Furan- and Furopyrimidine-Based Derivatives: Synthesis, VEGFR-2 Inhibition, and In Vitro Cytotoxicity

Akram H Abd El-Haleem; Manar Abd El-Karim Kassem; Mohamed R Elnagar; Safinaz E-S Abbas; Ahmed M El Kerdawy; Ahmed K B A W Farouk

doi:10.1021/acsmedchemlett.4c00438

Furan- and Furopyrimidine-Based Derivatives: Synthesis, VEGFR-2 Inhibition, and In Vitro Cytotoxicity

ACS Med Chem Lett. 2024 Nov 25;15(12):2150-2157. doi: 10.1021/acsmedchemlett.4c00438. eCollection 2024 Dec 12.

Authors

Akram H Abd El-Haleem¹, Manar Abd El-Karim Kassem¹, Mohamed R Elnagar^{2

3}, Safinaz E-S Abbas⁴, Ahmed M El Kerdawy^{4

5}, Ahmed K B A W Farouk⁴

Affiliations

¹ Pharmaceutical Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Sixth of October City, Giza 77, Egypt.
² Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11823, Egypt.
³ Department of Pharmacology, College of Pharmacy, The Islamic University, Najaf 54001, Iraq.
⁴ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt.
⁵ School of Health and Care Sciences, College of Health and Science, University of Lincoln, Joseph Banks Laboratories, Green Lane, Lincoln, Lincolnshire LN6 7DL, United Kingdom.

PMID: 39691520
PMCID: PMC11647721 (available on 2025-12-12)
DOI: 10.1021/acsmedchemlett.4c00438

Abstract

New derivatives 4a-d, 6, 7a-d, 8a-c, 9, 11a, 11b, 12a-f, 13a-c, and 14 were synthesized and evaluated for their VEGFR-2 inhibition. Compounds 4c, 7b, and 7c showed remarkable enzyme inhibition (IC₅₀ = 57.1, 42.5, and 52.5 nM, respectively) relative to sorafenib (IC₅₀ = 41.1 nM) and were assessed for their cytotoxicity versus HepG2, MCF-7, A549, HT-29, and PC3 cancer cell lines in addition to WI-38. Compound 7b displayed nearly equipotent cytotoxicity against A549 and HT-29 (IC₅₀ = 6.66 and 8.51 μM) compared to sorafenib (IC₅₀ = 6.60 and 8.78 μM). Cell cycle analysis and apoptotic assay of 7b in the HT-29 cell line showed cellular growth arrest at the G2/M phase in addition to the induction of apoptosis. Western blot analysis of compound 7b revealed the deactivation of VEGFR-2. Moreover, a wound healing assay of 7b showed inhibition of wound closure. Additionally, molecular modeling studies of compounds 4c, 7b, and 7c were carried out.