Design and synthesis of novel isatin derivatives as potent analgesic, anti-inflammatory and antimicrobial agents

Article abstract of DOI:10.1007/s12039-020-01795-0

Abstract: A powerful analgesic, anti-inflammatory and antimicrobial drug was developed by synthesizing a set of new indole-2,3-dione derivatives. The chemical structures of the synthesized derivatives were confirmed by spectroscopic and elemental analyses

Full text of DOI:10.1007/s12039-020-01795-0

J. Chem. Sci.
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6
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3
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H
)
1
7
3
6
C
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5
4
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)
C
H N O S : C , 5 8. 7 4 ; H , 4 . 7 4; N , 1 8 . 4 4 . F ou n d : C ,
2 5 7 4
2
6
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7
f 1-(4-Hydroxybenzylidene)-4-(4-(1-((dimethylamino)
methyl)-5-nitro-2-oxoindolin-3-ylideneamino)
phenyl) thiosemicarbazide (VIf
1
9
p
8
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H
A
r
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6
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5
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1
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C
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2
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5
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)
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5
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S
(
).
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H
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M
1
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0
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4
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1
1
8
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C
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7
)
N
(
2
C H ) ) , 4 . 3 8 ( s , 2 H , C H l i n k ag e ), 5 . 36 ( s , 1 H , O H ) ,
3 2 2
1
3
7
7
.
6
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C
2
-
9
7
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4
(
H
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2
,
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4
7
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7
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H
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S
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s
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3
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N , 18 .3 2.
5
6
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1
4
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8
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2
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1
9
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0
C
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-
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7
C
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(
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S
1
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1
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1
6
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5 .
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5
1
.
9
8
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1
4
3
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1
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H
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20
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3
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C
40
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2
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C
.
a
n
d
C
-
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2 d 1-(4-Methylbenzylidene)-4-(4-(1-((dimethylamino)
methyl)-5-nitro-2-oxoindolin-3-ylideneamino)
.
7
1
2
9
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8
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C
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n
d
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0
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C
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4
1
6
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1
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1
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C
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4
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1
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2
C
5
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8
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C
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6
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1
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3
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5
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C
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a
n
d
)
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60
)
4
2
H
1
.
-
7
)
,
7
.
-
9
)
I -
,
phenyl) thiosemicarbazide (VId
1
2
)
:
Y
9
1
1
i
e
l
a
1
0
d
n
5
9
=
d
(
7
5
%
;
M
.
p
.
1
1
5
.
4
(
C
:
-
3 00
a
n
d
M ?
C
-
5 00
. Anal. Calcd for C H N O S : C ,
2 5 2 3 7 4
,
0
.
)
2
5
6
(
N
H
)
)
.
E
3
2
2
2
–
6
2
2
(
)
.
4 °
A
C
C
2
.
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6
I
)
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(
R
(
K
B
8
)
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r
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m-
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4
7
3
3
3
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N
H
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7
2
M
S
m
/
z
5
1
7
(
)
3
0
2
r
-
2
C
9
=
7
C
(
C
-
C
C
N
=
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m
,
,
.
1
1
6
6
3
5
8
.
0
2
;
H
,
4
.
4
8
;
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,
1
8
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9
