Discovery of new 1,3-diphenylurea appended aryl pyridine derivatives as apoptosis inducers through c-MET and VEGFR-2 inhibition: design, synthesis, in vivo and in silico studies

Heba A Elsebaie; Mohamed S Nafie; Haytham O Tawfik; Amany Belal; Mohammed M Ghoneim; Ahmad J Obaidullah; Salwa Shaaban; Abdelmoneim A Ayed; Mohamed El-Naggar; Ahmed B M Mehany; Moataz A Shaldam

doi:10.1039/d4md00280f

Discovery of new 1,3-diphenylurea appended aryl pyridine derivatives as apoptosis inducers through c-MET and VEGFR-2 inhibition: design, synthesis, in vivo and in silico studies

RSC Med Chem. 2024 Jun 12;15(7):2553-2569. doi: 10.1039/d4md00280f. eCollection 2024 Jul 17.

Authors

Heba A Elsebaie¹, Mohamed S Nafie^{2

3}, Haytham O Tawfik^{1

4}, Amany Belal⁵, Mohammed M Ghoneim⁶, Ahmad J Obaidullah⁷, Salwa Shaaban^{8

9}, Abdelmoneim A Ayed¹⁰, Mohamed El-Naggar¹¹, Ahmed B M Mehany¹², Moataz A Shaldam^{4

13}

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University Tanta 31527 Egypt [email protected].
² Department of Chemistry, College of Sciences, University of Sharjah Sharjah 27272 United Arab Emirates.
³ Chemistry Department, Faculty of Science, Suez Canal University Ismailia 41522 Egypt.
⁴ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, AlSalam University in Egypt Kafr Al Zaiyat 6615062 Egypt.
⁵ Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University P.O. Box 11099 Taif 21944 Saudi Arabia.
⁶ Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University Ad Diriyah Riyadh 13713 Saudi Arabia.
⁷ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University P.O. Box 2457 Riyadh 11451 Saudi Arabia.
⁸ Department of Microbiology & Immunology, Faculty of pharmacySuef University Beni-Suef Egypt.
⁹ Department of Clinical Laboratory Sciences, Faculty of Applied medical Sciences, King Khalid University Abha Saudi Arabia.
¹⁰ Department of Chemistry, Faculty of Science, Cairo University Giza Cairo 12613 Egypt.
¹¹ Chemistry department, Faculty of Sciences, Pure and Applied Chemistry Group, University of Sharjah P. O. Box 27272 Sharjah United Arab Emirates.
¹² Zoology Department, Faculty of Science (Boys), Al-Azhar University Cairo 11884 Egypt.
¹³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University P.O. Box 33516 Kafrelsheikh Egypt [email protected].

PMID: 39026631
PMCID: PMC11253870 (available on 2025-06-12)
DOI: 10.1039/d4md00280f

Abstract

Interest has been generated in VEGFR-2 and c-MET as potential receptors for the treatment of different malignancies. Using aryl pyridine derivatives with 1,3-diphenylurea attached, a number of promising dual VEGFR-2 and c-MET inhibitors were developed and synthesized. Regarding the molecular target, compounds 2d, 2f, 2j, 2k, and 2n had potent IC₅₀ values of 65, 24, 150, 170, and 18 nM against c-MET, respectively. Additionally, they had potent IC₅₀ values of 310, 35, 290, 320, and 24 nM against VEGFR-2, respectively. Regarding cytotoxicity, compounds 2d, 2f, 2j, 2k and 2n exhibited potent cytotoxicity against MCF-7 with IC₅₀ values in the range 0.76-21.5 μM, and they showed promising cytotoxic activity against PC-3 with IC₅₀ values in the range 1.85-3.42 μM compared to cabozantinib (IC₅₀ = 1.06 μM against MCF-7 and 2.01 μM against PC-3). Regarding cell death, compound 2n caused cell death in MCF-7 cells by 87.34-fold; it induced total apoptosis by 33.19% (8.04% for late apoptosis, 25.15% for early apoptosis), stopping their growth in the G₂/M phase, affecting the expression of apoptosis-related genes P53, Bax, caspases 3 and 9 and the anti-apoptotic gene, Bcl-2. In vivo study illustrated the anticancer activity of compound 2n by reduction of tumor mass and volume, and the tumor inhibition ratio reached 56.1% with an improvement of hematological parameters. Accordingly, compound 2n can be further developed as a selective target-oriented chemotherapeutic against breast cancer.