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  3. Triazole-functionalized benzofuran and benzothiophene semicarbazides as novel VEGFR-2-targeted anti-cancer agents

Triazole-functionalized benzofuran and benzothiophene semicarbazides as novel VEGFR-2-targeted anti-cancer agents

  • Bioorg Chem. 2025 Jun 22:163:108702. doi: 10.1016/j.bioorg.2025.108702.
Mohamed S Nafie 1,  Mariam I Youssef 2,  Anwar A El-Hamaky 3,  Zainab M Elsayed 2,  Eman F Khaleel 4,  Eslam Roshdy 5,  Mohammad M Al-Sanea 6,  Mostafa M Elbadawi 7,  Manabu Abe 8,  Wagdy M Eldehna 9,  Hatem A Abdel-Aziz 10,  Haytham O Tawfik 11
Affiliations

Affiliations

  • 1 Department of Chemistry, College of Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.
  • 2 Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
  • 4 Department of Medical Physiology, College of Medicine, King Khalid University, Asir 61421, Saudi Arabia.
  • 5 Department of Chemistry, Graduate School of Advanced Science and Engineering, Hiroshima University, Higashi-Hiroshima City, Hiroshima 739-8526, Japan; Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
  • 6 Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72388, Saudi Arabia. Electronic address: malsanea@ju.edu.sa.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
  • 8 Department of Chemistry, Graduate School of Advanced Science and Engineering, Hiroshima University, Higashi-Hiroshima City, Hiroshima 739-8526, Japan.
  • 9 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt. Electronic address: wagdy2000@gmail.com.
  • 10 Applied Organic Chemistry Department, National Research Center, Dokki, Cairo 12622, Egypt.
  • 11 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt. Electronic address: haytham.omar.mahmoud@pharm.tanta.edu.eg.
PMID: 40561649 DOI: 10.1016/j.bioorg.2025.108702
Abstract

Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) plays a crucial role in tumor angiogenesis, which makes it a prime target for anti-cancer therapies. Developing novel small molecules targeting VEGFR-2 and angiogenesis is essential to expand the therapeutic arsenal for Cancer treatment. In this work, we designed, synthesized, and evaluated two series of triazole-based benzofuran and benzothiophene semicarbazides 9a-h and 12a-h, demonstrating their potential as promising VEGFR-2 inhibitors. Compounds 12g exhibited remarkable cytotoxicity against A549 and MCF-7 Cancer cells with IC50 values of 0.43 μM and 3.8 μM, respectively. Interestingly, compound 12g exhibited potent VEGFR-2 inhibition with an IC50 value of 18.04 nM, causing inhibition of 92.3 % compared to sorafenib (IC50 = 9.8 nM, 96.1 % inhibition). Compound 12g activated apoptotic lung Cancer cell death, increasing total Apoptosis by 23.12 % (19.21 % for early and 3.91 % for late) compared to control 0.68 % (0.57 % for early and 0.11 % for late), so it induced total Apoptosis by 34-fold, arresting the cell proliferation as the G1-phase. Furthermore, compound 12g treatment affected the gene expression levels of the apoptosis-related genes, confirming the Apoptosis induction. Unveiling molecular docking and dynamics, compound 12g exhibits remarkable interactions within the VEGFR-2 binding pocket.

Keywords

Anti-lung cancer; Apoptosis; In silico studies; Semicarbazides; VEGFR-2 kinase inhibition.

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