Synthesis, Molecular Docking Study and Cytotoxicity Evaluation of some Quinazolinone Derivatives as Nonclassical Antifolates and Potential Cytotoxic Agents

Abstract

New 4(3H)-quinazolinone derivatives (S1-S4) were synthesized and characterized by FTIR, 1HNMR, and 13CNMR. Their cytotoxic activity against a set of human cancer cell lines MCF-7 (breast) and A549 (lung) was evaluated using MTT assay. To detect their selectivity toward cancer cells, the compounds were also tested against epithelial cells derived from normal human fibroblast (NHF). Methotrexate (MTX) was used as a positive control. All the tested compounds (S1-S4) exhibited toxicity against the normal cells lower than cancer cells. With the exception of compounds (S3 and S4), the tested compounds showed no siginificant differences from MTX regarding their inhibition rate against the normal cells (NHF) in all concentrations. All tested compounds displayed higher cytotoxicity against the lung cancer cell line (A549) than MTX with the most potent one is being compound S2 (IC50: 5.73 μM). Among the tested compounds, compound S1 exhibited the highest cytotoxic activity against the breast cancer cell line (MCF-7) (IC50: 3.38 μM) compared to MTX (IC50: 27.32 μM). The binding modes of the synthesized compounds with the target proteins (DHFR and TS) were investigated by molecular docking studies using GOLD software. Molecular docking study showed that both compounds S1 and S2 displayed partially a similar binding mode with the active site of DHFR in comparison with the co-crystallized ligand (MTX), whereas compound S1 showed a different binding mode with the active site of TS when compared with the co-crystallized ligand (raltitrexed).