Abstract：
Dihydropyrimidines are widely recognized for their diverse biological properties and are often synthesized by the Biginelli reactions. In this backdrop, a novel series of Biginelli dihydropyrimidines were designed, synthesized, purified, and analyzed by FT-IR, 1H NMR, 13C NMR, and mass spectrometry. Anticancer activity against MCF-7 breast cancer cells was evaluated as part of their cytotoxicity in comparison with the normal Vero cells. The cytotoxicity of dihydropyrimidines ranges from moderate to significant. Among the 38 dihydropyrimidines screened, compounds 16, 21, and 39 exhibited significant cytotoxicity. These 3 compounds were subjected to flow cytometry studies and EGFRwt Kinase inhibition assay using lapatinib as a standard. The study included evaluation for the inhibition of EGFR and HER2 expression at five different concentrations. At a concentration of 1000 nM compound 21 showed 98.51 % and 96.79 % inhibition of EGFR and HER2 expression. Moreover, compounds 16, 21 and 39 significantly inhibited EGFRwt activity with IC50 = 69.83, 37.21 and 76.79 nM, respectively. In addition, 3D-QSAR experiments were conducted to elucidate Structure activity relationships in a 3D grid space by comparing the experimental and predicted cytotoxic activities. Molecular docking studies were performed to validate the results by in silico method. All together, we developed a new series of Biginelli dihydropyrimidines as dual EGFR/HER2 inhibitors.
摘要：
二氢嘧啶因其不同的生物学特性而被广泛认可，并且通常通过Biginelli反应合成。在这个背景下,设计了一系列新颖的Biginelli二氢嘧啶，合成，纯化,并通过FT-IR进行了分析，1HNMR,13CNMR,和质谱。与正常Vero细胞相比，对MCF-7乳腺癌细胞的抗癌活性被评估为其细胞毒性的一部分。二氢嘧啶的细胞毒性范围从中等到显著。在筛选的38种二氢嘧啶中，化合物16、21和39表现出显著的细胞毒性。使用拉帕替尼作为标准对这3种化合物进行流式细胞术研究和EGFRwt激酶抑制测定。该研究包括评估五种不同浓度下EGFR和HER2表达的抑制。在1000nM浓度下,化合物21显示98.51%和96.79%的EGFR和HER2表达抑制。此外，化合物16、21和39显著抑制EGFRwt活性，IC50=69.83、37.21和76.79nM，分别。此外,进行3D-QSAR实验以通过比较实验和预测的细胞毒性活性来阐明3D网格空间中的结构活性关系。通过计算机模拟方法进行分子对接研究以验证结果。一起,我们开发了一系列新的Biginelli二氢嘧啶作为EGFR/HER2双重抑制剂.
