Synthesis, Type II Diabetes Inhibitory Activity, and Antimicrobial Tests of Benzothiazole Derivatives Bridged with Indenedione by Methylenehydrazone

Article abstract of DOI:10.1134/S1070363219090226

Benzothiazolyl hydrazones are synthesized and tested as hypoglycemic and antimicrobial agents. Condensation of 2-acyl-(1H)-indene-1,3(2H)-diones with 2-hydrazinylbenzo[d]thiazole/2-hydrazinyl-6-substitutedbenzo[d]thiazoles gives the corresponding hydrazones in high yields. Preliminary biological assay of the products reveals significant antidiabetic and antimicrobial activities. The α-amylase and α-glucosidase inhibition assay is used for determination of Type II diabetes inhibitory activity.

Full text of DOI:10.1134/S1070363219090226

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 9, pp. 1867–1873. © Pleiades Publishing, Ltd., 2019.
Synthesis, Type II Diabetes Inhibitory Activity,
and Antimicrobial Tests of Benzothiazole Derivatives Bridged
with Indenedione by Methylenehydrazone
a
a
a
b
c
c
S. Mor *, S. Sindhu , M. Khatri , N. Singh , N. Vasudeva , and N. Panihar
a
Department of Chemistry, Guru Jambheshwar University of Science and Technology,
Hisar, Haryana, 125001 India
Department of Bio and Nanotechnology, Guru Jambheshwar University of Science and Technology,
Hisar, Haryana, 125001 India
Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology,
Hisar, Haryana, 125001 India
b
c
*
e-mail: satbirˍmor@yahoo.co.in
Received April 5, 2019; revised September 3, 2019; accepted September 10, 2019
Abstract—Benzothiazolyl hydrazones are synthesized and tested as hypoglycemic and antimicrobial agents. Conden-
sation of 2-acyl-(1H)-indene-1,3(2H)-diones with 2-hydrazinylbenzo[d]thiazole/2-hydrazinyl-6-substitutedbenzo[d]-
thiazoles gives the corresponding hydrazones in high yields. Preliminary biological assay of the products reveals
significant antidiabetic and antimicrobial activities. The α-amylase and α-glucosidase inhibition assay is used for
determination of Type II diabetes inhibitory activity.
Keywords: antibacterial, antidiabetic, antifungal, α-amylase, α-glucosidase
DOI: 10.1134/S1070363219090226
INTRODUCTION
present herein the synthesis, characterization, antidiabetic
and antimicrobial activities of benzothiazolyl hydrazones.
Benzothiazole derivatives are well known for their
broad spectrum of well documented biological activities.
Benzothiazole nucleus is incorporated in molecules of
some marketed drugs such as riluzole, sibenadet hydro-
chloride (viozan), and pramipexole [1]. Benzothiazolyl
hydrazones exhibited anticoagulant and antimicrobial
activity [2] and can act as highly potent selective inhibi-
RESULTS AND DISCUSSION
Synthesis of benzothiazolyl hydrazones (3) (Scheme 1)
was based on condensation of 2-acyl-(1H)-indene-
,3(2H)-diones (1) with 2-hydrazinylbenzo[d]thiazole/
-hydrazinyl-6-substitutedbenzo[d]thiazoles (2) in the
presence of catalytic amount of glacial acetic acid.
-Acyl-(1H)-indene-1,3(2H)-diones (1) were prepared
1
2
tors of Bcl-X [3].
L
2
Up to date there are found no publications on ben-
zothiazolyl hydrazones as inhibitors of α-amylase and
α-glycosidase. In continuation of our recent studies on
nitrogen and sulfur containing heterocycles [4–6], we
by the Claisen condensation of diethylphthlate and
an appropriate ketone [7, 8]. 2-Hydrazinylbenzo[d]-
thiazole/2-hydrazinyl-6-substitutedbenzo[d]thiazoles
(2) were synthesized by the method developed earlier
Scheme 1. Synthesis of benzothiazolyl hydrazone derivatives 3a–3o.
O
O
7
4
H
1
3
N N 2' N 3'
N
O
CH OH
reflux
3
6
5
4'
NHNH2
+
2
R1
S
R2
S
5'
R1
1
'
O
O
7'
1
2
6'
R2
3
aꢀ3o
1
2
R = CH (a–e), CH CH(CH ) (f–j), CH(CH ) (k–o); R = H (a, f, k), CH (b, g, l), Br (c, h, m), OCH (d, i, n), Cl (e, j, o).
