Title page for ETD etd-11272000-120319

Type of Document Master's Thesis
Author Isin, Emre M.
Author's Email Address eisin@vt.edu
URN etd-11272000-120319

Potential Prodrugs of the Neuronal Nitric Oxide Synthase and Monoamine Oxidase Inhibitor 7-Nitroindazole and Structurally Related Compounds

Degree Master of Science
Department Chemistry
Advisory Committee
Advisor Name Title
Castagnoli, Neal Jr. Committee Chair
Dorn, Harry C. Committee Member
Kingston, David G. I. Committee Member
Tanko, James M. Committee Member
  • indazole
  • neuroprotection
  • organic reaction mechanisms
  • SAR
  • tetrahydropyridinyl-based prodrugs
Date of Defense 2000-10-30
Availability unrestricted
Parkinson's disease (PD) is a progressive neurodegenerative disorder of unknown cause that afflicts about 1.5 million Americans. The characteristic feature of PD is a deficiency of dopamine in the terminals of nigrostriatal neurons. Two enzyme systems, the neuronal form of nitric oxide synthase (nNOS) and monoamine oxidase B (MAO-B), have been linked to neurodegenerative pathways leading to PD. Several MAO-B and nNOS inhibitors have been evaluated for their neuroprotective properties in the mouse model of neurodegeneration which employs the parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). One such compound is 7-nitroindazole (7-NI), a compound which is reported to inhibit both enzymes.

This thesis focuses on the synthesis and biological evaluation of a potential prodrug form of 7-NI and related indazolyl containing compounds which are designed to release the active drugs following a metabolic bioactivation process. These studies have led to a detailed description of the nucleophilic aromatic substitution reactions between 4-chloro-1-methylpyridinium iodide and the indazolyl reactants that were employed as the initial step in the synthesis of the target compounds. The MAO-B substrate and inhibition properties of these "prodrugs" as well as the parent indazolyl compounds were examined. The results are discussed in relation to a previously developed active site model of MAO-B.

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