New Quinazolin-4(3H)-one Derivatives as Potential Antitumoral Compounds: Synthesis, In Vitro Cytotoxicity Against the HepG2 Cell Line, and In Silico VEGFR-2 Targeting-Based Studies

Three new 2,3-disubstituted quinazolin-4(3<i>H</i>)-one derivatives (<b>5a</b>-<b>c</b>) were synthesized by the nucleophilic <i>S</i>-alkylation of 2-mercaptoquinazolin-4(3<i>H</i>)-one derivatives (<b>3a</b>-<b>c</b>) with 5-(2-bromoacetyl)-2-hydroxybenzamide (<b>4</b>) in alkaline conditions. The final compounds were characterized by recording the IR, MS, ¹H-NMR, and ¹³C-NMR spectra. The new synthesized compounds <b>5a</b>-<b>c</b> were evaluated in vitro for their cytotoxic activity using one normal cell line, human foreskin fibroblasts (BJ), and one cancerous cell line, derived from human hepatocellular carcinoma (HepG2). Sorafenib was used as a reference. The obtained results from the in vitro examination suggested that compound <b>5a</b> had lower cytotoxic effects on the BJ cells than the positive standard, and compound <b>5b</b> exhibited the strongest cytotoxic potential against the HepG2 cell line, being less effective compared to sorafenib. In order to evaluate their pharmacological profiles, the compounds were assessed in vitro and in silico by lipophilicity studies, targeted VEGFR-2 molecular docking, molecular dynamics, and MM-PBSA studies. Additionally, the electronic properties were evaluated by an in silico study of the HOMO and LUMO parameters. Compound <b>5b</b> exhibited the most interesting pharmacological profile in comparison with the other compounds due to its bulkier substituent from position 3 of the quinazolinone core.