Design, Synthesis, Anticancer Evaluation, and Molecular Docking Studies of Thiazole-Pyrimidine Linked Amide Derivatives

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 H-1 NMR, (CNMR)-C-13, 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.

Automated summary

A library of new amide-based thiazole-pyrimidines was designed and synthesized for potential multi-acting anticancer agents, showing that analogs with tri/di substitution have higher potential than mono-substituted analogs. Among them, 13b and 13h exhibited maximum anti-cancer activity against all tested cell lines and were superior to the reference standard Etoposide. Molecular interaction analysis indicated the current series of analogs as potential ATR kinase binders.