Abstract

A library of new amide-based thiazole–pyrimidines (13a–j) was designed by considering vital pharmacophoric features of the potential multi-acting anticancer agents. The analogs were synthesized by linking with fused imidazo–pyrazole nucleus and confirmed their structures by ¹H NMR, ¹³CNMR, and mass spectral analysis. The newly designed thiazole–pyrimidine analogs were subjected to investigate against various human cancer cell lines such as A549 (lung), MCF-7 (breast), Colo-205 (colon), and A2780 (ovarian) by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay technique. The anticancer screening data suggested that, the analogs with tri/di substitution are found to have much potential than mono-substituted analogs. The 13b and 13h depicted maximum anti-cancer activity against all of the tested cell lines and superior than reference standard Etoposide. Furthermore, the molecular interaction analysis against different enzymatic targets such as ribonucleotide reductase (RR), epidermal growth factor reductase (EGFR), APC–asef (Adenomatous Polyposis Coli (APC) directly interacts with the Rho guanine nucleotide exchange factor 4 (Asef)) protein–protein interaction interface, and ATR kinase has been carried out to find the possible binding protein. The comparative binding energies and violin plot suggested the current series of analogs as potential ATR kinase binders. The required substantial interactions of 13b and 13h with active site residues of ATR kinase has been discussed by comparing with lowest active analogs. In addition, the ADMET parameters of the current analogs is also provided with drug likeness and druggability scores.

摘要

通过考虑潜在的多效抗癌剂的重要药效团特征，设计了一个新的基于酰胺的噻唑-嘧啶 ( 13a-j ) 库。通过与稠合的咪唑-吡唑核连接合成类似物，并通过¹ H NMR、¹³ CNMR 和质谱分析证实了它们的结构。新设计的噻唑-嘧啶类似物通过 MTT (3-(4 ,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) 测定技术。抗癌筛查数据表明，具有三/二取代的类似物被发现比单取代的类似物具有更大的潜力。13b _和13h描绘了对所有测试细胞系的最大抗癌活性，并且优于参考标准依托泊苷。此外，针对不同酶靶点的分子相互作用分析，如核糖核苷酸还原酶 (RR)、表皮生长因子还原酶 (EGFR)、APC-asef（腺瘤性息肉病 (APC) 直接与 Rho 鸟嘌呤核苷酸交换因子 4 (Asef) 相互作用）蛋白质-蛋白质相互作用界面和ATR激酶已被用于寻找可能的结合蛋白。比较结合能和小提琴图表明当前系列的类似物是潜在的 ATR 激酶结合剂。13b和13h所需的实质性相互作用通过与最低活性类似物的比较，讨论了具有 ATR 激酶活性位点残基的残基。此外，当前类似物的 ADMET 参数还提供了药物相似性和成药性评分。