Synthesis, in-silico, and in-vitro study of novel chloro methylquinazolinones as PI3K-δ inhibitors, cytotoxic agents

Abstract

Through a two-step procedure, 3-amino-7-chloro-2-methylquinazolin-4(3H)-one was synthesized from 2-amino-4-chlorobenzoic acid as a starting material. The latter reacted with chloro acetylchloride, then nucleophilically substituted with various secondary amines to produce acetamide derivatives (5a-e), or underwent condensation reaction with various aldehydes to produce arylidine derivatives (6a-e). In-silico study of drug-likeness and ADME descriptors was conducted for all compounds. Compounds showed good oral bioavailability, as well as good gastrointestinal absorption potential and no symptoms of liver or CNS adverse effects. In-vitro cytotoxic activity of the compounds was moderate to good when compared to staurosporine in three cell lines: HCT, MCF-7, and HepG-2. Compound 5c showed the highest cytotoxic activity against the HCT cell line (IC50 = 8.00 ± 0.33 μM), Compound 5d showed the highest cytotoxic activity against the HepG-2 cell line (IC50 = 17.78 ± 0.58 μM). Acetamide derivatives revealed higher cytotoxic activity compared to arylidine derivatives. Compound 5d had the highest enzyme inhibition activity in the in-vitro PI3k-δ enzyme inhibition assay (IC50 = 1.24 ± 0.03 μM) followed by 5c (IC50 = 8.27 ± 0.19 μM). Both 5c and 5d were able to bind at the ATP binding site of the PI3k-δ enzyme in a mode similar to the native ligand where they formed H-bond interactions with the hinge region amino acid Val828 and hydrophobic interactions with other amino acids indicating an agreement between molecular docking simulation study and the biological screening.

Keywords

• 7-chloro-2-methylquinazolin-4(3H)-ones
• PI3k-δ enzyme
• Cytotoxic Activity
• Molecular docking
• Enzyme inhibition
• ADME studies