3
2
3 2
3 2
3
3
1
867

1868
MOR et al.
Table 1. The in vitro α-amylase inhibitory activity of
compounds 3a–3o
Table 2. The in vitro α-glucosidase inhibitory activity of
compounds 3a–3o
Inhibition, %
IC ,
Inhibition, %
IC ,
μg/mL
5
0
50
Compound
concentration, μg/mL
Compound
concentration, μg/mL
μg/mL
1
2.5
25
50
100
12.5
45.09
48.84
42.04
61.67
53.5
25
50
100
3
a
20.71 44.28 70.71 83.57
14.28 32.85 57.14 84.28
19.28 41.42 72.85 90.71
18.57 47.14 72.85 88.57
28.57 57.85 74.28 88.57
22.14 49.28 72.14 85.71
28.57 35.71 60.71 87.14
28.57 47.14 66.42 86.42
29.28 50.71 64.28 88.57
27.14 47.85 67.14 89.28
30.71 48.57 70.71 85.71
17.85 43.57 56.42 71.42
20.71 41.42 71.42 87.85
26.42 64.28 74.28 90.71
14.28 42.85 55.71 85.71
30.17
38.18
29.75
28.80
23.07
27.98
31.84
27.33
26.15
27.06
25.42
38.81
29.96
22.57
35.41
23.23
3a
3b
51.66
54.26
51.13
62.51
56.78
76.57
65.57
76.41
76.41
88.1
56.86 57.321 23.62
56.78 68.390 16.94
59.76 90.320 22.78
3
b
3
c
3c
3
d
3d
75.73 83.670
6.45
3
e
3e
60.3 75.880 13.42
3
f
3f
63.73
61.98
63.81
60.98
70.99
61.59
64.5
87.64 92.690
79.78 81.300
86.19 91.850
86.58 91.850
90.01 94.210
80.54 91.160
84.59 92.080
85.89 91.690
80.77 87.870
85.96 92.690
87.64 94.060
4.46
5.16
4.22
5.48
2.06
5.73
3.85
4.82
5.47
6.06
5.21
3
g
3g
3
h
3h
3
i
3i
3
j
3j
3
k
3k
70.46
76.57
76.41
22.57
70.69
78.86
3
l
3l
3
m
3m
3n
62.28
59.53
61.98
61.98
3
n
3
o
3o
Acarbose 30.71 51.42 75.71 92.14
Acarbose
[
3
9, 10]. Structures of the newly synthesized compounds
a–3o were confirmed by their FT-IR, H and C NMR,
In vitro α-glucosidase inhibitory activity of hydrazine
derivatives 3a–3o. The α-glucosidase inhibitory activity
of the synthesized compounds was evaluated by the Mc-
Cue’s procedure [12] (Table 2).All compounds displayed
good inhibitory activity, and compounds 3f, 3g, 3h, 3j, 3l,
and 3m demonstrated higher activity than the standard.
The compounds were more potent against α-glucosidase
than α-amylase enzyme. Consequently, 3j can be consid-
ered as a possible antidiabetic agent for further studies.
1
13
and mass spectra. Their FT-IR spectra exhibited strong
absorption bands at 3188–3240 (N–H), 1562–1598 (C=N)
and 1658–1683 (C=O) cm . H NMR spectra of deriva-
tives 3a–3o demonstrated an exchangeable singlet in the
range of 12.96–13.49 ppm attributed to N–H.
–
1 1
Biological evaluation. In vitro α-amylase inhibitory
activity of hydrazones (3). All synthesized hydrazine
derivatives 3a–3o were assessed for their α-amylase
inhibitory activity as antidiabetic agents following the
developed earlier procedure [11] using acarbose as the
standard (Table 1).Among the synthesized benzothiazolyl
hydrazones, compounds 3e and 3n were found to be more
active with IC values 23.07 and 22.57 μg/mL, respec-
tively (acarbose IC = 23.23 μg/mL). Other derivatives
3
inhibitory activity but lower than that of acarbose at all
concentrations.
