Synthesis and Biological Evaluation of Phthalazinone Inhibitors of ...
Synthesis and Biological Evaluation of Phthalazinone Inhibitors of ...
Synthesis and Biological Evaluation of Phthalazinone Inhibitors of ...
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ABSTRACT<br />
<strong>Phthalazinone</strong> <strong>Inhibitors</strong> <strong>of</strong> Cryptosporidium parvum Inosine-5’-Monophosphate<br />
Dehydrogenase<br />
A thesis presented to the Chemistry Department<br />
Graduate School <strong>of</strong> Arts <strong>and</strong> Sciences<br />
Br<strong>and</strong>eis University<br />
Waltham, Massachusetts<br />
By Corey R. Johnson<br />
Cryptosporidium parvum has a salvaged guanine nucleotide biosynthetic pathway<br />
for metabolism in which inosine-5’-monophosphate dehydrogenase (IMPDH) plays<br />
a key role. The characterization <strong>of</strong> C. parvum IMPDH has instigated a drug discovery<br />
program exploiting a nicotinamide adenine dinucleotide (NAD + ) active site for<br />
selective inhibition over its human counterpart. A series <strong>of</strong> N-aryl-4-oxophthalazine<br />
acetamide inhibitors are described. For acyclic substituted anilines, structureactivity<br />
relationship revealed that electron-withdrawing substituents at the paraposition<br />
are required. An additional substituent in the meta-position improved<br />
potency up to 10-fold. It was proposed that pseudo-ring formation due to π-π<br />
interactions <strong>of</strong> substituents at the 3- <strong>and</strong> 4- positions <strong>of</strong> the aniline ring may be<br />
ii
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