Synthesis and Biological Evaluation of Phthalazinone Inhibitors of ...

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D48 30 Me 3-CF3-4-ClPh 13 ± 0.82 25 ± 7.1 D50 31 Me 3-CF3-4-CNPh 81 ± 32 130 ± 100 D49 32 Me 3-Cl-4-CNPh 290 ± 51 470 ± 170 D60 33 Me 3-CF3-4-FPh 150 ± 32 150 ± 41 D53 34 Me 3-CF3-4-OMePh >5000 ND D54 35 Me 3-CF3-4-NH2Ph >5000 ND D51 36 Me 3-CF3Ph >5000 ND D58 37 H 3-CF3-4-ClPh 40 ± 1.7 61 ± 1.7 D59 38 H 3-CF3-4-BrPh 17* 42* D52 39 Me 3-F-4-ClPh 200 ± 41 140 ± 45 D68 40 Me 3-Me-4-ClPh 66 ± 12 100 ± 26 D74 41 Me 3-Me-4-BrPh 82* 150* D76 42 Me 3-Me-4-CNPh 650* 640* D69 43 Me 3-OMe-4-ClPh 31* 31* D57 44 Me 2-CF3-4-ClPh >5000 ND D56 45 Me 2-CF3-4-BrPh >5000 ND D33 46 Me 2-F-4-BrPh 1500* 1700* D38 47 Me 2,4-BrPh >5000 ND D41 48 Me 2-naphthyl 61* 134* D77 49 Me 3,4-CNPh 2500* 2500* D28 50 Me 2-(1,3,4- >5000 ND 6
D35 51 Me thiazolyl) 2-(5-Me(1,3,4- thiazolyl) >5000 ND The D series shares the same general trend with the other two series 6 ; that is, halogen groups in the para-position larger than fluorine (Compounds 14 and 15) are preferred for activity and potency increases with the van der Waals area/volume of the halogen 6,11 . For ether groups in the para position, this trend is not present as the bigger ethoxy group (Cmpd 11) is inactive. The 3,4- combination of halogens (Cmpds 23 and 28) exhibits greater potency but does not increase with van der Waals area of the functional groups. From this discovery came the idea that the substituents were forming pseudo-rings to suit a conformation preferred by CpIMPDH. We hypothesized that these interactions to be either halogen bonding or π-π interactions, and designed experiments to test either phenomena correlating to CpIMPDH inhibition. Halogen bonding is the non-covalent interaction between an electron-rich functional group and a halogen 8,9 ; it is analogous to hydrogen bonding. Halogen bonding improves with increased differences in lewis acidity of the acceptor halogen group (lewis acid) and the donor group (lewis base) 9 . Acidity increases down the periodic table. Fluorine is the least acidic halogen and the most basic, and astatine is the most acidic and least basic halogen 9 . For example, the difference in substituent lewis acidities of compound 27 (3,4-ClPh) is significantly less than 7
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: D21 9 Me 2-OMePh >5000 ND D23 10 Me
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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