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Bioorg Med Chem. 2012 Nov 1;20(21):6513-22. doi: 10.1016/j.bmc.2012.08.040. Epub 2012 Aug 30.

Novel multipotent phenylthiazole-tacrine hybrids for the inhibition of cholinesterase activity, β-amyloid aggregation and Ca²⁺ overload.

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  • 1Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.

Abstract

In this study, a series of multipotent phenylthiazole-tacrine hybrids (7a-7e, 8, and 9a-9m) were synthesized and biologically evaluated. Screening results showed that phenylthiazole-tacrine hybrids were potent cholinesterase inhibitors with pIC(50) (-logIC(50)) value ranging from 5.78 ± 0.05 to 7.14 ± 0.01 for acetylcholinesterase (AChE), and from 5.75 ± 0.03 to 10.35 ± 0.15 for butyrylcholinesterase (BuChE). The second series of phenylthiazole-tacrine hybrids (9a-9m) could efficiently prevent Aβ(1-42) self-aggregation. The structure-activity relationship revealed that their inhibitory potency relied on the type of middle linker and substitutions at 4'-position of 4-phenyl-2-aminothiazole. In addition, 7a and 7c also displayed the Ca(2+) overload blockade effect in the primary cultured cortical neurons. Consequently, these compounds emerged as promising molecules for the therapy of Alzheimer's disease.

Copyright © 2012 Elsevier Ltd. All rights reserved.

[PubMed - indexed for MEDLINE]
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