Chemistry Reference
In-Depth Information
With the solvent (H
2
O) molecules acting as electron donors, the bispyridinium compounds
1-11
behave as electron
acceptors. The increase of the
E
LUMO
of the molecule would result in its weaker solvation, and thus, a stronger
interaction with ChoK. A possible chemical meaning for the
E
LUMO
correlation is therefore offered by the hypothesis
that a higher value for
E
LUMO
indicates a weaker solvation of the compound (Fig.
5
) [24].
R
4
H
2
O
H
2
O
R
4
Electron-releasing
Drug
> E
LUMO
closer to zero
H
2
O
H
2
O
R
4
Drug
ChoK
R
4
R
4
Electron-withdrawing
H
2
O
H
2
O
H
2
O
H
2
O
Drug
> E
LUMO
more far away to zeo
H
2
O
H
2
O
H
2
O
Figure 5:
Solvation of model compounds.
QSAR Studies on the ChoK Inhibition and clog P
In order to study the possible influence of lipophilicity on the inhibition of ChoK under
ex vivo
conditions, we
selected structures with the following characteristics:
1.
Cationic heads that allow the dispersion to a great extent of the positive charge with a “zero electronic
effect”,
i. e.
, with no substituents at position 4. To this end unsubstituted quinolinium and
isoquinolinium rings have been used.
2.
Aralkyl spacers with different number of methylene groups.
Table 4:
Structures, activity data and parameters used for deriving equation (21).
Y
Y
X
X
(CH
2
)
n
2Br
(IC
50
)
ChoK
a
(
M)
(IC
50
)
HT-29
a
(
M)
clog
P
b
Comp
X
Y
n
12
=N
+
- =CH- 0 50 10 -0.71
13
=N
+
- =CH- 1 100 6.02 -0.86
14
=N
+
- =CH- 2 34 4 -0.43
15
=N
+
- =CH- 3 9 2.5 0.08
16
=CH- =N
+
- 0 >100 ND
c
-0.85
17
=CH- =N
+
- 1 60 20 -1.00
18
=CH- =N
+
- 2 60 20 -0.57
19
=CH- =N
+
- 3 20 2 -0.06
a
All values are the means of two independent determinations performed in duplicate.
b
Predicted by using the Ghose-Crippen modified atomic contribution system
(option ATOMIC5) of the PALLAS 2.0 programme [21].
c
ND: Not determined.
For these compounds, the ChoK inhibition activity is found to be correlated with lipophilicity as shown in equation
(21):
p
(IC
50
)
ChoK
= 4.83 (± 0.09) + 0.81 (± 0.15) clog
P n
= 7,
r
= 0.922,
s
= 0.151,
F
1,5
= 28.57 (significance at < 0.005)
(21)
On the basis of this equation (21), we suggest that hydrophobic interactions may occur between the bissalts
12-19
and ChoK. Hydrophobicity is not only related to absorption and distribution phenomena but also to the interactions
