Fragment merging approach for design, synthesis, and biological assessment of urea/acetyl hydrazide clubbed thienopyrimidine derivatives as GSK-3β inhibitors

New thienopyrimidine derivatives were designed and synthesized as GSK-3 beta inhibitors based on the structure of active binding site of GSK-3 beta enzyme. In this study, compounds 6b and 6a were found to be moderate GSK-3 beta inhibitors with IC50s 10.2 and 17.3 mu M, respectively. Molecular docking study was carried out by docking the targeted compounds in the binding site of the GSK-3 beta enzyme using the MOE program. Moreover, ADME study was performed to predict certain pharmacokinetic properties. The results showed that all synthesized compounds may not be able to penetrate the blood brain barrier; so, the chances of CNS side effects are predicted to be low. CYP1D6 is predicted to be inhibited by compounds (5a, 5d, 6a, 9a and 9b), So drug-drug interactions are expected upon administration of these compounds.

Automated summary

New thienopyrimidine derivatives were designed and synthesized as GSK-3 beta inhibitors based on the structure of the active binding site of the enzyme. Compound 6b and 6a showed moderate inhibitory activity against GSK-3 beta. Molecular docking study and ADME prediction suggested that the synthesized compounds may have limited ability to penetrate the blood brain barrier, reducing the chances of CNS side effects, but may also lead to drug-drug interactions.