Biomedical Engineering Reference
In-Depth Information
dimethyl groups in 8 may be the main pharmacophoric features for all three
activities of all the derivatives of 8. It is suggested that these features closely
match the K
ATP
-channel binding requirements and are responsible for the muscle
relaxation potencies [
51
]. The study has provided a composite rationale for three
related biological endpoints of these compounds.
Satuluri and Gupta [
49
] have correlated the vasorelaxant activity of these
benzothiazine derivatives (8) with
C
log
P
of the compounds and two indicator
variables (
I
3
and
I
4
) (12). In (12),
C
log
P
alone accounted for 44% of the variance
in the activity.
pEC50
¼
7
:
653
ð
1
:
508
Þ þ
0
:
916
ð
0
:
474
Þ
C
log
P
1
:
098
ð
1
:
012
Þ
I
3
2
:
743
ð
1
:
014
Þ
I
4
(12)
Q
2
n
¼
15
;
r
¼
0
:
946
;
¼
0
:
80
;
s
¼
0
:
84
;
F
¼
31
:
35
:
Here, the indicator variable
I
3
is defined for an R
1
-substituent, which is 2-oxo-
pyrrilidinyl group and
I
4
is defined for an R
2
-substituent, which is simply bromine.
The regression coefficients of both these indicators suggested the unfavorable
nature of R
1
- and R
2
- substituents for the activity. The results of 2D- and 3D-
QSAR are in agreement with each other. However, the 2D-models provided
fundamental explanation to the activity of the analogues. Additionally, as Satuluri
and Gupta have investigated both benzopyran (6 and 7) and benzothiazine (8)
derivatives, their findings have led to suggest that in benzopyran derivatives the
steric factors may be more crucial for the activity, whereas in benzothiazine
derivatives the hydrophobic property appears to be prominently influencing the
activity [
49
]. This study has vividly explained the structural requirement for the
K
ATP
-channel blockers by making use of the fundamental descriptors involved in
the equations.
2.4 Benzothiadiazine 1,1-Dioxide Derivatives
Boverie and coworkers have investigated different 3-alkylamino-4
H
-1,2,
4-benzothiadiazine 1,1-dioxides (9) for the pancreatic and vascular (rat aorta)
K
ATP
channel opening activity [
53
-
55
]. In these compounds (9), R
3
substituent
represents various alkyl and aminoalkyl moieties and R
6
and R
7
represent the
groups such as halo, nitro, alkylesters, alkyl and aminoalkyl. For these com-
pounds, inhibition of glucose-induced insulin secretion (evaluated on isolated
rat pancreatic islets) is reported in terms of IC
50
, and myorelaxant effect on the
contractile activity of KCl-depolarized rat aorta rings is reported in terms of EC
50
.
For these compounds, Sharma et al. [
56
] developed QSAR models (13 and 14),
showing the dependence of activities on hydrophobic, steric and some indicator
parameters.