4
.
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o
u
n
d
:
C
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5
8
.
1
5
;
H
,
4
.
4
7
;
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,
(
C
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1
H
6
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1
l
3
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n
(
p
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2
5
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1
8
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9
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1
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C
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C
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z
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1
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s
8
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8
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0
2
H
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,
C
1
H
H
)
)
)
2
.
7
g 1-(4-(Dimethylamino)benzylidene)-4-(4-(1-((dimethy-
lamino)methyl)-5-nitro-2-oxoindolin-3-ylideneamino)
phenyl)thiosemicarbazide (VIg
3
2
3
2
l
i
n
k
a
g
e
.
8
7
.
9
(
m
,
1
1
H
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8
.
(
s
,
N
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C
4
8
C
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H
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3
6
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s
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C
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M
N
H
1
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8
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1
,
.
C
S
(
(
6.
2
,
N
H
.
,
,
)
:
Y
i
e
l
d
=
7
2
%
;
M
.
p
.
1
3
1
N
M
R
C
C
(
)
C
,
D
1
C
l
1
2
5
-
=
6
z
)
d
p
C
p
m
1
7
5
C
C
0
(
1
3
=
-
S
2
0
1
r
=
–
- C
2
H
0
4
°
C
.
I
R
(
K
B
r
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c
:
3
3
2
9
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n
d
3
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6
2
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N
H
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3
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3
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3
1
6
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8
9
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600
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N
3
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5
5
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0
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8
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1
5
0
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6
10
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A
)
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2
9
5
7
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a n
C
d
H
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C
4
H
8
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1
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7
O
2
0
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,
C
1
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2
O
5
)
0
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1
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6
C
6
=
1
S
(
)
C
.
=
N
H
)
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,
N
1
M
6
1
R
7
3
1
1
4
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5
)
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1
4
4
C
H
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300
1
a
3
8
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3
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C
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400
)
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H
)
1
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,
1
3
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C
200
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C
C
)
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1
5
1
4
)
2
40
)
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1
3
.
8
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C
1
2
H
M?
-
100
)
,
3
C
a
0
-
.
(
C
n
50
2
d
C
-
500
3
,
3
0
.
C
-
( CD C l , 5 0 0 M H z ) d p p m : 2 . 4 9 ( s , 6 H , N ( CH ) ) , 2 . 9 2 ( s ,
3 3 2
6 H , N ( C H ) ) , 4 . 1 5 ( s , 2 H , C H l i nk a g e ) , 6. 8 7- 8 . 01 ( m ,
a
(
n
C
d
-
),
C
-
)
,
2
(
7
C
)
.
5
-
30
a
n
C
-
)
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1
2
.
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C
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-
4
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2
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3
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2
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2
1
.
20
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d
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1
0
2
r
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1
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7
)
1
1
5
.
(
C
S
C
-
1
1
H
. 0
,
7
A
( s
r
,
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H
1
)
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,
8
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.
C
7
8
S
(
N
s
H
,
1
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H
,
N
=
M
C
H
R
)
,
9
.
2
8
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s
,
1
2
H
5
,
C
M
S
N
H
)
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1
3
9
m/z
7
4
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C
,
4
2
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1
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.
N
(
C
H
)
)
,
3
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8
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I
-
M
1
0
C
-
N
(
C
D C l , 1
3
H
z
)
d
2
3
2
3
:
5
5
(
)
.
A
n
a
l
C
a
l
c
d
f
o
C
N
O S :
7 3
,
p
p
m
:
1
7
8
.
2
(
C
=
S
)
,
1
6
5
.
9
(
C
-
2
)
,
1
6
3
.
6
(
C
-
3
)
,
1
5
2
.
6
(
C
-
8
)
,
2
6
2
5

