J. Trujillo-Ferrara et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1825–1827
1827
Starting with this evidence, we presuppose the existence
of more arylamide conformers than arylimide con-
formers at the assay conditions. This fact make us sup-
pose the increase in the steric and electronic interactions
between arylamides here presented and the residues
located in the enzyme’s gorge. These interactions could
make difficult the entrance and displacement of aryl-
amides 1a and 2a through the gorge, and consequently
diminish their inhibitory potency in comparison to
arylimides 1b and 2b.
because of this reaction to be made requires high-energy
conditions and the presence of a catalyzst; therefore,
arylamides at the assay conditions (pH 8, T=37 ꢀC,
phosphates buffer) are only able to be solvated, but not
cycled.
In summary, arylimide 2a was more potent than tacrine
and galanthamine (1.5- and 10.8-fold, respectively),
while compound 2b was less potent than tacrine (1.9-
fold) but more potent than galanthamine (3.9-fold).
Four compounds were more potent than aminophenol
derivatives reported by our workgroup.7 Furthermore,
preliminary toxicity probes showed that compounds 1a,
2a and 1b are relatively low toxicity (LD50 >1000 mg/kg).
We analyzed molecules by means of theoretical calcula-
tions for four compounds. Energy minimization and
nuclei charge of each molecule was carried out at semi-
empirical AM1 level using Mopac 6.0 included in Vega
package;11 optimized molecules were treated to obtain
their respective p orbitals. As observed, compounds 2a
and 2b possess more p orbitals distributed along the
molecule than compounds 1a and 1b and, therefore,
more electron density. This fact makes us suppose that
compounds 1a and 1b have an advantage compared to
compounds 2a and 2b because we know that the acet-
ylcholinesterase’s gorge has, at least, 14 aromatic resi-
dues8 which may interact with electron-enriched
compounds through p–p stacking, principally; this way,
the diffusion through the gorge of compounds 2a and 2b
is lower than compounds 1a and 1b. Low diffusion
through the active site has as consequence the limitation
in inhibitory potency for compounds 2a and 2b, as
observed experimentally.
Further studies on improved arylamides and arylimides
are in progress and will be reported in due course.
Acknowledgements
The authors would like to thank Dr. Hiram I. Beltran
for the suggestions made to the discussion and
CONACYT and SEGEPI-IPN for financial support.
References and Notes
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Also, it is possible that molecules 1b and 2b may be
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in the enzyme active site, and the behavior of the mole-
cules may be more complicated than presented above,
but currently we are working on elucidating all possible
mechanisms; but experimentally we know that, at pH 9,
compounds 1b and 2b keep their cyclic structure,
whereas at pH >9and room temperature compounds
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this effect is spectroscopically observed, since at pH >9
N.; Hopfl, H. Magn. Reson. Chem. 1999, 37, 682.
¨
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Farfan, N.; Hopfl, H. Eur. J. Pharm. Sci. in press.
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1
A4 and A2 systems in the H NMR spectra from imidic
fragment of molecules 1b and 2b, respectively, changes
1
to A2B2 and AB systems in the H NMR spectra, cor-
responding to the amidic 1a and 2a forms. Therefore,
imides here presented are stable at assay pH, being
much more stable than arylimide 1b. On the other hand,
the possibilities of ring closing in arylamides are low,
11. Pedretti, A.; Villa, L.; Vistoli, G. J. Mol. Graph. 2002, 21,
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