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Hybrid Quinazoline 1,3,5‐Triazines as Epidermal Growth Factor Receptor (EGFR) Inhibitors with Anticancer Activity: Design, Synthesis, and Computational Study
Author(s) -
Pathak Prateek,
Rimac Hrvoje,
Grishina Maria,
Verma Amita,
Potemkin Vladimir
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000646
Subject(s) - in vivo , chemistry , quinazoline , epidermal growth factor receptor , pharmacology , egfr inhibitors , docking (animal) , lipophilicity , in vitro , in silico , biochemistry , stereochemistry , receptor , biology , medicine , microbiology and biotechnology , nursing , gene
We report a series of hybrid quinazoline‐1,3,5‐triazine derivatives as EGFR inhibitors, which were synthesised and tested by using a variety of in vitro, in silico , and in vivo techniques. The derivatives were found to be active against different cancer cell lines and nontoxic against normal ones, with compounds 7 c , 7 d , 7 e , and 7 j being the most potent ones. The derivatives were also evaluated for angiogenesis inhibition potency in chicken eggs, and molecular docking and dynamics simulation studies were carried out to elucidate the fundamental substituent groups essential for their bioactivity. Additionally, a SAR study of the derivatives was performed for future compound optimisation. These studies suggested that the derivatives have a high affinity towards EGFR with favourable pharmacological properties. The most active compound ( 7 e ) was further evaluated for in vivo anticancer activity against DMBA‐induced tumours in female Sprague‐Dawley rats as well as its effects on plasma antioxidant status, biotransformation enzymes, and lipid profile. The study suggested that 7 e has lead properties against breast cancer and can serve as a starting compound for further development of anti‐EGFR compounds.