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  3. Design and synthesis of novel 2-S-alkylated Quinazolinones as dual BRAFV600E and EGFR inhibitors in melanoma: Mechanistic insights from apoptosis and cell cycle modulation

Design and synthesis of novel 2-S-alkylated Quinazolinones as dual BRAFV600E and EGFR inhibitors in melanoma: Mechanistic insights from apoptosis and cell cycle modulation

  • Bioorg Chem. 2025 Jul 1:161:108526. doi: 10.1016/j.bioorg.2025.108526.
Hamed W El-Shafey 1,  Mohammad M Al-Sanea 2,  Mohamed R Elnagar 3,  Abdallah M Gendy 4,  Marwa I Serag 5,  Aya M Almatary 6,  Mohamed A Khalaf 7,  Maha-Hamadien Abdulla 8,  Noura S Alhassan 9,  Mansoor-Ali Vaali Mohammed 9,  Wagdy M Eldehna 10,  Abdelrahman Hamdi 11
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Institute for Biomedicine and Glycomics, Griffith University, Gold Coast, Campus, Queensland, 4222, Australia.
  • 2 Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf, 72388, Saudi Arabia. Electronic address: mmalsanea@ju.edu.sa.
  • 3 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11823, Egypt; Department of Pharmacology, College of Pharmacy, The Islamic University, Najaf 54001, Iraq.
  • 4 Pharmacology and Toxicology Department, Faculty of Pharmacy, October 6 University, Giza 12585, Egypt.
  • 5 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt.
  • 7 Department of Chemistry, University of South Florida, Tampa, FL, USA.
  • 8 Colorectal Research Chair, Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia. Electronic address: mabdulla@ksu.edu.sa.
  • 9 Colorectal Research Chair, Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
  • 10 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria; Canal El Mahmoudia St., Alexandria 21648, Egypt.
  • 11 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: abdelrahmanhamdi2012@yahoo.com.
PMID: 40311244 DOI: 10.1016/j.bioorg.2025.108526
Abstract

Melanoma, an aggressive and highly metastatic form of skin Cancer, remains challenging to treat due to its resistance to conventional therapies and frequent mutations in the BRAF signaling pathway. In this study, we report the design and synthesis of a novel series of thirteen quinazolinone derivatives, featuring a phenyl thiazole moiety linked via a triazole acetamide spacer. These compounds were developed as potential dual inhibitors of BRAFV600E and EGFR, which should offer a promising therapeutic strategy for melanoma treatment. The antiproliferative activity of these compounds was evaluated against the NCI-60 cell line panel, with six compounds advancing to a five-dose screening. Three compounds, 7k, 7l, and 7m, exhibited broad-spectrum Anticancer activity, with mean growth inhibition (GI%) exceeding 100 %. Compound 7l demonstrated exceptional efficacy against melanoma subpanels (GI% = 152 %) and potent dual kinase inhibition, with IC50 values of 0.048 μM against B-RafV600E and 0.037 μM against EGFR. In vitro studies of compound 7l revealed significant cytotoxicity against MALME-3 M (IC50 = 3.16 μM) and LOX-IMVI (IC50 = 2.50 μM) melanoma cell lines, with minimal toxicity towards normal Vero cells. Cell cycle analysis showed G1-phase arrest and disrupted DNA synthesis in melanoma cells, while Apoptosis assays demonstrated a dramatic increase in early apoptotic cells from 7.28 % to 40.69 %. Compound 7l modulated key apoptotic markers, increasing the Bax/Bcl-2 ratio by 14.42-fold and elevating Caspase 3 and 9 levels, indicating its potential to overcome drug resistance and enhance therapeutic efficacy in melanoma treatment.

Keywords

Antiproliferative activity; Apoptosis; BRAF(V600E); Cell cycle arrest; EGFR; Melanoma; Quinazolinone derivatives.

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