Cu(I)‐Catalyzed One‐Pot Synthesis of [1,2,3]Triazolo[5,1‐ <i>a</i> ] isoquinolin‐6(5H)‐one Derivatives as EGFR‐Targeting Anticancer Agents
Rajkumar Samala, Satheesh Kumar Nukala, Narasimha Swamy Thirukovela, Vasudeva Reddy Nagavelli, Sirassu Narsimha
Abstract
Abstract The CuI promoted one‐pot multi‐component synthesis of new fused [1,2,3]triazolo[5,1‐ a ]isoquinoline derivatives ( 4 a – 4 h , 8 a – 8 f & 9 a – 9 f ) without isolating unsafe azides and their in vitro cytotoxic activity against MCF‐7 & MDA‐MB‐231 (breast cancer cells) and A‐549 (alveolar carcinoma) was reported herein. Out of all, compounds 9‐chloro‐1‐(morpholinomethyl)‐[1,2,3]triazolo[5,1‐a]isoquinolin‐6(5H)‐one ( 8 d ), 9‐fluoro‐1‐(morpholinomethyl)‐[1,2,3]triazolo[5,1‐a]isoquinolin‐6(5H)‐one ( 8 e) , 9‐chloro‐1‐((1,1‐dioxidothiomorpholino)methyl)‐[1,2,3]triazolo[5,1‐a]isoquinolin‐6(5H)‐one ( 9 d ), and 1‐((1,1‐dioxidothiomorpholino)methyl)‐9‐fluoro‐[1,2,3]triazolo[5,1‐a]isoquinolin‐6(5H)‐one ( 9 e) showed superior potency against all the cell lines than the standard drug erlotinib with IC 50 values ranging from 2.45 to 7.19 μ M. The most active compounds 8 d , 8 e , 9 d , and 9 e were also screened for their efficacy in inhibiting tyrosine kinase EGFR and results revealed that compound 9 d showed comparable activity with standard drug erlotinib, whereas, compounds 8 d , 8 e , and 9 e showed superior activity than the erlotinib. Molecular modeling studies for active compounds on EGFR (PDB‐ID‐4HJO) were also conducted and the obtained free energies were observed to be in agreement with the in vitro activity data. Finally, compounds 8 d , 8 e , 9 d , and 9 e didn't show AMES toxicity and followed the rules of Egan, Ghose, Veber, Lipinski, and Muegge rules without any deviation.