The structure activity relationships (SAR) approach
to the compounds 3a–3o revealed that their inhibitory
potential depended mostly on the substituents on phenyl
ring of the benzothiazole motif. Among the synthesized
derivatives, compounds 3j against α-glucosidase and
3n against α-amylase demonstrated higher activity than
acarbose probably due to the presence of chlorine and me-
thoxy group on benzothiazole skeleton. Compounds 3b
and 3l containing the methyl substituent on benzothiazole
ring exhibited moderate activity against α-amylase. The
50
5
0
f, 3h, 3i, 3j, and 3k exhibited considerable α-amylase
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

SYNTHESIS, TYPE II DIABETES INHIBITORY ACTIVITY, AND ANTIMICROBIAL TESTS
1869
Table 3. In vitro Antibacterial activity of hydrazones 3a–3o
Table 4. In vitro antifungal activity of compounds 3a–3o
against A. niger
Zone of inhibition, mm
Inhibition, %
gram-positive
bacteria
gram-negative
bacteria
Compound
concentration, μg/mL
Compound
1
25
250
500
1000
68.84
91.62
76.17
68.32
69.10
78.27
80.62
76.96
82.98
67.01
81.93
84.55
83.76
84.55
75.65
92.40
P.
B. subtilis S. aureus E. coli
aeruginosa
3
a
58.11
46.07
33.24
45.02
49.47
63.87
63.08
57.32
72.25
51.3
63.08
84.55
66.75
52.09
52.09
70.68
65.96
66.23
76.45
57.32
73.56
74.34
71.98
74.34
63.35
85.6
68.32
88.74
73.29
62.04
66.23
74.86
73.29
72.25
79.31
59.42
78.79
80.89
78.79
80.89
72.77
89.73
3
a
−
12
21
12
−
18
15
−
−
3b
3
b
16
12
14
15
14
−
20
13
14
12
15
13
24
−
3
c
3
c
3
d
3
d
13
12
15
15
19
13
23
18
18
23
24
16
28
3
e
3
e
−
3
f
3
f
14
13
24
14
21
17
14
21
18
17
30
3
g
3
g
3
h
3
h
20
−
3
i
3
i
3
j
3
j
22
16
16
25
26
15
26
21
18
16
21
20
13
24
3
k
64.13
69.63
59.68
69.63
54.97
74.08
3
k
3
l
3
l
3
m
3
m
3
n
3
n
3
o
3
o
Streptomycin
Fluconazole
compound 3a containing no substituents on benzothiazole
demonstrated lower activity against α-glucosidase than
acarbose. Thus, such effects could be due to the resonance
effect (+R) of the groups present as substituents on the
phenyl ring of benzothiazole in hydrazones 3a‒3o.
parable to that of the standard. On the other hand, some
compounds were inactive against the specific bacteria.
In vitro antifungal activity of hydrazones 3a–3o. All
synthesized hydrazones were tested for their in vitro
antifungal activity against A. niger by the quantitative
microspectrophotometric assay [14] (Table 4).
In vitro antibacterial assay of hydrazones 3a–3o.
All synthesized compounds were tested for their in vitro
antibacterial activity against B. subtilis (NCIM 2063), S.
aureus (NCIM 5021), E. coli (MTCC 723), and P. aeru-
ginosa (MTCC 7093) by the agar well diffusion method
using streptomycin as the reference drug [13] (Table 3).
The derivatives 3a–3o were found to inhibit fungal
growth with inhibition ranging from 33.24 to 91.62% at
various concentrations. The highest activity 91.62% was
determined for 3c. Other derivatives demonstrated moder-
ate activity at different concentrations against A. niger.
The derivative 3n was characterized by the maximum
inhibition zone against B. subtilis, equivalent to that of
streptomycin. Compound 3h exhibited the highest activ-
ity against S. aureus and P. aeruginosa. Compound 3n
displayed maximum inhibition zone against E. coli. Com-
pound 3m demonstrated activity against B. subtilis com-
According to the accumulated data for antimicrobial
activity of the products, the following structure activity
relationships (SAR) have been established. Presence of
1
2
R = i-propyl and R = H, CH , Br, OCH , Cl in synthe-
3
3
sized hydazones led to increase in antibacterial activity
1
in all bacterial strains tested. Presence of R = i-butyl
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

1870
MOR et al.
2
and R = Br, Cl in synthesized hydazones enhanced their
antibacterial activity against all bacterial strains under
22.10, 69.68, 100.67, 106.92, 111.6, 119.01, 122.80,
130.06, 133.48, 135.85, 138.06, 142.93, 149.22, 151.73,
152.63, 154.77, 157.82, 195.83. HRMS (m/z) calculated
1
2
study. However, the hydazones containing R = R = CH
demonstrated improved antifungal activity.
