Abstract
•Design and synthesis of novel penipanoid C-inspired quinazolin-4(1H)-ones.•Evaluated in vitro anticancer activity against panel of the human cancer cell lines.•EGFR kinase and its EGFR L858R and T790M mutants inhibition was determined.•Molecular docking and ADMET properties were investigated.•Structure-activity relationship of the compounds have been studied .
A novel class of penipanoid C-inspired 2-benzoyl-1-methyl-2,3-dihydroquinazolin-4(1H)-ones (3a-3f) and 1-methyl-2-(3,4,5-trihydroxybenzoyl)-2,3-dihydroquinazolin-4(1H)-one derivatives (10–15) was successfully synthesized using the I2/DMSO method. The newly synthesized compounds were characterized and tested for cytotoxicity against three cancer cell lines: HepG2 (human liver), MCF7 (human breast), and HCT116 (human colorectal). The majority of the tested molecules had a considerable cytotoxic impact, in some cases larger than doxorubicin. Furthermore, the inhibitory effect of six compounds (10–15) against epidermal growth factor receptor (EGFR) kinases were investigated, with three compounds (10, 11 and 12) showing good IC50 values. The IC50 values for compounds 10 and 12 against wildtype EGFR were 0.222 and 0.172 µM, respectively. Compound 12 had good enzyme inhibitory efficacy with 71.30 and 421.53 µM for the EGFR L858R and T790M mutants, respectively, which is more effective than the positive control, erlotinib, and close to lapatinib. The results of the biological screening were also confirmed by docking studies, which predicted the potential binding interactions of the target compounds with the EGFR active sites. Compounds 10 and 12 appear to be interesting lead compounds with the potential to be developed as anticancer agents, based on the findings.
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