Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 20, Issue 21, Pages 6513-6522Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.08.040
Keywords
Alzheimer's disease; Phenylthiazole-tacrine hybrids; Cholinesterase inhibition; beta-Amyloid aggregation; Ca2+ overload
Funding
- Key Project of National Natural Science Foundation of China [30930104]
- International Science & Technology Cooperation Program of China [2011DFA32670]
- Important National Science & Technology Specific Projects [2012ZX09103-101-045]
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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 A beta(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 Ca2+ overload blockade effect in the primary cultured cortical neurons. Consequently, these compounds emerged as promising molecules for the therapy of Alzheimer's disease. (C) 2012 Elsevier Ltd. All rights reserved.
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