Design, synthesis, computational study and cytotoxic evaluation of some new quinazoline derivatives containing pyrimidine moiety

Quinazoline derivatives, as an important category of heterocyclic compounds, have received much attention for the design and development of new drugs due to their various pharmacological properties. Besides, there is a great deal of evidence showing pyrimidine analogs as anticancer agents. Thus, in the present study, for the design of new target compounds with cytotoxic activity, we focused on various quinazolinone and pyrimidine hybrids. A new series of quinazoline-pyrimidine hybrid derivatives (6a-6n) have been designed and synthesized as novel antiproliferative agents. All the synthesized compounds characterized based on their IR, NMR and Mass spectroscopic data. Antiproliferative activities of the new compounds were evaluated against three human cancer cell lines (MCF-7, A549, SW-480). The compounds were found to have appropriate potential with IC50 values ranging from 2.3 +/- 5.91 to 176.5 +/- 0.7 mu M against the tested cell lines. Compound 6n exerted the highest antiproliferative activity with IC50 values of 5.9 +/- 1.69 mu M, 2.3 +/- 5.91 mu M and 5.65 +/- 2.33 mu M against A549, SW-480 and MCF-7 respectively. The results indicated that 6n could induce apoptosis in A549 cell line in a dose dependent manner and arrest in the S phase of cell cycle. Docking studies were also done to investigate the detailed binding pattern of the synthesized compounds against EGFR. Furthermore, molecular dynamic simulation and binding free energy calculation have been done to rescore initial docking pose of the synthesized compounds using ensemble-based MMGB/PBSA free energy method. According to the results, free energy calculation confirmed biological activity of compounds and also, Arg 817 and Lys 721 residues had the pivotal role in the high potency of 6n. Finally, the drug likeness and in silico ADME study were also predicted.

Automated summary

Quinazoline derivatives, as an important class of heterocyclic compounds, have shown promise in the design and development of new drugs. In this study, a series of quinazoline-pyrimidine hybrid derivatives were synthesized and evaluated for their antiproliferative activity against human cancer cell lines. Some of the compounds exhibited significant antiproliferative activity and were found to induce apoptosis and cell cycle arrest. Docking studies and molecular dynamic simulation provided insights into the binding pattern of the synthesized compounds with EGFR, and identified key residues contributing to their high potency.