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

Mohamed, Amira M.; Abou-Ghadir, Ola M. F.; Mostafa, Yaser A.; Dahlous, Kholood A.; Bräse, Stefan 1,2; Youssif, Bahaa G. M.
1 Institut für Biologische und Chemische Systeme (IBCS), Karlsruher Institut für Technologie (KIT)
2 Institut für Organische Chemie (IOC), Karlsruher Institut für Technologie (KIT)

Abstract:

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. ... mehr


Verlagsausgabe §
DOI: 10.5445/IR/1000174416
Veröffentlicht am 20.09.2024
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Organische Chemie (IOC)
Publikationstyp Zeitschriftenaufsatz
Publikationsmonat/-jahr 08.2024
Sprache Englisch
Identifikator ISSN: 2296-2646
KITopen-ID: 1000174416
Erschienen in Frontiers in Chemistry
Verlag Frontiers Media SA
Band 12
Seiten Art.-Nr.: 1447618
Vorab online veröffentlicht am 30.08.2024
Nachgewiesen in Web of Science
Dimensions
Scopus
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