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Curcumin‐Derived Pyrazoles and Isoxazoles: Swiss Army Knives or Blunt Tools for Alzheimer's Disease?
Author(s) -
Narlawar Rajeshwar,
Pickhardt Marcus,
Leuchtenberger Stefanie,
Baumann Karlheinz,
Krause Sabine,
Dyrks Thomas,
Weggen Sascha,
Mandelkow Eckhard,
Schmidt Boris
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700218
Subject(s) - curcumin , moiety , chemistry , chelation , peptide , amyloid (mycology) , stereochemistry , protein aggregation , combinatorial chemistry , biochemistry , organic chemistry , inorganic chemistry
Curcumin binds to the amyloid β peptide (Aβ) and inhibits or modulates amyloid precursor protein (APP) metabolism. Therefore, curcumin‐derived isoxazoles and pyrazoles were synthesized to minimize the metal chelation properties of curcumin. The decreased rotational freedom and absence of stereoisomers was predicted to enhance affinity toward Aβ 42 aggregates. Accordingly, replacement of the 1,3‐dicarbonyl moiety with isosteric heterocycles turned curcumin analogue isoxazoles and pyrazoles into potent ligands of fibrillar Aβ 42 aggregates. Additionally, several compounds are potent inhibitors of tau protein aggregation and depolymerized tau protein aggregates at low micromolar concentrations.