Chalcone/1,3,4-Oxadiazole/Benzimidazole hybrids as novel anti-proliferative agents inducing apoptosis and inhibiting EGFR & BRAFV600E

BMC Chemistry

Research

Dalia Abdelhamid¹  Samar H. Abbas¹  Mohamed Abdel-Aziz¹  Fatma Fouad Hagar¹  Bahaa G. M. Youssif²  Ahmed M. Sayed³  Hesham A. M. Gomaa⁴ 

[1] Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, 61519, Minia, Egypt;Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, 71526, Assiut, Egypt;Pharmacognosy Department, Faculty of Pharmacy, Nahda University, 62513, Beni-Suef, Egypt;Pharmacology Department, College of Pharmacy, Jouf University, 72314, Sakaka, Saudi Arabia;

关键词: Benzimidazole;    Oxadiazole;    Chalcone;    Apoptosis;    Anticancer Agents;    EGFR, BRAF;   

DOI  :  10.1186/s13065-023-01003-3

 received in 2023-03-06, accepted in 2023-07-10,  发布年份 2023

来源: Springer

【 摘 要 】

IntroductionOne of the most robust global challenges and difficulties in the 21st century is cancer. Treating cancer is a goal which continues to motivate researchers to innovate in design and development of new treatments to help battle the disease.ObjectivesOur objective was developing new antiapoptotic hybrids based on biologically active heterocyclic motifs "benzimidazole?oxadiazole-chalcone hybrids'' that had shown promising ability to inhibit EGFR and induce apoptosis. We expected these scaffolds to display anticancer activity via inhibition of BRAF, EGFR, and Bcl-2 and induction of apoptosis through activation of caspases.MethodsThe new hybrids 7a-x were evaluated for their anti-proliferative, EGFR & BRAFV600E inhibitory, and apoptosis induction activities were detected. Docking study & dynamic stimulation into EGFR and BRAFV600E were studied.ResultsAll hybrids exhibited remarkable cell growth inhibition on the four tested cell lines with IC50 ranging from 0.95 μM to 12.50 μM. which was comparable to Doxorubicin. Compounds 7k-m had the most potent EGFR inhibitory activity. While, compounds 7e, 7g, 7k and 7l showed good inhibitory activities against BRAFV600E. Furthermore, Compounds 7k, 7l, and 7m increased Caspases 3,8 & 9, Cytochrome C and Bax levels and decreased Bcl-2 protein levels. Compounds 7k-m received the best binding scores and showed binding modes that were almost identical to each other and comparable with that of the co-crystalized Erlotinib in EGFR and BRAF active sites.ConclusionCompounds 7k-m could be used as potential apoptotic anti-proliferative agents upon further optimization.

【 授权许可】

CC BY   
© Springer Nature Switzerland AG 2023

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