Harnessing potential COX-2 engagement for boosting anticancer activity of substituted 2-mercapto-4(3H)-quinazolinones with promising EGFR/VEGFR-2 inhibitory activities

  • Bioorg Chem. 2024 Nov 12:153:107951. doi: 10.1016/j.bioorg.2024.107951.
Abdelrahman Hamdi  1 ,  Samar S Tawfik  2 ,  Ahmed R Ali  3 ,  Wafaa A Ewes  2 ,  Abdullah Haikal  4 ,  Adel S El-Azab  5 ,  Ahmed H Bakheit  5 ,  Mohamed M Hefnawy  5 ,  Hazem A Ghabbour  6 ,  Alaa A-M Abdel-Aziz  5
Affiliations
  • 1. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: [email protected].
  • 2. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 3. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 4. Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 5. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P. O. Box 2457, Riyadh 11451, Saudi Arabia.
  • 6. School of Health and Biomedical Sciences, RMIT University, Melbourne 3083, Australia.
PMID: 39541892 DOI: 10.1016/j.bioorg.2024.107951
Abstract

We designed and synthesized new quinazolinone-tethered phenyl thiourea/thiadiazole derivatives 4-26. Based on their structural characteristics, these compounds were proposed to have a multi-target mode of action for their Anticancer activities. Using the MTT assay method, antiproliferative effects were assessed against three human Cancer cell lines (HEPG-2, MCF-7, and HCT-116). In vitro assessment for enzymatic inhibitory activity of the most active compounds 4, 9 and 20 was done for EGFR, VEGFR-2 and COX-2 as potential targets. The screened compounds showed low micromolar IC50 inhibitory effects against the three targets. Compound 9 demonstrated similar EGFR/VEGFR-2 inhibitory effect to the control drugs and potential inhibitory activity for COX-2 enzyme. In MCF-7 cells, the most active analog 9 caused 41.02% total Apoptosis, and arrested the cell cycle at the G2/M phase. Taken as a whole, the findings of this study provide significant new understandings into the relationship between COX inhibition and Cancer therapy. Furthermore, the outcomes showcased the encouraging efficacy of these compounds with a multi-target mechanism, making them excellent choices for additional research and development into possible Anticancer drug.

Keywords
2-mercapto-4(3H)-quinazolinones; Anticancer activity; Apoptosis; COX-2 inhibitory activity; Cell cycle; EFGR inhibitory activity; Molecular modeling; Quinazolin-4(3H)-one; Thiourea; VEGFR-2 inhibitory activity.
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