J. Chem. Sci.
(
2
0
2
0
)
1
3
2
:
9
4
P
a
g
e
7
o
f
1
5
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1
1
5
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0
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.
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8
7
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C
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2
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)
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1
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1
5
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4
7
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C
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200
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1
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2
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8
5
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)
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1
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N
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C
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a
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M
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D
9
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l
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p
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2
m
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s
k
.
,
6
H
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3
1
3
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C
)
3
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C
600
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1
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30
a
n
50
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C
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3
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s
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H
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5
7
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C H lin
2
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3
1
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2
3
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1
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.
1
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C
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500
S m/z
7
1
1
3
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1
9
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8
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1
4
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m
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1
H
r
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9
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6
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s
1
.
H
,
N
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C
H
R
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-
.
2
C
6
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,
9
4
D
8
1
0
C
(
l
1
3
C
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60
,
(
(
1
C
M?
.
7
C
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,
N
1
1
9
H
d
C
-
3
C
9
9
)
,
1
0
(
.
9
(
C
3 00
C H ) ). E
a
I
n
d
C
H
S
N
H
)
,
1
0
.
1
(
s
,
H
,
C
=
C
N
H
C
(
-
C
N
M
(
C
3
7
8
.
4
1
7
H
)
,
4
0
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2
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C
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)
,
.
2
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-
M
2
5
H
z
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d
p
p
m
)
:
1
7
9
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8
6
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C
S
)
,
1
6
2
.
3
4
-
2
)
1
5
2
6
-
.
6
0
.
(
C
-
2
3
2
3
2
5
4
)
. Anal
0.
.
F
a
n
l
c
f
o
r
5
H N O S :
7 2 8 8 3
C
,
,
5
9
.
5
4
;
H
),
=
5
7
.
5
(
C
-
8
,
1
-
4
.
2
(
1
-
10
)
,
1
C-
4
.
7
(
C
)
,
4
1
.
9
2
5
.
8
;
N
,
2
5
7
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d e r i v a t i v e III. P re s e n c e o f C = S i n
n
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s
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t
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c
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9
4
P
a
g
e
1
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o
f
1
5
J. Chem. Sci.
(
2
0
2
0
)
1
3
2
:
9
4
O
O
N
NH2
O2N
p-Amino aniline
O2N
HNO3 / H2SO4
Nitration
O
O
C2H5OH
CH3COOH
O
N
H
N
I
H
N
H
II
1
37% Formaldehyde
Dimethylamine
R
VIa
VIb
VIc
VId
VIe
VIf
VIg
VIh
VIi
= H
= 4-NO2
= 4-Cl
N
NH2
= 4-CH3
N
NH
O2N
= 4-OCH3
= 4-OH
O2N
S
CS2
NaOH
O
NaS
O
= 4-N(CH3)2
= 3-NO2
N
CH3
N
CH3
N
= 3-Cl
N
III
CH3
VIj
VIk
VIl
= 3-CH3
CH3
= 3-OCH3
= 3-OH
(CH3)2SO4
VIm
= 3-N(CH3)2
N
NH
N
NH
O2N
S
O2N
S
NH2NH2. H2O
HN
O
H3CS
O
CH3
N
NH2
CH3
N
N
N
V
CH3
CH3
IV
R
CHO
N
NH
O2N
S
HN
O
N
N
CH3
HC
N
CH3
R
VIa- VIm
Scheme 1.
S
y
n
t
h
e
t
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c
p
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(
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I
a
–
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1
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1
2
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1
d IV
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t
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f
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p
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t
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a
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1
s
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f
3
p
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5
n
0
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n
l
e
t
o
f
r
.
t
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m
l
f
t
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f
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6
m
p
t
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p
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n
r
o
t
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g
l
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a
n
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o
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t
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n
2
.
0
0
–
2
.
p
g
m
t
a
n
p
e
a
2
n
4
e
p
d
9
.
1
p
m
c
o
r
r
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n
d
s
t
o
N
a
n
t
h
r
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e
p
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t
s
t
w
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a
n
d
2
p
r
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s
s
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n
l
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p
e
a
k
s
a
t
d
1
p

