| Autor: |
Al-Wahaibi LH; Department of Chemistry, College of Sciences, Princess Nourah bint Abdulrahman University, Riyadh 11564, Saudi Arabia., Abou-Zied HA; Medicinal Chemistry Department, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt., Hisham M; Medicinal Chemistry Department, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt., Beshr EAM; Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt., Youssif BGM; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt., Bräse S; Institute of Biological and Chemical Systems, IBCS-FMS, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany., Hayallah AM; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Sphinx University, Assiut 71515, Egypt., Abdel-Aziz M; Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt. |
| Abstrakt: |
A series of novel 3-cyanopyridone/pyrazoline hybrids ( 21-30 ) exhibiting dual inhibition against EGFR and BRAF V600E has been developed. The synthesized target compounds were tested in vitro against four cancer cell lines. Compounds 28 and 30 demonstrated remarkable antiproliferative activity, boasting GI 50 values of 27 nM and 25 nM, respectively. These hybrids exhibited dual inhibitory effects on both EGFR and BRAF V600E pathways. Compounds 28 and 30 , akin to Erlotinib, displayed promising anticancer potential. Compound 30 emerged as the most potent inhibitor against cancer cell proliferation and BRAF V600E . Notably, both compounds 28 and 30 induced apoptosis by elevating levels of caspase-3 and -8 and Bax, while downregulating the antiapoptotic Bcl2 protein. Molecular docking studies confirmed the potential of compounds 28 and 30 to act as dual EGFR/BRAF V600E inhibitors. Furthermore, in silico ADMET prediction indicated that most synthesized 3-cyanopyridone/pyrazoline hybrids exhibit low toxicity and minimal adverse effects. |
