Synthesis, evaluation of cytotoxic activity, and studies of some 3-methylenamino-4(3)-quinazolone derivatives.

A series of 3-methylenamino-4(3)-quinazolone derivatives were synthesized by imine formation reactions of 3-amino-6-chloro-2-phenyl-4(3)-quinazolone with various substituted aromatic aldehydes at 80 °C for 1-3 hours using the reflux method. Twenty 3-methylenamino-4(3)-quinazolone derivatives were synthesized with good to excellent yields (66 to 90%). Compound 5 (2-chloro-6-fluorobenzylidene) exhibited good cytotoxic activity against the RD cell line with an IC value of 14.65 μM but exhibited weak cytotoxic activity against the MDA-MB-231 cell line (IC = 147.70 μM) compared to the reference drug paclitaxel (PTX, IC RD = 0.58 μM and IC MDA-MB-231 = 0.04 μM). Meanwhile, compounds 6 (benzo[][1,3]dioxol-5-ylmethylene) and 7 (4-bromo-2-hydroxybenzylidene) showed good cytotoxic activity against MDA-MB-231 with IC values of 10.62 and 8.79 μM, respectively. However, these compounds showed weak cytotoxic activity against the RD cell line (IC = 50-55 μM). In particular, potential compounds 5, 6, and 7 exhibited weak cytotoxic activity against the normal cell line LLC-PK1 (IC = 34.82-60.18 μM) compared to the highly toxic agent PTX (IC = 1.31 μM). Furthermore, compounds 5, 6, and 7 showed strong interactions with the EGFR target with binding affinities of -9.6, -10.1, and -9.8 kcal mol, respectively, compared to reference drug Gefitinib (-7.8 kcal mol). The ADMET results suggested that these potent derivatives possess a good ADMET profile. Therefore, these three compounds are potential candidates for novel cancer drug development, as demonstrated by and studies.