Synthesis and Biological Evaluation of Phthalazinone Inhibitors of ...

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the very acidic amide hydrogen. Compound 30 is only soluble in DMSO at low concentrations; the same phenomena exists for the precursor acid. Compound 56, however, dissolves in a variety of solvents which is why it was used for the screening against other bacteria. Table V. Anti-parasitic activities against potential biowarfare agents. Performed by the New England Regional Center of Excellenece/ Biodefense and Emerging Infectious Diseases (NERCE/BEID). Minimum inhibitory concentrations [MIC] (µM) Cmpd E. coli A. baumannii S. aureus S. pneumoniae B. anthracis F. tularensis Y. pestis 56 ≥20 10 20 20 20 0.039 20 The bacteria used in this screening were selected based on a structural motif of their IMPDHs. Compound 56 because of its solubility in the prescribed buffer for this screen over compound 30 was selected and tested for its minimum concentration necessary for complete inhibition of bacterial growth. Compound 56 exhibited significant activity against Franciscella tularensis with a MIC in the nanomolar range. 18
Conclusion We have hypothesized, applied, and tested a new phenomenon of pseudoring formations due to π-π interactions between functional groups to the synthesis of very potent furan-based inhibitors which exploited the structural-activity relationships of trending CpIMPDH inhibition. We conclude that inhibition of CpIMPDH is exclusive to hydrogen or halogen-bond acceptor groups in either the 4 or 3,4-positions of the aniline ring. Then, we submitted our best compounds from the enzyme assay for cell-culture model assays attaining low micromolar inhibition. Future endeavors include x-ray diffraction of compounds 29 30, 34, and 42 for further analysis of the CpIMPDH inhibition trend discussed in this article, and optimization and screening of new dibenzofuranamide derivatives against F. tularensis. Methods Biology Determination of IC50 values. (performed by Minjia Zhang of Hedstrom Laboratory) Inhibition of recombinant CpIMPDH, purified from E. coli, was assessed by monitoring the production of NADH by fluorescence at varying inhibitor concentrations (25 pM - 5 μM). IMPDH was incubated with inhibitor for 5 min at 19
Page 1 and 2: Synthesis and Biological Evaluation
Page 3 and 4: inducing enzyme inhibition. Further
Page 5 and 6: List of Tables Table I. Table II. I
Page 7 and 8: Introduction Outbreaks worldwide ha
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: Trends in potency seemed to increas
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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