Synthesis and Biological Evaluation of Phthalazinone Inhibitors of ...

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List of Illustrations/Figures Figure I. Figure II: IMPDH reaction scheme. CpIMPDH inhibitor identified by HTS. Figure III. Intramolecular interactions of 3-halo-, 3-methyl- and 3- trifluoromethyl- series. Figure IV. Figure V. Scheme I. Ball-and-stick model of Cmpd 30. (ChemBio3D Ultra) Ball-and-stick model of Cmpd 34. (ChemBio3D Ultra) General Procedure for the Synthesis of Amide Derivatives. vi
Introduction Outbreaks worldwide have instigated drug discovery programs against the waterborne protozoan parasite Cryptosporidium parvum 1 . A calf is capable of producing enough oocysts to infect millions of people rendering C. parvum a bioterrorism threat 2 . Drug discovery for C. parvum is challenging due to absence of continuous cell culture. Moreover, drugs currently on the market for C. parvum are ineffective. Genomic analysis of C. parvum has revealed a guanine nucleotide biosynthetic pathway which implies that inosine-5’-monophosphate dehydrogenase (IMPDH) could serve a key role in parasite metabolism 3 . Guanine nucleotide pathways generally abide by the following sequence: AMP is converted to IMP by adenine deaminase (ADA); IMP is converted to XMP by IMPDH; XMP is converted to GMP by GMP synthase. The absence of guanine/xanthine phosphoribosyltransferases or guanosine/xanthosine kinases, or collectively salvage enzymes in this scheme, indicates that IMPDH controls the guanine nucleotide metabolism sequence for this parasite. IMPDH oxidizes IMP to XMP via a redox reaction that produces NADH and a Cysteine-linked covalent enzyme intermediate E-XMP*, and a hydrolysis reaction which releases XMP. Since NADH absorbs light at wavelength 340 nm, its production via concentration can be detected by UV-VIS spectrometer, a decrease in its concentration was used as the indicator of C. parvum IMPDH inhibition. 1
Page 1 and 2: Synthesis and Biological Evaluation
Page 3 and 4: inducing enzyme inhibition. Further
Page 5: List of Tables Table I. Table II. I
Page 9 and 10: Compound 7 and its analogs were pre
Page 11 and 12: D21 9 Me 2-OMePh >5000 ND D23 10 Me
Page 13 and 14: D35 51 Me thiazolyl) 2-(5-Me(1,3,4-
Page 15 and 16: Figure III. Intramolecular interact
Page 17 and 18: Figure IV. Ball-and-stick model of
Page 19 and 20: methoxy group. We believe that this
Page 21 and 22: enzofuran series of inhibitors. How
Page 23 and 24: Trends in potency seemed to increas
Page 25 and 26: Conclusion We have hypothesized, ap
Page 27 and 28: chemical shift values are also repo
Page 29 and 30: General procedure for the synthesis
Page 31 and 32: (15) N-(4-bromophenyl)-2-(3-methyl-
Page 33 and 34: 1H, J= 7 Hz), (8.17, d, 1H, J= 9 Hz
Page 35 and 36: (7.95, q, 2H, J= 7-8 Hz), (7.87, t,
Page 37 and 38: 1H, J= 8 Hz), (7.31, d, 1H, J= 8 Hz
Page 39: Bibliography 1. Huang, D.R.; White,

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