Chemistry Reference
In-Depth Information
The inhibitory potency of ChoK of the analogues correlates well with the energy of the lowest unoccupied molecular
orbital (
E
LUMO
) [equation (19)] and with the energy of the highest occupied molecular orbital (
E
HOMO
) [equation (20)]:
p
(IC
50
)
ChoK
= 5.33 (± 0.17) + 0.02 (± 0.00)
E
LUMO
n
= 10,
r
= 0.878,
s
= 0.207,
F
1,8
= 26.83, < 0.001
(19)
p
(IC
50
)
ChoK
= 8.83 (± 0.85) + 0.01 (± 0.00)
E
HOMO
n
= 10,
r
= 0.874,
s
= 0.210,
F
1,8
= 25.81, < 0.001
(20)
E
LUMO
and
E
HOMO
are given in Kcal/mol. When
p
(IC
50
)
ChoK
was related with the energy of the frontier orbitals, it was
found that the higher the energies of the HOMO or the LUMO are (
i.e
. closer to zero), the more potent the
compound. If HOMO is considered to contribute at the level of interaction of the compound with ChoK, it follows
that the compound acts as an electron donor, with the enzyme acting as an “electron sink”.
Table 3:
Structures for the model compounds mod 1-11, and biological data for the symmetrical bispyridinium compounds 1-11.
a
R
4
N
Me
p
(IC
50
)
ChoK
b
mod 1
-NMe
2
-296.7 -30.62 4.77
mod 2
-NH
2
-315.4 -36.77 4.64
mod 3
-CH
2
OH -338.4 -55.03 4.00
mod 4
-Me -341.0 -56.41 4.00
mod 5
-COOH -346.4 -78.69 3.86
mod 6
-CN -357.7 -88.26 -
c
mod 7
-N(Allyl)
2
-285.1 -27.92 4.77
mod 8
-NC
4
H
8
d
-293.2 -28.61 4.70
mod 9
-NC
5
H
10
e
-290.0 -26.17 5.02
mod 10
-NC
6
H
12
f
-290.8 -27.36 4.82
mod 11
-H -344.6
-63.50
4.51
a
Model compound numbers (
mod 1-10
) correspond to the compound numbers of Table
2
(
1-10
); in addition, the R
4
-unsubstituted model compound has been included;
b
All values are the means of two independent determinations performed in duplicate;
p
IC
50
= -log IC
50
; the
p
IC
50
of the corresponding bispyridinium compound of
table
2
is given for simplicity;
c
It cannot be accurately calculated because IC
50
> 1000 M;
d
pirrolidino;
e
piperidino;
f
perhydroazepino.
E
HOMO
(kcal/mol)
E
LUMO
(kcal/mol)
Comp
R
4
Fundamental chemical concepts are in discordance with this because these compounds are electron deficient and
cannot act as electron donors. It is therefore difficult to attribute a chemical meaning to the
E
HOMO
correlation. In any
thorough investigation of substituent effects, it is essential to prove that one's conclusions are
both
statistically valid
and
make chemical sense. Neither approach is sufficient alone [24].
Solvation of the Model Compounds
However, if LUMO is assumed to contribute at the level of interaction of the compound with ChoK, it is necessary
to consider the possibility of the formation of a charge transfer interaction of the HOMO of ChoK with the LUMO
of the compound (Fig.
4
).
R
4
Electron-releasing
LUMO
Drugs
HOMO
ChoK
R
4
Electron-withdrawing
ChoK-Drug
Figure 4:
Interaction between HOMO of ChoK and LUMO of drugs.
