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 F. Teich, Ottavio Arancio, Gregory R.J. Thatcher

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Learning and memory deficits in Alzheimers disease (AD) result from synaptic failure and neuronal loss, the latter caused in part by excitotoxicity and oxidative stress. A therapeutic approach is described that 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.

Original languageEnglish (US)
Pages (from-to)6784-6801
Number of pages18
JournalJournal of Medicinal Chemistry
Volume55
Issue number15
DOIs
StatePublished - Aug 9 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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