Design and synthesis of novel thiazole/1,2,4-triazole/quinoline hybrids as antiproliferative agents, apoptosis inducers, immunomodulators, and multi-EGFR/BRAFV600E/HER-2 inhibitors
摘要
We developed a novel category of quinoline-based compounds that operate as multi-target inhibitors of EGFR, HER-2, and BRAFV600E. The new compounds’ antiproliferative activity was tested against four cancer cell lines. All compounds had GI50 values ranging from 25 to 76 nM. Compounds 8f, 8k, and 8 m exhibited the most potent antiproliferative action, with 8f and 8k surpassing erlotinib in all evaluated cancer cell lines. 8f and 8k are the most potent multi-target inhibitors of EGFR, HER-2, and BRAFV600E, surpassing the reference EGFR inhibitor, while failing to match the efficacy of Lapatinib and Vemurafenib. We evaluated the apoptotic potential of 8f and 8k, revealing that both compounds induce apoptosis by activating caspase-3, 8, 9, p53, and Bax, while downregulating the expression of Bcl-2, a protein that inhibits apoptosis. An integrated in silico workflow validated docking, 100-ns molecular dynamics (MD), and SwissADME were applied to compound 8f against EGFR, BRAFV600E, and HER-2.