J. Chem. Sci.
(
2
0
2
0
)
1
3
2
:
9
4
P
a
g
e
1
1
o
f
1
.
5
9
4
Table 1.
P
e
r
c
e
n
t
a
n
a
l
g
e
s
i
c
a
c
t
i
v
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y
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f
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y
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t
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d
c
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m
p
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n
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(
T
a
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l
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c
k
m
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t
h
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d
)
P
e
r
c
e
n
t
a
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s
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c
a
c
t
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v
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t
y
C
o
m
p
o
u
n
d
D
o
s
e
(
m
g
/
k
g
)
3
0
m
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p
v
t
3
3
.
.
2 Biological activities
a Analgesic activity
f
f
u
o
r
t
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l
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c
.
F
u
r
t
h
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r
,
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n
c
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a
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i
n
2
:
T
a
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l
fl
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c
k
m
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t
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d
w
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m
p
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a
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h
l
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r
i
n
e

9
4
P
a
g
e
1
2
o
f
1
5
J. Chem. Sci.
(
2
0
2
0
)
1
3
2
:
9
4
f
Table 2.
t
P
m
e
r
c
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n
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d
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)
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d
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x
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p
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d
D
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e
(
m
g
/
k
g
)
3
0
m
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n
1
h
2
h
3
h
U
l
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n
d
e
x
VIa
VIb
VIc
VId
VIe
VIf
VIg
VIh
VIi
1
0
2
3
1
2
3
4
3
4
1
2
1
2
3
4
1
2
3
4
3
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c Ulcerogenicity
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t E. coli
p
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t i v i t y . D e r i v a t i v e s VIb
e x h i b i t ed e q u i po t e n c y
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t VIc
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C
:
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6
t P. aeruginosa
2
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t A. niger
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t A. fumigatus
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l
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s
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t
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8
i
m
a
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d
d
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t
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VIm
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r
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t
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t
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m
n
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s
m
r
s
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e
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h
y
r
m
e
t
h
o
x
y
r
d VIj–
m
VIb, VIc, VIh and VIi
o
g
a
i
s
m
s
.
F
r
m
t
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e
a
n
m
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c
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g
a
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t
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e
(
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l
:
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1
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g
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L
s s e r a c t iv i ti e s ( M I C :
o
)
t
i
e
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r
t
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e
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t
r
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n
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o
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a
t
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p
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o
1
t
5
h
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r
d
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e
2
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t
g
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s
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l
p
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y
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n
v
i
t
r
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)
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M
o
d
r
a
e
s
h
t
i
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t i t l e
o
.
6
2
–
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5
l
/
m
)
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h
a
n
p
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fl
x
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c
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n
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g
a
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n
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t
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u
r
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b
d
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p
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o
a
y
e
e
d
n
b
y
u
n
u
b
t
i
u
o
e
eus. A g a i ns t S. epidermidis, e n t ir e s e ri e s o f c o m -
w
e
r
i
v
t
i
e
.
T
h
e
l
e
s
t
c
n
c
t
r
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t
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w
h
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l
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y
e
d
l
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r
p
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t
e
n
c
y
(
M
I
C
:
Table 3.
M
s
I
C
(
M
i
n
i
m
u
m
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n
h
i
b
i
t
o
r
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c
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c
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n
t
r
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t
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o
n
i
n
l
g
/
m
L
)
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f
s
y
n
t
h
e
s
i
z
e
d
c
o
m
p
o
u
n
d
s
.
S.
S.
aureus epidermidis
M.
luteus
B.c
P.
K.
ereus E. coli aeruginosa pneumoniae
A.
niger
A.
fumigatus
C
o
m
p
o
u
n
d
VIa
VIb
VIc
VId
Vie
VIf
VIg
VIh
VIi
1
7
7
1
3
6
6
7
7
1
3
6
6
7
–
5
.
6
1
1
6
2
5
5
1
1
6
2
5
5
1
2
3
1
1
3
3
3
3
1
1
3
3
6
3
7
–
1
5
5
1
1
1
1
5
5
1
1
2
1
.
.
.
.
.
.
.
.
.
.
.
.
.
2
6
6
2
2
2
2
6
6
2
2
5
2
1
5
2
2
5
5
5
5
2
2
5
5
6
7
1
3
6
6
1
1
1
6
6
6
1
1
–
2
.
5
1
6
2
5
5
3
7
7
7
3
6
6
7
7
1
3
1
6
3
–
1
.
2
1
1
1
2
5
5
1
1
6
2
5
3
7
7
1
6
6
6
1
1
1
6
6
1
7
–
1
.
2
1
1
6
5
5
5
6
6
6
5
5
5
3 1 .
1 5 .
3 1 .
3 1 .
3 1 .
3 1 .
3 1 .
1 5 .
3 1 .
3 1 .
3 1 .
3 1 .
3 1 .
1 5 .
–
2 5
6 2
2 5
2 5
2 5
2 5
2 5
6 2
2 5
2 5
2 5
2 5
2 5
6 2
3
7
7
1
3
3
6
7
7
3
3
3
6
3
–
1
.
2
1
1
6
2
2
5
1
1
2
2
2
5
5
6
1
1
3
6
6
1
1
1
3
6
6
1
–
7
2
5
5
1
2
2
2
5
5
1
2
2
2
.
.
.
.
.
.
5
6
6
2
5
5
6
1
3
3
6
1
1
3
3
6
6
1
1
–
1
2
5
1
1
2
2
2
1
1
2
2
2
2
.
.
.
.
.
5
5
.
.
.
.
5
6
2
2
5
.
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