由于其多种药理学特性，吡嗪啉衍生物作为重要的杂环化合物类别，引起了许多关注，并被用于设计和开发新药物。此外，大量证据表明吡嘧啶类似物可以作为抗癌药物。因此，在本研究中，我们针对细胞毒作用的新目标化合物设计上，侧重于各种喹喔啉和吡嘧啶的杂交物。一系列新的吡嗪喹喔啉/吡嘧啶杂交衍生物（6a-6n）已被设计和合成为新型抑制增殖剂。所有合成的化合物均基于其红外、核磁共振和质谱数据进行了表征。对新化合物的抑制增殖活性进行了评估，针对三种人类癌细胞系（MCF-7、A549、SW-480）。发现这些化合物在被测试的细胞系中具有适当的抑制活性，IC50值范围为2.3±5.91至176.5±0.7μM。化合物6n表现出最高的抑制增殖活性，对A549、SW-480和MCF-7的IC50值分别为5.9±1.69μM、2.3±5.91μM和5.65±2.33μM。结果表明，6n能够以剂量依赖的方式诱导A549细胞系的凋亡，并使细胞周期停滞在S期。还进行了对合成化合物对EGFR的详细结合模式的对接研究。此外，通过基于集合的MMGB/PBSA自由能方法，还对合成化合物的初步对接位姿进行了分子动力学模拟和结合自由能计算。根据结果，自由能计算确认了化合物的生物活性，同时还发现Arg 817和Lys 721残基在6n的高效活性中起关键作用。最后，还预测了药物样性和体外ADME研究。© 2023. Springer Nature Limited.

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 μM against the tested cell lines. Compound 6n exerted the highest antiproliferative activity with IC50 values of 5.9 ± 1.69 μM, 2.3 ± 5.91 μM and 5.65 ± 2.33 μM 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.© 2023. Springer Nature Limited.