Diaryl hydrazones as multifunctional inhibitors of amyloid self-assembly.
The design and application of an effective, new class of multifunctional small molecule inhibitors of amyloid self-assembly are described. Several compounds based on the diaryl hydrazone scaffold were designed. Forty-four substituted derivatives of this core structure were synthesized using a variety of benzaldehydes and phenylhydrazines and characterized. The inhibitor candidates were evaluated in multiple assays, including the inhibition of amyloid β (Aβ) fibrillogenesis and oligomer formation and the reverse processes, the disassembly of preformed fibrils and oligomers. Because the structure of the hydrazone-based inhibitors mimics the redox features of the antioxidant resveratrol, the radical scavenging effect of the compounds was evaluated by colorimetric assays against 2,2-diphenyl-1-picrylhydrazyl and superoxide radicals. The hydrazone scaffold was active in all of the different assays. The structure-activity relationship revealed that the substituents on the aromatic rings had a considerable effect on the overall activity of the compounds. The inhibitors showed strong activity in fibrillogenesis inhibition and disassembly, and even greater potency in the inhibition of oligomer formation and oligomer disassembly. Supporting the quantitative fluorometric and colorimetric assays, size exclusion chromatographic studies indicated that the best compounds practically eliminated or substantially inhibited the formation of soluble, aggregated Aβ species, as well. Atomic force microscopy was also applied to monitor the morphology of Aβ deposits. The compounds also possessed the predicted antioxidant properties; approximately 30% of the synthesized compounds showed a radical scavenging effect equal to or better than that of resveratrol or ascorbic acid.
Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125-3393, USA.
Béla
B
Török
Abha
A
Sood
Seema
S
Bag
Rekha
R
Tulsan
Sanjukta
S
Ghosh
Dmitry
D
Borkin
Arleen R
AR
Kennedy
Michelle
M
Melanson
Richard
R
Madden
Weihong
W
Zhou
Harry
H
Levine
Marianna
M
Török
D000682:Amyloid / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000737:chemistry; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018625:Microscopy, Atomic Force; D015394:Molecular Structure; D010851:Picrates / Q000737:chemistry; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000737:chemistry
D000682:Amyloid; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D001713:Biphenyl Compounds; D006835:Hydrazones; D010851:Picrates; D013481:Superoxides; C004931:1,1-diphenyl-2-picrylhydrazyl