Synthesis and Biological Evaluation of Phthalazinone Inhibitors of ...

compound 31 (3-Cl-4-BrPh) because bromine is more acidic than chlorine. The
increase in potency from compound 27 to compound 31 correlates to the increased
differences in substituent lewis acidities for these compounds which insists halogen
bonding induces enzyme inhibition. Also, the difference in substituent lewis
acidities for compound 29 (3-CF3-4-BrPh) is significantly less than that of
compound 30 (3-CF3-4-ClPh). However, there was no increase in potency from
compound 30 to compound 29. Compounds 29 and 30 did not follow the expected
potency differences correlating to the differences in substituent lewis acidities
which insists that enzyme inhibition is not induced by halogen bonding. This
discovery lead to designed experiments for which the presence of halogen-pi or pipi
interactions could be determined vital to induction of enzyme inhibition.
Compounds 33 (3-CF3-4-FPh) and 31 (3-CF3-4-CNPh) with the more
electron-withdrawing fluorine and cyano moieties in the para-position did not
exhibit greater potency than 30 (3-CF3-4-ClPh). We believe this is due to the
electron-withdrawing of the para-positioned functional group. Bromine is not very
electron-withdrawing, but cyano and fluorine groups are. The cyano and fluorine
groups are more competitive with the trifluoromethyl group for electronwithdrawal
from the aromatic ring which perturbs the basicity of the fluorine
groups of the trifluoromethyl substituent and disrupt the interactive relationship.
The inactivity of 13 (4-FPh) suggests presence of pseudo-ring formation in 33 (3-
CF3-4-FPh).
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