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

The copper‐catalyzed regioselective domino synthesis of 4 H ‐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(1 H )‐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 4 H ‐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(1 H )‐ones 2 . In addition, the reaction with 1,2‐diodobenzene yielded the corresponding 2‐methyl‐4 H ‐benzo[4,5]thiazolo[3,2‐ a ]pyrimidin‐4‐one ( 3 a ) in 70 % yield. Docking studies explained that the derivatives 3 h , 3 e , and 3 p bind to the lipophilic pocket of the phosphoinositide 3‐kinase beta (PI3 Kβ) and epidermal growth factor receptor (EGFR) with high affinities. In addition, the complex 3 h ‐4bfr formed a very stable complex with PI3 Kβ 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 3 h exhibited cytotoxic activity against HepG2 cells comparable to that of Erlotinib, a standard EGFR inhibitor (IC 50 values of 19.1 and 14.7 μM). Four of the tested compounds ( 3 e , 3 f , 3 o , and 3 p ) showed moderate anti‐proliferative activities (IC 50 values of 53.9 to 92.2 μM).