Synthesis and Biological Evaluation of Phthalazinone Inhibitors of ...

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substitutions are strongly electron-donating in opposition to the 3,4-halogen and pseudo-halogen counterparts which confirms that increasing inhibition is not due to the electron-deficiency of the aniline ring which one may interpret from the Topliss Tree 10 ; Topliss Tree suggests next compound be the extremely electronwithdrawing 3-CF3-4-NO2Ph from 3-CF3-4-ClPh for enhanced inhibition; in this work we have achieved higher inhibition with the extremely electron-donating dibenzofuran from 3-CF3-4-ClPh. Cell-culture model of infection Table IV. Anti-cryptosporidial/toxoplasmodial activities. Performed by the Striepen Laboratory at Univ. of Georgia. Cmpd Toxo WT (µM) Toxo HX (µM) Toxo WT/ CpIMPDH (µM) Selectivity WT/ CpIMPDH C. parvum (µM) LIVE/DEAD assay (µM) 29 5 ± 3 12 ± 11 0.24 ± 0.2 40 - - 30 23 ± 4 17 ± 12 0.10 ± 0.2 83 3.1 - 31 - - - - - >10 55 - - - - - 7.7 56 3 ± 3 3 ± 2 0.40 ± 0.08 7 >10 - *minimum concentration where toxicity observed. 16
Trends in potency seemed to increase with added energy in the benzofuran series. However, compound 56 is inactive in the cell-culture model of infection of the parasite, and compound 30 is active. The acidities of the amide hydrogen in both compounds differ. It was hypothesized that the decreasing the acidity of the amide enhances the solubility of 56 over 30 in aqueous solvents. However, there is no correlation between solubility and potency in this series. Furthermore, the amide hydrogen is strongly acidic in the presence of an electron-deficient aromatic ring (30) and less acidic in presence of an electron-rich aromatic ring (56). Often, acidic protons will stabilize hydrogen-bond donation to nearby acceptors such as N-3 of the phthalazine ring. In the case of 56, the acetamide linker should be non-planar to the phthalazine ring whereas 30 should be planar due to pseudo-ring formation. The parasite in cell-culture is selective of the conformation of 30 but not 56. This is more apparent in the cell-culture model data of compound 55 which is still a high-energy molecule compared to the initial series, but maintains potency against the parasite. Compound 55 is not as electron-donating as 56 due to resonance of the aromatic versus non-aromatic ring. The amide proton is more acidic in 55 than in 56 which would enhance formation of the pseudo-ring with N-3 of the phthalazine ring. Moreover, the 1 H NMR spectra of 56 shows 2 peaks for the amide nitrogen indicating free rotation, different conformations about the amide bond. Compound 30 exhibited insignificant activity in a mouse model of infection (250 mg/kg in corn oil with 10% DMSO), which we accredit to its insolubility correlating to pseudo-ring conformation due to the strong H-bond between N-3 and 17
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: enzofuran series of inhibitors. How
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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