Synthesis and Biological Evaluation of 3-thiazolocoumarinyl Schiff-base Derivatives as Cholinesterase Inhibitors

Department of Pharmaceutical Sciences, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan Department of Chemistry, Quaid-i-Azam University, Islamabad-45320, Pakistan School of Computational Sciences, KIAS, Dongdaemun-gu, Seoul 130-722, South Korea.
Chemical Biology &amp Drug Design (Impact Factor: 2.49). 06/2012; 80(4):605-15. DOI: 10.1111/j.1747-0285.2012.01435.x
Source: PubMed


On the basis of the observed biological activity of the coumarins, a new set of 3-thiazolocoumarinyl Schiff-base derivatives with chlorine, hydroxy and methoxy functional group substitutions were designed and synthesized. These compounds were tested against acetylcholinesterase from Electrophorus electricus and butyrylcholinesterase from horse serum and their structure-activity relationship was established. Studies revealed them as the potential inhibitors of cholinesterase (acetylcholinesterase and butyrylcholinesterase). The 3f was found to be most potent against acetylcholinesterase with K(i) value of 1.05 ± 0.3 μm and 3l showed excellent inhibitory action against butyrylcholinesterase with K(i) value of 0.041 ± 0.002 μm. The synthesized compounds were also docked into the active sites of the homology models of acetylcholinesterase and butyrylcholinesterase to predict the binding modes of these compounds. It was predicted that most of the compounds have similar binding modes with reasonable binding affinities. Our docking studies have also shown that these synthesized compounds have better interaction patterns with butyrylcholinesterase over acetylcholinesterase. The main objective of the study was to develop new potent and selective compounds, which might be further optimized to prevent the progression of the Alzheimer's disease and could provide symptomatic treatment.

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    • "The homology models of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) [42] were used for molecular docking simulations of synthesized compounds. First hydrogen atoms were added and OPLS_2005 force field-based charges were assigned to the model structures. "
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