3
+
for C H N O S [M + H] : 336.0807, found: 336.3228.
1
8
13
3
2
Based on the above, it was concluded that the antimi-
crobial activity of the synthesized hydazones containing
the substituent R followed the order: i-propyl > i-butyl >
2-{1-[2-(6-Methylbenzo[d]thiazol-2-yl)hydrazono]-
ethyl}-1H-indene-1,3(2H)-dione (3b). Yield 78%, mp
238–240°C. FTIR spectrum, ν, cm : 1571 (C=N), 1672
1
–1
methyl. However, no general trend has been established
for the substituent R2.
(C=O), 2848, 2976 (aliphatic C–H), 3066‒3120 (aromatic
C–H), 3188 (N–H). 1H NMR spectrum, δ , ppm: 2.32 s
H
2
(
3H, CH ), 2.66 s (3H, CH ), 4.40 s (1H, H ), 7.02‒7.75
3
3
EXPERIMENTAL
m (7H, H4–7, H
4',5',7'
13
), 12.97 s (1H, NH). C NMR spec-
trum, δ , ppm: 21.09, 26.93, 69.91, 97.56, 106.42, 112.35,
C
All solvents and reagents were used without further
purification. Melting points were determined on an
Electrothermal Melting Point apparatus, LABCO Co.,
India, in open glass capillaries and are uncorrected. FT-
IR spectra (KBr) were recorded on an IR Affinity-1 Shi-
1
1
21.26, 124.98, 128.59, 131.01, 133.52, 134.86, 136.44,
39.86, 143.00, 149.38, 152.95, 160.75, 195.37. HRMS
+
(m/z) calculated for C H N O S [M + H] : 350.0963,
1
9
15
3
2
found: 350.0943.
1
13
2-{1-[2-(6-Bromobenzo[d]thiazol-2-yl)hydrazono]-
ethyl}-1H-indene-1,3(2H)-dione (3c). Yield 81%, mp
madzu spectrophotometer. H and C NMR spectra were
measured on a Bruker AVANCE III NMR spectrometer
–
1
2
76–278°C. FTIR spectrum, ν, cm : 1573 (C=N), 1672
(
400 MHz) using CDCl as a solvent and TMS as an
3
(
C=O), 2879, 2976 (aliphatic C–H), 3115 (aromatic C–H),
internal standard. HRMS spectra were measured on a
QTOF analyzer using the electrospray ionization (ESI)
method. Purity of the synthesized compounds was tested
by TLC on precoated plates (SIL G/UV254,ALUGRAM)
using hexane–ethyl acetate as an eluent and visualized
under UV light.
1
3
195 (N–H). H NMR spectrum, δ , ppm: 2.66 s (3H,
H
CH ), 4.42 s (1H, H ), 7.02‒8.03 m (7H, H4–7, H4',5',7'),
2
3
1
3
1
6
1
1
2.96 s (1H, NH). C NMR spectrum, δ , ppm: 21.67,
C
9.05, 98.68, 114.55, 120.54, 122.81, 125.53, 128.77,
29.78, 133.75, 136.79, 140.42, 143.25, 147.17, 150.49,
56.37, 157.58, 195.29. HRMS (m/z) calculated for
2
-Acyl-(1H)-indene-1,3(2H)-dione (1) was synthe-
sized according to the procedure reported in literature
7, 8].
-Hydrazinylbenzo[d]thiazole/2-hydrazinyl-6-sub-
+
C H BrN O S [M + H] : 413.9912, found: 413.4340.
1
8
12
3
2
2
-{1-[2-(6-Methoxybenzo[d]thiazol-2-yl)hydra-
[
zono]ethyl}-1H-indene-1,3(2H)-dione (3d). Yield
2
–
1
8
6%, mp 230–236°C. FTIR spectrum, ν, cm : 1570
stituted benzo[d]thiazoles (2) were synthesized follow-
ing the method presented in [9, 10].
(
(
C=N), 1674 (C=O), 2837, 2980 (aliphatic C–H), 3070
1
aromatic C–H), 3189 (N–H). H NMR spectrum, δ ,
H
Synthesis of benzothiazole linked hydrazones
ppm: 2.65 s (3H, CH ), 3.76 s (3H, OCH ), 4.49 s (1H,
3
3
3
2
a‒3o (general procedure). Equimolar quantities of
-acyl-(1H)-indene-1,3(2H)-diones (1) and hydrazines
H ), 7.02‒7.65 m (7H, H4–7, H4',5',7'), 12.98 s (1H, NH).
