Synthesis of some New 9-Substituted 4-aryl-4,6-dihydropyrimido[5,4-c]quinoline-2,5(1H,3H)-diones as EGFR Inhibitors: In-vitro, Molecular Docking, Cytotoxic Evaluation, and ADMET Studies

A new series of 9-substituted 4-aryl-4,6-dihydropyrimido[5,4-c]quinoline-2,5(1H,3H)-diones were designed, synthesized, and evaluated as epidermal growth factor receptor (EGFR) inhibitors. Most of the synthesized compounds showed moderate to high anticancer activity against four cancer cell lines such as MCF-7, MDA-MB-468, HepG2, and HT-29 using an MTT assay. Two compounds 7c and 7e were found to be potent anticancer agents among synthesized derivatives. The IC50 of 7c were 3.20 +/- 0.14, 4.09 +/- 0.01, 4.21 +/- 0.65, 4.26 +/- 0.57 mu M and 3.59 +/- 0.44, 3.59 +/- 0.44, 3.92 +/- 0.62, and 4.35 +/- 0.29 4.19 +/- 0.10 mu M for 7e against MCF-7, MDA-MB-468, HepG2 and HT-29, respectively. Compounds 7c and 7e inhibited the EGFR kinase with a micromolar IC50 values comparable to the reference drug erlotinib. The EGFR inhibition of compounds7c and 7e was 1.27 +/- 0.11 and 1.13 +/- 0.09 mu M, respectively. Further, docking studies were carried out on the 1M17 protein of EGFR kinase by using AutoDock software. Two compounds 7c and 7e exhibited excellent docking score of -9.6 and -9.1 kcal/mol than the reference drug erlotinib (-7.5 kcal/mol).