Design, synthesis, anticancer evaluation, molecular docking and in silico ADME analysis of novel substituted 1,3,4-thiadazoloaryl incorporated pyrimidine-thiazole derivatives as propitious anticancer agents

Abstract

A novel library of 1,3,4-thiadazoloaryl based pyrimidine-thiazole derivatives (10a-j) was synthesized and their chemical structures were confirmed by 1HNMR, 13CNMR, and mass spectral data. in silico ADME studies have demonstrated that all these compounds have a good pharmacokinetic profile. Further, these compounds were evaluated for their anticancer activity against a panel of human cancer cell lines such as prostate (PC3 and DU-145), lung (A549), and breast (MCF-7). The outcome results were compared with the standard reference as etoposide. Most of the tested compounds demonstrated remarkable anticancer activities, with IC50 values ranging from 0.01 ± 0.0017 µM to 23.6 ± 8.43 µM, where standard showed IC50 values from 1.97 ± 0.45 µM to 3.08 ± 0.135 µM, respectively. Particularly, these compounds 10a, 10b, 10c, 10d, 10e, and 10j displayed more prominent anticancer activities as etoposide. Molecular docking studies of the synthesized compounds were carried out against SARM (PDB ID: 3V49) and Abl-Tyrosine kinase (PDB ID: 1IEP), in which 10b and 10 h showed comparable dock scores of −7.3 and −7.5 against SARM (PDB ID: 3V49) and 10b and 10c −8.5 and −7.7 against Abl-Tyrosine kinase (PDB ID: 1IEP).