Cu‐Catalyzed Synthesis of 4H‐benzo[4,5]thiazolo[3,2‐a]pyrimidin‐4‐ones: Molecular Docking Studies and Anti‐Proliferative Activities Against HepG2 Hepatocellular Carcinoma Cells

Abstract

The copper‐catalyzed regioselective domino synthesis of 4H‐benzo[4,5]thiazolo[3,2‐a]pyrimidin‐4‐ones 3 through N,S‐arylation strategies has been accomplished. This transformation was operated by the reaction of 1‐bromo‐2‐iodobenzenes 1 with 2‐thioxo‐2,3‐dihydropyrimidin‐4(1H)‐ones 2 in the presence of trans‐4‐hydroxy‐L‐proline as a ligand in DMSO as a solvent. Using this method, a library of diversely functionalized 4H‐benzo[4,5]thiazolo[3,2‐a]pyrimidin‐4‐one derivatives 3 were obtained in yields ranging 66‐85%. The described process revealed a very good tolerance to substituents on both 1‐bromo‐2‐iodobenzenes 1 and 2‐thioxo‐2,3‐dihydropyrimidin‐4(1H)‐ones 2. In addition, the reaction with 1,2‐diodobenzene yielded the corresponding 2‐methyl‐4H‐benzo[4,5]thiazolo[3,2‐a]pyrimidin‐4‐one (3a) in 70% yield. Docking studies explained that the derivatives 3h, 3e, and 3p bind to the lipophilic pocket of the phosphoinositide 3‐kinase beta (PI3Kβ) and epidermal growth factor receptor (EGFR) with high affinities. In addition, the complex 3h‐4bfr formed a very stable complex with PI3Kβ with the lowest binding free energy of ‐7.89 kcal/mol. The anti‐proliferative activity against HepG2 hepatocellular carcinoma cells was evaluated using MTT assay. The compound 3h exhibited cytotoxic activity against HepG2 cells comparable to that of Erlotinib, a standard EGFR inhibitor (IC50 values of 19.1 and 14.7 µM). Four of the tested compounds (3e, 3f, 3o, and 3p) showed moderate anti‐proliferative activities (IC50 values of 53.9 to 92.2 µM).