2
13
C NMR spectrum, δ , ppm: 22.46, 56.34, 71.77, 95.47,
C
(2) were mixed in dry methanol in presence of catalytic
1
1
11.75, 112.81, 114.71, 118.55, 122.74, 126.84, 130.39,
37.43, 138.69, 140.87, 143.07, 147.72, 154.20, 156.36,
195.44. HRMS (m/z) calculated for C H N O S [M +
amount of glacial acetic acid (4–5 drops). Refluxing of
the mixture for 15 min on a water bath led to precipita-
tion of a solid, which was recrystallized from a mixture
of ethyl acetate and ethanol to afford the corresponding
hydrazones 3a‒3o as orange solids [15].
1
9
15
3
3
H]+: 366.0912, found: 366.4084.
-{1-[2-(6-Chlorobenzo[d]thiazol-2-yl)hydrazono]-
ethyl}-1H-indene-1,3(2H)-dione (3e). Yield 80%, mp
2
–
1
2
-{1-[2-(Benzo[d]thiazol-2-yl)hydrazono]ethyl}-
258–261°C. FTIR spectrum, ν, cm : 1577 (C=N), 1672
1
2
H-indene-1,3(2H)-dione (3a). Yield 82%, mp 218–
20°C. FTIR spectrum, ν, cm : 1570 (C=N), 1672
(C=O), 2831, 2976 (aliphatic C–H), 3115 (aromatic C–H),
–
1
1
3209 (N–H). H NMR spectrum, δ , ppm: 2.66 s (3H,
H
CH ), 4.42 s (1H, H ), 7.35‒7.92 m (7H, H4–7, H4',5',7'),
2
(
C=O), 2879, 2993 (aliphatic C–H), 3061 (aromatic
3
1
13
C–H), 3199 (N–H). H NMR spectrum, δ , ppm: 2.71
12.98 s (1H, NH). C NMR spectrum, δ , ppm: 22.51,
H
C
s (3H, CH ), 4.11 s (1H, H ), 7.09‒7.76 m (8H, H4–7,
2
71.55, 97.36, 109.88, 113.78, 117.45, 120.40, 122.25,
123.64, 132.19, 135.12, 139.08, 142.42, 145.37, 151.35,
3
H4'–7'), 12.98 s (1H, NH). C NMR spectrum, δ , ppm:
13
C
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

SYNTHESIS, TYPE II DIABETES INHIBITORY ACTIVITY, AND ANTIMICROBIAL TESTS
1871
1
1
56.81, 157.79, 195.63. HRMS (m/z) calculated for
3074 (aromatic C–H), 3219 (N–H). H NMR spectrum,
+
3
C H ClN O S [M + H] : 370.0417, found: 370.6644.
δ , ppm (J, Hz): 0.97 d [6H, CH CH(CH ) , J
=
18
12
3
2
H
2
3 2
HH
6
.68], 2.09‒2.22 m [1H, CH CH(CH ) ], 3.09 d [2H,
2 3 2
2
-{1-[2-(Benzo[d]thiazol-2-yl)hydrazono]-3-me-
3
CH CH(CH ) , J = 7.24 Hz], 3.75 s (3H, OCH ), 4.38
s (1H, H ), 7.03‒7.91 m (7H, H4–7, H4',5',7'), 13.11 s (1H,
NH). C NMR spectrum, δ , ppm: 22.74, 28.01, 34.33,
56.21, 70.10, 98.64, 106.20, 114.56, 120.71, 125.71,
133.47, 137.08, 138.74, 140.92, 147.46, 148.66, 151.60,
thylbutyl}-1H-indene-1,3(2H)-dione (3f). Yield 89%,
mp 230–236°C. FTIR spectrum, ν, cm : 1568 (C=N),
660 (C=O), 2872, 2970 (aliphatic C–H), 3066, 3124 (aro-
matic C–H), 3208 (N–H). H NMR spectrum, δ , ppm (J,
Hz): 0.97 d [6H, CH CH(CH ) , J = 6.64], 2.13‒2.20
2
3 2
HH
3
2
–
1
1
3
1
C
1
H
3
2
3 2
HH
1
53.19, 155.13, 159.30, 195.10. HRMS (m/z) calculated
m [1H, CH CH(CH ) ], 3.10 d [2H, CH CH(CH ) ,
2
3 2
2
3 2
+
3JHH = 7.20], 4.41 s (1H, H ), 7.08‒7.74 m (8H, H4–7,
2
for C H N O S [M + H] : 408.1382, found: 408.1382.
