Design and Synthesis of Neuroprotective Methylthiazoles and Modification as NO-Chimeras for Neurodegenerative Therapy

Zhihui Qin; Jia Luo; Lawren VandeVrede; Ehsan Tavassoli; Mauro Fa’; Andrew Teich; Ottavio Arancio; Gregory R. J Thatcher

doi:10.1021/jm300353r

Back

Design and Synthesis of Neuroprotective Methylthiazoles and Modification as NO-Chimeras for Neurodegenerative Therapy

Journal article

Open access

Peer reviewed

Design and Synthesis of Neuroprotective Methylthiazoles and Modification as NO-Chimeras for Neurodegenerative Therapy

Zhihui Qin, Jia Luo, Lawren VandeVrede, Ehsan Tavassoli, Mauro Fa’, Andrew Teich, Ottavio Arancio and Gregory R. J Thatcher

Journal of medicinal chemistry, Vol.55(15), pp.6784-6801

08/09/2012

DOI: 10.1021/jm300353r

PMCID: PMC3680370

PMID: 22779770

Files and links (1)

url

https://doi.org/10.1021/jm300353rView

Published (Version of record) Open Access

Abstract

Learning and memory deficits in Alzheimer’s disease (AD) result from synaptic failure and neuronal loss, the latter caused in part by excitotoxicity and oxidative stress. A therapeutic approach is described, which uses NO-chimeras directed at restoration of both synaptic function and neuroprotection. 4-Methylthiazole (MZ) derivatives were synthesized, based upon a lead neuroprotective pharmacophore acting in part by GABA A receptor potentiation. MZ derivatives were assayed for protection of primary neurons against oxygen-glucose deprivation and excitotoxicity. Selected neuroprotective derivatives were incorporated into NO-chimera prodrugs, coined nomethiazoles. To provide proof of concept for the nomethiazole drug class, selected examples were assayed for: restoration of synaptic function in hippocampal slices from AD-transgenic mice; reversal of cognitive deficits; and, brain bioavailability of the prodrug and its neuroprotective MZ metabolite. Taken together the assay data suggest that these chimeric nomethiazoles may be of use in treatment of multiple components of neurodegenerative disorders, such as AD.

Alzheimer’s disease

Amyloid β

GABA

Neuroprotection

Nitric oxide

Synaptic plasticity

Details

Title: Subtitle: Design and Synthesis of Neuroprotective Methylthiazoles and Modification as NO-Chimeras for Neurodegenerative Therapy
Creators: Zhihui Qin - University of Illinois Chicago
Jia Luo - University of Illinois Chicago
Lawren VandeVrede - University of Illinois Chicago
Ehsan Tavassoli - University of Illinois Chicago
Mauro Fa’ - Columbia University
Andrew Teich - Columbia University
Ottavio Arancio - Columbia University
Gregory R. J Thatcher - University of Illinois Chicago
Resource Type: Journal article
Publication Details: Journal of medicinal chemistry, Vol.55(15), pp.6784-6801
DOI: 10.1021/jm300353r
PMID: 22779770
PMCID: PMC3680370
NLM abbreviation: J Med Chem
ISSN: 0022-2623
eISSN: 1520-4804
Grant note: U01 AG031294 || AG / National Institute on Aging : NIA
Language: English
Date published: 08/09/2012
Academic Unit: Pathology
Record Identifier: 9984201119102771

Metrics

18 Record Views

33 Times Cited - Web of Science