Design, synthesis, biological evaluation and in silico studies of EGFR inhibitors based on 4-oxo-chromane scaffold targeting resistance in non-small cell lung cancer (NSCLC)

Abstract

Allosteric kinase inhibitors targets kinases with oncogenic driver mutations in malignancies as a potential new therapy strategy. EGFR inhibitors with a 4-oxo-chromane scaffold targeting the L858R/T790M/C797S mutation were identified, optimized, synthesized, and assessed for anticancer and EGFR enzyme inhibitory activity. Compounds 4i and 4l were shown to be very effective with IC50 values of 132 and 146 nM, respectively, and excellent selectivity in in silico study. Compound 4i showed substantial antioxidant activity at a concentration of 100 µM, with a DPPH radical scavenging value of 91.46%. The synthesized compounds 4i, 4k and 4l were found to be selective toward cancer cells since they did not exhibit cytotoxicity even at IC50 > 20 µM on normal cells. Compound potency was further assessed using in silico and in vitro biological evaluation. [Figure not available: see fulltext.]