Synthesis, molecular docking studies, and drug-likeness evaluation of new thiazolotriazolopyrimidine derivatives containing benzyloxy phenyl groups as cholinesterase enzymes inhibitors
Subject Areas :Mohammad Azimi 1 , Zahra Najafi 2 , Aida Iraji 3 , Amadreza Solgi 4 , Soheila Esmaili 5
1 - Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
2 -
3 - Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
4 - Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
5 - Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
Keywords: Synthesis, Thiazolotriazolopyrimidine, Cholinesterase inhibitors, Alzheimer's disease, Molecular docking study, Drug-likeness,
Abstract :
The acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are effective targets in managing the symptoms of Alzheimer's disease (AD), one of the most common neurological disorders in the elderly. Their inhibitors increase the acetylcholine levels in brain synapses and provide symptomatic treatment for the disease. Therefore, in this study, a series of new thiazolotriazolopyrimidine derivatives containing benzyloxy phenyl groups were synthesized in a three-component reaction with good yields, and their inhibitory activities were evaluated using the Ellman method against AChE and BChE enzymes. The results showed that compound containing 4-Me exhibited the highest inhibitory activity against AChE (22.15 ± 1.74 μM), while compound containing 4-F had the best inhibitory effect against BChE (11.70 ± 1.5 μM). Structure-activity relationships (SAR) analysis revealed that the nature, size, and position of the R substituent on the benzyl ring play a decisive role in the inhibitory activities. Molecular docking studies revealed a nearly identical binding pattern in both enzymes. They also demonstrated that hydrogen bonding and p-p interactions were the most important pharmacophoric interactions in the active sites of both enzymes. Additionally, the evaluation of pharmacokinetic properties according to Lipinski’s rule confirmed the favorable drug-likeness of the compounds. These results indicate the high potential of the synthesized derivatives for the development of cholinesterase inhibitors for the treatment of AD.
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