22 21
3
3
H4'–7'), 13.11 s (1H, NH). C NMR spectrum, δ , ppm:
13
2-{1-[2-(6-Chlorobenzo[d]thiazol-2-yl)hydrazono]-
3-methylbutyl}-1H-indene-1,3(2H)-dione (3j). Yield
90%, mp 210–212°C. FTIR spectrum, ν, cm : 1562
(C=N), 1660 (C=O), 2872, 2958 (aliphatic C–H), 3140
(aromatic C–H), 3209 (N–H). H NMR spectrum,
C
2
1
1
2.75, 28.01, 34.35, 69.89, 99.89, 111.72, 120.79, 121.19,
22.09, 123.45, 127.83, 133.58, 137.66, 138.76, 139.91,
47.60, 149.95, 152.99, 160.05, 194.40. HRMS (m/z)
calculated for C H N O S [M + H] : 378.1276, found:
–
1
+
1
21
19
3
2
3
3
78.4556.
-{3-Methyl-1-[2-(6-methylbenzo[d]thiazol-2-yl)-
hydrazono]butyl}-1H-indene-1,3(2H)-dione (3g). Yield
δ , ppm (J, Hz): 0.97 d [6H, CH CH(CH ) , J
H
6
=
2
3 2
HH
.64], 2.07‒2.21 m [1H, CH CH(CH ) ], 3.09 d [2H,
2 3 2
2
3
2
CH CH(CH ) , J
7.10‒7.94 m (7H, H4–7, H4',5',7'), 13.12 s (1H, NH). C
NMR spectrum, δ , ppm: 22.74, 27.96, 34.33, 69.18,
98.47, 117.54, 119.47, 121.29, 123.30, 125.40, 125.55,
127.33, 129.90, 132.07, 136.86, 149.60, 154.98, 155.80,
= 7.12 Hz], 4.43 s (1H, H ),
2
3 2
HH
13
–
1
8
(
(
8%, mp 216–218°C. FTIR spectrum, ν, cm : 1566
C=N), 1658 (C=O), 2870, 2962 (aliphatic C–H), 3118
aromatic C–H), 3197 (N–H). H NMR spectrum, δ ,
ppm (J, Hz): 0.97 d [6H, CH CH(CH ) , J = 6.64],
C
1
H
3
2
3 2
HH
1
57.42, 195.2. HRMS (m/z) calculated for C H Cl-
2
3
.13‒2.20 m [1H, CH CH(CH ) ], 2.31 s (3H, CH ),
21 18
2
3 2
3
3
N O S [M + H]+: 412.0887, found: 412.0853.
.10 d [2H, CH CH(CH ) , J = 7.08], 4.39 s (1H,
3
2
2
3 2
HH
H ), 7.00‒7.75 m (7H, H4–7, H4',5',7'), 13.10 s (1H, NH).
2
2-{1-[2-(Benzo[d]thiazol-2-yl)hydrazono)-2-me-
13
C NMR spectrum, δ , ppm: 21.06, 22.74, 27.96, 34.33,
thylpropyl)-1H-indene-1,3(2H)-dione (3k). Yield 94%,
C
7
1
1
2.03, 99.04, 111.44, 116.47, 120.78, 121.97, 122.30,
23.38, 128.60, 133.55, 137.64, 143.97, 145.07, 147.43,
–1
mp 222–224°C. FTIR spectrum, ν, cm : 1598 (C=N),
683 (C=O), 2929, 2972 (aliphatic C–H), 3057 (aro-
1
51.77, 154.92, 159.19, 193.64. HRMS (m/z) calculated
1
matic C–H), 3214 (N–H). H NMR spectrum, δ , ppm
(J, Hz): 1.32 d [6H, CH(CH ) , J = 7.08], 2.83‒2.90
m [1H, CH(CH3)2], 4.55 s (1H, H ), 7.57‒7.95 m (8H,
H4–7, H4'–7'), 13.47 s (1H, NH). C NMR spectrum, δ ,
ppm: 20.86, 28.82, 69.74, 98.22, 120.26, 121.63, 122.46,
123.59, 126.32, 128.46, 130.85, 131.34, 135.56, 136.52,
150.88, 152.90, 157.07, 161.36, 195.83. HRMS (m/z)
H
+
for C H N O S [M + H] : 392.1433, found: 392.4673.
