Studies on the Synthesis and Rearrangement of Indazolylpyridinium Derivatives Precursors to Potential Neuroprotective Prodrugs Bearing a 1,2,3,6-Tetrahydropyridinyl Carrier
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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-NIâ 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 â prodrugsâ 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 â prodrugsâ , 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 â prodrugsâ 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.
- Doctoral Dissertations