Cu‐Catalyzed Synthesis of 4H‐benzothiazolopyrimidin‐4‐ones: Molecular Docking Studies and Anti‐Proliferative Activities Against HepG2 Hepatocellular Carcinoma Cells

• Published in: Asian journal of organic chemistry 2024-06, Vol.13 (6)
• Main Authors: Aljaar, Nayyef, Aboalrub, Husam F, Shtaiwi, Majed, Abu Sarhan, Ayman H, Younes, Eyad A, Mousa Al‐Noaimi, Shtaiwi, Amneh, Tahtamouni, Lubna H, Kayed A Abu‐Safieh, AlObaid, Abeer A, Malakar, Chandi C
• Format: Article
• Language: English
• Subjects: Chemical synthesis; Copper; Free energy; Growth factors; Kinases; Liver cancer; Molecular docking
• ISSN: 2193-5807; 2193-5815
• DOI: 10.1002/ajoc.202400065

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 (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 (IC50 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 (IC50 values of 53.9 to 92.2 μM).