hydrazone/1,2,3-triazole hybrids was rationally designed and synthesized to target multiple cancer-related pathways, including COX-2, VEGFR-2, and tumor-associated carbonic anhydrases (CA IX and XII). In vitro COX-2 inhibition assays revealed eight hybrids with nanomolar potency (IC50 = 50-90 nM), comparable to celecoxib, with compounds 5h and 5j exhibiting comparable selectivity indices to celecoxib. For VEGFR-2 inhibition, compound 5f surpassed sunitinib (IC50 = 64 vs. 92 nM), while 5j retained ∼75 % of its activity. Compounds 5f, 5j, and 5l were potent and selective inhibitors of hCA IX (Kᵢ = 27.3-37.2 nM). Cytotoxicity screening identified 5h and 5j as the most active against MCF7, A549, Caco-2, and MDA-MB-231 cell lines (IC50 = 1.3-12.49 μM) with good safety in normal WI-38 cells. Mechanistic studies on 5j indicated cell cycle arrest and Apoptosis induction via upregulation of Caspase-9 and Bax and downregulation of Bcl-2. Compound 5j was also subjected to additional cell-based evaluations, including wound-healing, cell viability assays under hypoxic conditions, and PGE2 quantification, which further supported its multi-target profile. The in vitro human plasma stability of compound 5j was confirmed, exhibiting a half-life (t1/2) of approximately 7 h. In vivo, 5j significantly reduced tumor growth in an MDA-MB-231 xenograft model, comparable to 5-FU. Docking simulations confirmed favorable interactions with COX-2, VEGFR-2, and hCA IX, supporting the observed biological activities.

Keywords

1,2,3-triazole; Apoptosis; COX-2; Cancer; Carbonic anhydrases; Isatin hydrazone; VEGFR-2.

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