Synthesis and Biological Evaluation of Phthalazinone Inhibitors of ...

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D64 53 >5000 ND D62 54 70 ± 22 100 ± 45 D67 55 20 ± 6.6 150 ± 25 D73 56 4.0 ± 1.8 33 ± 14 D72 57 >5000 ND D78 58 1500* 1900* D70 59 >5000 ND D71 60 >5000 ND The benzofuran analog (52) exhibited moderate inhibitory activity as expected. A methyl was added at the 2-position to investigate generality of the 14
enzofuran series of inhibitors. However, the “naked” double bond of the benzofuran moiety is very prone to oxidation which would deem it metabolically labile to liver enzymes 12 ; with acyclic substituents in the 2,3-positions of the furan ring as large as a phenyl group, the double bond is still metabolized to the highly reactive epoxide intermediate 12 . Therefore, fused rings were added to the 2,3- positions of the benzofuran (Cmpds 55, 56, and 57) in an effort to divert oxidation from this site to that of the fused ring moieties should in vivo testing with these compounds be attempted. Fused ring analogs were more active than its methylated and non-methylated counterparts. Aromatization of the fused-ring in Compound 55 (6,7,8,9-tetrahydrodibenzofuran-3-yl) to 56 (dibenzofuran-3-yl) resulted in ~3-fold increase of inhibitory activity. Aromatic rings are significantly higher in energy than their saturated counterparts with the exception of cyclohexadiene; the heats of hydrogenation of benzene and cyclohexene are 208 and 102 kJ/mol 13 . The inactivity of 57 (dibenzofuran-2-yl) verifies the requirement of the ether oxygen in the paraposition of the aniline ring and intolerance in the meta-position. The carbazoles (Cmpds 59 and 60) were completely inactive, which implies that the amines are not tolerated by the enzyme. This suggests that functional groups only capable of very weak hydrogen-bond acceptor capabilities such as olefins, halogens, ether oxygens, and resonating small alkyl groups are permitted by the enzyme. Moreover, the fused furan 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. Moreover, the fused furan 15
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: methoxy group. We believe that this
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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