新设计的4-氨基喹唑啉衍生物（5a-f，6a，b，7，8，9，10a-c，11a，b，12a，b和13a，b）已合成并评估它们潜在的多靶点抗癌活性，细胞凋亡和抗增殖效应。因此，在美国NCI对所有合成化合物在NCI60人类癌细胞系（九个亚系）中的体外细胞毒作用进行了筛选。成功地，2-吗啡啉基-N-（喹唑啉-4-基）乙酰腙5e被授予一个NSC代码，因为它对多种癌细胞系，包括白血病K-562、非小细胞肺癌NCI-H522细胞、结肠癌SW-620、黑色素瘤LOX IMVI、MALME-3M、肾癌RXF 393、ACHN和乳腺癌MDA-MB231 / ATCC（GI％= 99.6，161，126.03，90.22，174.47，139.7，191和97）具有明显的效力和广泛的活性谱。在针对NCI 60细胞系的五种剂量测试中，化合物5e在对黑色素瘤LOX IMVI的最佳抑制活性（GI50 = 1.3μM）方面表现最好。此外，与拉帕替尼和利波西林（IC50 = 0.03±0.002μM和0.067±0.004μM）相比，化合物5e显示了可比的EGFR和CDK2抑制活性结果（IC50 = 0.093±0.006μM和0.143±0.008μM）。针对黑色素瘤LOX IMVI的化合物5e的Western blotting分析表明，与拉帕替尼（31.18％）和利波西林（29.66％）相比，它可以显着降低EGFR和CDK2蛋白质表达百分比，分别降低32.97％和34.09％。此外，化合物5e在肾UO-31细胞的S期和乳腺癌MCF7以及卵巢癌IGROV1的G1期引起了清晰的细胞周期阻滞，并伴随着控制组的DNA含量显着增加。相应地，它表现出有前途的抗增殖和凋亡活性，并显示出在与未处理细胞相比的肾癌UO-31、乳腺癌MCF7和卵巢IGROV1癌细胞中总凋亡百分比的显着增加（分别从1.79％到46.72％，2.19％到39.02％和1.66到42.51％）。本研究的主要目标得到分子建模和动态模拟研究结果的支持。Copyright © 2023 Elsevier Inc. All rights reserved.

Newly designed 4 - aminoquinazoline derivatives (5a-f, 6a, b, 7, 8, 9, 10a-c, 11a, b, 12a, b and 13a, b) have been synthesized and evaluated for their potential multitarget anticancer activities, apoptotic and anti-proliferative effects. Thereupon, in vitro cytotoxic activities of all the synthesized compounds were screened against NCI 60 human cancer cell lines (nine subpanels) at NCI, USA. Successfully, 2-morpholino-N-(quinazolin-4-yl) acetohydrazide 5e was granted an NSC code, owing to its significant potency and broad spectrum of activity against various cancer cell lines; leukemia K-562, non-small cell lung cancer NCI-H522 cells, colon cancer SW-620, melanoma LOX IMVI, MALME-3M, renal cancer RXF 393, ACHN and breast cancer MDA-MB231/ATCC (GI% = 99.6, 161, 126.03, 90.22, 174.47, 139.7, 191 and 97, respectively). Compound 5e showed the best inhibitory activity (GI50 = 1.3 µM) against melanoma LOX IMVI, when tested at five doses against NCI 60 cell lines. Furthermore, compound 5e showed comparable EGFR and CDK2 inhibitory activity results (IC50 = 0.093 ± 0.006 μM and 0.143 ± 0.008 μM, respectively) to those of lapatinib and ribociclib (IC50 = 0.03 ± 0.002 μM and 0.067 ± 0.004 μM, respectively). Western blotting analysis of compound 5e against melanoma LOX IMVI marked out significant reduced EGFR and CDK2 protein expression percentages, up to 32.97% and 34.09%, respectively, if compared to lapatinib (31.18%) and ribociclib (29.66%). Moreover, compound 5e caused clear cell cycle arrests at S phase of renal UO-31 cells and at G1 phase of both breast cancer MCF7 and ovarian cancer IGROV1, associated with remarkable increase of DNA content of the controls. In accordance, it demonstrated promising anti- proliferative and apoptotic activities, showing a significant increase in total apoptotic percentages of renal cancer UO-31, breast cancer MCF7 and ovarian IGROV1 cancer cell lines, if compared to the control untreated cells (from 1.79% to 46.72%, 2.19% to 39.02% and 1.66 to 42.51%, respectively). Molecular modelling and dynamic simulation study results supported the main objectives of the present work.Copyright © 2023 Elsevier Inc. All rights reserved.