2. Academic Validation
  3. ADMET, docking, anticancer evaluations, design and synthesis of pyrazolo[1,5-a]pyrimidines substituted with furan and phenyldiazene as dual EGFRT790M and VEGFR-2 inhibitors

ADMET, docking, anticancer evaluations, design and synthesis of pyrazolo[1,5-a]pyrimidines substituted with furan and phenyldiazene as dual EGFRT790M and VEGFR-2 inhibitors

  • Bioorg Chem. 2025 Aug:163:108746. doi: 10.1016/j.bioorg.2025.108746.
Marwa Alsulaimany 1,  Felemban Athary Abdulhaleem M 2,  Raed Alghamdi 1,  Nour E A Abd El-Sattar 3,  Sara A Almadani 4,  Waad A Samman 4,  Hussam Y Alharbi 5,  Majed S Aljohani 5,  Saeed M Tayeb 6,  Tamer Nasr 7,  Khaled El-Adl 8,  Kurls E Anwer 9
Affiliations

Affiliations

  • 1 Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Madinah, Saudi Arabia.
  • 2 Department of Biology, Faculty of Science, Umm Al-Qura University, 21955 Makkah, Saudi Arabia.
  • 3 Department of Chemistry, Faculty of Science, Ain Shams University, Abbassia, Cairo, Egypt; Basic & Medical Sciences Department, Faculty of Dentistry, Alryada University for Science & Technology, Egypt.
  • 4 Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Madinah, Saudi Arabia.
  • 5 Department of Chemistry, College of Science, Taibah University, Madinah, Saudi Arabia.
  • 6 Department of Pharmaceutical Science, College of Pharmacy, Umm Al-Qura University, Makkah 24381, Saudi Arabia.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Ain-Helwan, Cairo 11795, Egypt; Medicinal Chemistry Department, Faculty of Pharmacy, Egypt-Japan University of Science and Technology (E-JUST), P.O. 21934, Alexandria, Egypt.
  • 8 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt; Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11884 Cairo, Egypt. Electronic address: khaled.eladl@hu.edu.eg.
  • 9 Department of Chemistry, Faculty of Science, Ain Shams University, Abbassia, Cairo, Egypt.
PMID: 40680557 DOI: 10.1016/j.bioorg.2025.108746
Abstract

Novel pyrazolopyrimidine heterocyclic rings substituted with furan and phenyldiazene moieties have been designed and synthesized employing traditional and microwave approaches. Cytotoxic activities of our derivatives were estimated on A549, HCT-116, MCF-7 and HepG2 cancers mutually targeting VEGFR-2 and EGFRT790M. Derivative 6 has the greatest activity on HCT116, MCF-7, HepG2 and A549 cancers with IC50 = 9.90, 7.95, 5.35 and 5.60 μM congruently. It presented higher activities than erlotinib (IC50 = 13.91, 8.20, 7.73 and 5.49 μM respectively) while revealed lower activities than sorafenib, (IC50 = 5.05, 5.58, 4.00 and 4.04 μM respectively) on the estimated cell lines. Cytotoxicity of the highest potent compounds 4, 5, 6, 7, 8 and 9 were studied on normal VERO cells. The tested compounds displayed IC50 values ranging from 54.90 to 57.60 μM with normal VERO cells low toxicity. Additionally, all compounds were estimated as dual EGFRT790M and VEGFR-2 inhibitors. Derivatives 6, 4, 5 and 3 were discovered to be very good VEGFR-2 inhibitors at IC50 = 0.95, 1.20, 1.36 and 1.85 μM, congruently. As well, derivatives 6, 5, 4 and 9 produced EGFRT790M inhibition at IC50 = 0.26, 0.36, 0.40 and 0.55 μM congruently. Additionally, the highest potent derivatives 4, 5 and 6 were in silico inspected of ADMET properties compared to sorafenib and erlotinib as standard ligands. The achieved data presented that our derivatives could be advantageous as a pattern for imminent optimization and design to yield further potent mutually inhibitors of EGFRT790M and VEGFR-2 with higher Anticancer activities.

Keywords

ADMET; Docking; EGFR(T790M) and VEGFR-2 dual inhibitors; Phenyldiazenes.

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