Synthesis of Quinoline‐Morpholine‐Coupled 1,2,3‐Triazole Hybrids as In vitro EGFR inhibitors

Abstract

AbstractHerein we described the synthesis of some new quinoline‐morpholine coupled 1,2,3‐triazole hybrids (6 a–n) from 5‐chloroquinolin‐8‐ol using well known reactions like Mannich reaction, O‐propargylation, and finally copper (I) catalyzed azide‐alkyne cycloaddition (CuAAC). The structures of all newly synthesized hybrids were confirmed by 1H–NMR, 13C–NMR, and Mass spectra. All of them were screened for their in vitro cytotoxicity towards three human cancer cell lines including MCF‐7, A549 and HepG2 by MTT assay where four compounds (6 c, 6 j, 6 m and 6 n) exhibited more potency than the reference erlotinib against all the three cell lines. In vitro tyrosine kinase EGFR inhibition assay for the same four compounds revealed that 6 m has triple inhibiting power with IC50 value of 0.14 μM and 6 j has nearly double inhibiting power with IC50 value of 0.22 μM compared to erlotinib. Molecular docking studies with EGFR have shown that all the above four compounds have more binding energies (−9.09 kcal/mol to −9.96 kcal/mol) than that of erlotinib (‐7.69 kcal/mol). Finally, in silico pharmacokinetic profile was achieved using SWISS/ADME and pkCSM, where all the four compounds followed Lipinski rule, Veber rule, Egan rule and Muegge rule and the lipophilicity (ClogP) was found to be ranging from 2.98 to 3.69.