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

Abstract We developed a novel category of quinoline-based compounds that operate as multi-target inhibitors of EGFR, HER-2, and BRAF V600E . The new compounds’ antiproliferative activity was tested against four cancer cell lines. All compounds had GI 50 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 BRAF V600E , 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, BRAF V600E , and HER-2.