Dual VEGFR-2 and EGFRT790M inhibitors of phenyldiazenes: anticancer evaluations, ADMET, docking, design and synthesis

  • Future Med Chem. 2025 Feb;17(3):287-300. doi: 10.1080/17568919.2025.2453409.
Marwa Alsulaimany  1 ,  Ahmed K B Aljohani  2 ,  Nour E A Abd El-Sattar  3  4 ,  Sara A Almadani  5 ,  Omar M Alatawi  6 ,  Hussam Y Alharbi  7 ,  Majed S Aljohani  7 ,  Adel H Al-Shareef  8 ,  Read Alghamdi  2 ,  Saeed M Tayeb  9 ,  Doaa E Keshek  10  11 ,  Khaled El-Adl  12  13 ,  Kurls E Anwer  3
Affiliations
  • 1. Department of Pharmacognosy & Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Medina, Saudi Arabia.
  • 2. Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia.
  • 3. Department of Chemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.
  • 4. Basic & Medical Sciences Department, Faculty of Dentistry, Alryada University for Science & Technology, Sadat City, Egypt.
  • 5. Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Medina, Saudi Arabia.
  • 6. Department of Chemistry, Faculty of Science, University of Tabuk, Tabuk, Saudi Arabia.
  • 7. Department of Chemistry, Faculty of Science, Taibah University, Yanbu, Saudi Arabia.
  • 8. Department of Chemistry, College of Science, University of Jeddah, Jeddah, Saudi Arabia.
  • 9. Department of Pharmaceutical Science, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
  • 10. Department of biology, Al-Jumum College University, Umm Al-Qura University, Makkah, Sudia Arabia.
  • 11. Agriculture Genetic Engineering Research Institute (AGERI), Agriculture Research Centre, Giza, Egypt.
  • 12. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt.
  • 13. Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Egypt.
PMID: 39819342 DOI: 10.1080/17568919.2025.2453409
Abstract

Aim: New phenyldiazene scaffold-linked heterocyclic pyrazole, pyrimidinone, pyrimidinthione, and/or triazine rings have been developed and synthesized.

Methods & results: Cytotoxicity of our derivatives was estimated on four Cancer and VERO normal cell lines targeting EGFRT790M (epidermal growth factor receptor) and VEGFR-2 (vascular endothelial growth factor receptor-2) Enzymes. Our new derivatives selectively inhibited both VEGFR-2 and EGFR as they have the essential structural requirements for inhibitors of both receptors. Derivative 14 was the most active on A549, HCT116, HepG2, and MCF-7 cancers with half-maximal inhibitory concentration (IC50) = 5.50, 9.77, 7.12, and 7.85 µM respectively. The assessed derivatives 5, 7, 8, 9, 10, 12 and 14 showed IC50 = 54.40-62.60 μM against normal VERO (normal kidney) cells with low toxicity. In addition, derivatives 14, 8, 10, 7 and 9 were discovered to be very good active inhibitors of VEGFR-2 at IC50 values of 1.15, 1.35, 140, 1.78 and 1.90 µM, respectively. Furthermore, derivatives 14, 10, 8, and 9 strongly repressed EGFRT790M with IC50 = 0.28, 0.33, 0.35, and 0.50 µM correspondingly. Additionally, the highly active compounds 8, 10, and 14 showed good ADMET profile.

Conclusion: Our derivatives could be considered as Anticancer agents with dual VEGFR-2 and EGFRT790M inhibition.

Keywords
ADMET; EGFRT790M; Phenyldiazenes; VEGFR-2; docking; dual inhibitors.
Products