Title page for ETD etd-04272004-162852


Type of Document Dissertation
Author Isin, Emre Mehmet
Author's Email Address eisin@vt.edu
URN etd-04272004-162852
Title Studies on the Synthesis and Rearrangement of Indazolylpyridinium Derivatives Precursors to Potential Neuroprotective Prodrugs Bearing a 1,2,3,6-Tetrahydropyridinyl Carrier
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Castagnoli, Neal Jr. Committee Chair
Bevan, David R. Committee Member
Carlier, Paul R. Committee Member
Kingston, David G. I. Committee Member
Tanko, James M. Committee Member
Keywords
  • Regiospecific synthesis
  • Monoamine oxidase
  • Bioactivation
  • Docking
  • Neuroprotection
  • Rearrangement
Date of Defense 2004-03-22
Availability unrestricted
Abstract

The neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI) protects against the neurotoxicity of MPTP in a mouse model of neurodegeneration. Since 7-NI also inhibits the monoamine oxidase-B (MAO-B) catalyzed bioactivation of MPTP, the role of nNOS inhibition as a mediator of 7-NI’s neuroprotective properties have been challenged. In order to examine in greater detail the neuroprotective effects of indazolyl derivatives, the synthesis of water soluble indazolyltetrahydropyridinyl derivatives as potential “prodrugs” that may undergo MAO bioactivation in the brain was undertaken. During the course of the studies on the synthesis of indazolylpyridinium derivatives, precursors to these “prodrugs”, an interesting reaction involving the rearrangement of 4-(2H-indazolyl)-1-methylpyridinium iodide to the corresponding 1H-isomer was encountered. A detailed investigation of this rearrangement reaction is reported in this thesis.

The syntheses and interaction of nitroindazolyltetrahydropyridinyl “prodrugs” with MAO-B have been investigated previously. Molecular docking studies that attempt to explain the MAO-B substrate and inhibitor properties of members of this series of compounds are described. Finally, the MAO-A substrate properties of nitroindazolyltetrahydropyridinyl derivatives are reported.

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