Design and synthesis of new 1,2,4-oxadiazole/quinazoline-4-one hybrids with antiproliferative activity as multitargeted inhibitors.

Autor: Mohamed AM; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, Egypt., Abou-Ghadir OMF; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, Egypt., Mostafa YA; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, Egypt., Dahlous KA; Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia., Bräse S; Institute of Biological and Chemical Systems, IBCS-FMS, Karlsruhe Institute of Technology, Karlsruhe, Germany., Youssif BGM; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, Egypt.
Jazyk: angličtina
Zdroj: Frontiers in chemistry [Front Chem] 2024 Aug 30; Vol. 12, pp. 1447618. Date of Electronic Publication: 2024 Aug 30 (Print Publication: 2024).
DOI: 10.3389/fchem.2024.1447618
Abstrakt: Introduction: The combination of BRAF and tyrosine kinase (TK) inhibitors has been demonstrated to be highly effective in inhibiting tumor development and is an approach for overcoming resistance in clinical trials. Accordingly, a novel series of 1,2,4-oxadiazole/quinazoline-4-one hybrids was developed as antiproliferative multitargeted inhibitors.
Methods: The structures of the newly synthesized compounds 9a-o were validated using IR, NMR, MS, and elemental techniques. 9a-o were tested as antiproliferative agents.
Results and Discussion: The results showed that the majority of the tested compounds showed significant antiproliferative action with 9b, 9c, 9h, 9k, and 9l being the most potent. Compounds 9b, 9c, 9h, 9k, and 9l were tested as EGFR and BRAF V600E inhibitors. These in vitro tests revealed that compounds 9b, 9c, and 9h are strong antiproliferative agents that may act as dual EGFR/BRAF V600E inhibitors. 9b, 9c, and 9h were further investigated for their inhibitory effect on mutant EGFR (EGFR T790M ), and the results showed that the tested compounds had considerable inhibitory action. Cell cycle study and apoptosis detection demonstrated that compound 9b exhibits cell cycle arrest at the G2/M transition. Molecular docking simulations reveal the binding mechanism of the most active antiproliferative agents.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Mohamed, Abou-Ghadir, Mostafa, Dahlous, Bräse and Youssif.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje