Synthesis and Biological Evaluation of Phthalazinone Inhibitors of ...

lone pair. Electron-withdrawing para-substitutions will compete with the
trifluoromethyl group for electrons withdrawn from the aromatic ring.
Compounds 40 and 41 (3-Me-4-Cl, 4-Br) instigated the idea of resonance
hybrid double-bond interactions with the electron-donating methyl group in the
meta-position which enhanced inhibitory activity from 14 (4-ClPh) and is
equipotent with its 3-chloro counterparts (Cmpds 23 and 28). Compound 42 (3-Me-
4-CNPh) confirms that the existing trend is due exclusively to π-π interactions of
resonance hybrids with no halogen substituents on the aniline ring. Therefore, we
conclude that one or more of the fluorines of the trifluoromethyl group or the
methyl group in the meta-position is forming pseudo-rings via π-π interactions with
the para-substituent via resonance hybridization. Outstandingly, compounds 23
(3,4-ClPh) and 40 (3-Me-4ClPh) have similar potencies against CpIMPDH. Other
factors concerning the 3-trifluoromethyl SAR were discussed earlier in this work.
Compound 37 (3-CF3-4-ClPh) suggests that removal of the methyl at N-2 is
detrimental to inhibitory activity when 3-trifluoromethyl-4-chloro moiety is
installed on aromatic ring. The enhanced inhibitory activity from 37 (3-CF3-4-ClPh)
to 38 (3-CF3-4-BrPh) shows that this subseries of compounds follows the size trend
for the other series (A, C) of inhibitors against CpIMPDH 6 .
ChemBio3D Ultra MM2 minimizations of compounds 30 and 34.
10