3
22
21
3
2
3
2
HH
2
2-{1-[2-(6-Bromobenzo[d]thiazol-2-yl)hydrazono]-
13
3
9
-methylbutyl}-1H-indene-1,3(2H)-dione (3h). Yield
C
–
1
0%, mp 198–202°C. FTIR spectrum, ν, cm : 1568
(C=N), 1660 (C=O), 2870, 2960 (aliphatic C–H), 3132
1
(
aromatic C–H), 3201 (N–H). H NMR spectrum,
3
+
δ , ppm (J, Hz): 0.97 d [6H, CH CH(CH ) , J
=
calculated for C H N O S [M + H] : 364.1120, found:
H
2
3 2
HH
20 17
3
2
6
.60], 2.07‒2.19 m [1H, CH CH(CH ) ], 3.09 d [2H,
364.1089.
2
3 2
3
2
CH CH(CH ) , J = 7.28], 4.43 s (1H, H ), 7.03‒8.05
m (7H, H4–7, H4',5',7'), 13.09 s (1H, NH). C NMR spec-
trum, δ , ppm: 22.74, 28.09, 34.33, 98.26, 105.81, 109.97,
2
3 2
HH
2-{2-Methyl-1-[2-(6-methylbenzo[d]thiazol-2-yl)-
hydrazono]propyl}-1H-indene-1,3(2H)-dione (3l).
Yield 96%, mp 226–228°C. FTIR spectrum, ν, cm : 1562
13
–1
C
111.00, 118.02, 122.38, 126.89, 132.03, 135.14, 136.37,
(C=N), 1681 (C=O), 2872, 2968 (aliphatic C–H), 3136
1
38.00, 143.02, 149.08, 155.10, 156.16, 158.86, 193.71.
1
(
aromatic C–H), 3207 (N–H). H NMR spectrum, δ ,
H
+
HRMS (m/z) calculated for C H BrN O S [M + H] :
3
2
1
18
3
2
ppm (J, Hz): 1.31 d [6H, CH(CH ) , J = 7.08], 2.36
3 2 HH
4
56.0381, found: 456.3622.
-{1-[2-(6-Methoxybenzo[d]thiazol-2-yl)hyd-
razono]-3-methylbutyl}-1H-indene-1,3(2H)-dione (3i).
s (3H, CH ), 2.82‒2.89 m [1H, CH(CH ) ], 4.53 s (1H,
3
3 2
H ), 7.55‒7.92 m (7H, H4–7, H4',5',7'), 13.45 s (1H, NH).
2
2
13
C NMR spectrum, δ , ppm: 20.87, 21.29, 28.80, 69.73,
C
–
1
Yield 92%, mp 225–228°C. FTIR spectrum, ν, cm :
568 (C=N), 1683 (C=O), 2916, 2954 (aliphatic C–H),
98.18, 119.91, 121.48, 123.57, 127.42, 128.44, 130.81,
131.42, 131.74, 135.57, 136.49, 146.98, 150.82, 156.70,
1
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

1872
MOR et al.
1
57.55, 195.90. HRMS (m/z) calculated for C H N O S
Antibacterial activity. Antibacterial activity of hy-
drazones 3a–3o was tested by the agar well diffusion
method [13]. The test microorganisms viz. Bacillus
subtilis (NCIM 20630), Staphylococcus aureus (NCIM
5021), Escherichia coli (MTCC 723), and Pseudomonas
aeruginosa (MTCC 7093) were stimulated by inoculation
in 25 mL of nutrient broth. Sterile DMSO was used as
a negative control, whereas Streptomycin was used as a
positive control.
21
19
3
2
+
[
M + H] : 378.1276, found: 378.1252.
-{1-[2-(6-Bromobenzo[d]thiazol-2-yl)hydrazono]-
-methylpropyl}-1H-indene-1,3(2H)-dione (3m). Yield
2
2
–
1
9
2%, mp 238–242°C. FTIR spectrum, ν, cm : 1562
(
(
(
C=N), 1681 (C=O), 2872, 3008 (aliphatic C–H), 3124
aromatic C–H), 3213 (N–H). H NMR spectrum, δ , ppm
J, Hz): 1.32 d [6H, CH(CH ) , J = 7.08], 2.83‒2.90
1
H
3
3
2
HH
2
m [1H, CH(CH ) ], 4.57 s (1H, H ), 7.49‒8.06 m (7H,
H4–7, H4',5',7'), 13.47 s (1H, NH). 13C NMR spectrum,
δC, ppm: 20.82, 28.85, 69.71, 98.27, 114.13, 121.71,
3
2
An aliquot of each bacterial strain was spread on
nutrient agar plates. Wells were produced in nutrient
agar plates by using sterile cork borer of 8 mm diameter,
and then each well was inoculated with 100 μL of each
tested compounds in DMSO. At 37°C, the plates were
incubated for 24 h and the zone of inhibition around the
well was measured by using Colony Counter Digital and
reported in mm.
1
1
23.64, 124.18, 128.40, 129.28, 130.94, 133.52, 135.55,
36.58, 150.69, 152.13, 157.75, 161.99, 195.68. HRMS
+
(m/z) calculated for C H BrN O S [M + H] : 442.0225,
20 16 3 2
found: 442.0204.
2
-{1-[2-(6-Methoxybenzo[d]thiazol-2-yl)hyd-
razono]-2-methylpropyl}-1H-indene-1,3(2H)-dione
–1
Antifungal activity. Hydrazones 3a–3o were evaluated
for antifungal activity against Aspergillus niger (MTCC
9933) by the quantitative microspectrophotometric as-
say [14] in 96-well microplates. Growth inhibition was
observed at 595 nm. At 27°C, the fungus was grown on
potato dextrose broth (PDB), and after 7 days, spores of
the fungus were collected from cultures on broth plates.
The sporangial suspension concentration was observed by
(3n). Yield 91%, mp 202–206°C. FTIR spectrum, ν, cm :
1
3
568 (C=N), 1681 (C=O), 2870, 2956 (aliphatic C–H),
122 (aromatic C–H), 3240 (N–H). H NMR spectrum,
1
3
δ , ppm (J, Hz): 1.31 d [6H, CH(CH ) , J = 7.08],
H
2
3 2
HH
.82‒2.89 m [1H, CH(CH ) ], 3.77 s (3H, OCH ), 4.52
3 2 3
s, (1H, H ), 7.42‒7.90 m (7H, H4–7, H4',5',7'), 13.46 s (1H,
2
13
NH). C NMR spectrum, δ , ppm: 20.87, 28.79, 56.07
C
(OCH ), 69.71, 98.18, 105.84, 114.17, 120.69, 123.56,
3
5
hemocytometer and made to 1.7 × 10 spores/mL, and the
1
1
28.40, 130.77, 132.46, 135.57, 136.49, 146.97, 150.98,
fungal spore suspension was stored at ‒40°C. Experiment
was accomplished with 100 μL of a solution of potato
dextrose broth (25 ml) with 0.147 ml of the fungal spore
suspension solution and 100 μL of hydrazones 3a–3o.
Fluconazole was used as a positive control, and DMSO
was used as a negative control. After incubation at 27°C
for 48 h, growth was observed by measuring absorbance
at 595 nm in an ELISA plate reader. Growth inhibition
was reported by using the following equation:
55.54, 156.39, 159.62, 195.95. HRMS (m/z) calculated
+
for C H N O S [M + H] : 394.1225, found: 394.1201.
21
19
3
3
2-{1-[2-(6-Chlorobenzo[d]thiazol-2-yl)hydrazono]-
2-methylpropyl}-1H-indene-1,3(2H)-dione (3o). Yield
–
1
9
4%, mp 232–234°C. FTIR spectrum, ν, cm : 1566
(
(
(
C=N), 1665 (C=O), 2873, 3010 (aliphatic C–H), 3120
aromatic C–H), 3221 (N–H). H NMR spectrum, δ , ppm
J, Hz): 1.32 d [6H, CH(CH ) , J = 7.08], 2.83‒2.90
1
H
3
3
2
HH
2
m [1H, CH(CH ) ], 4.56 s (1H, H ), 7.60‒7.99 m (7H,
H4–7, H4',5',7'), 13.49 s (1H, NH). 13C NMR spectrum,
3
2
Growth inhibition = [(Acontrol – Asample)/( Acontrol)]×100%,
δC, ppm: 20.82, 28.85, 69.72, 98.27, 121.26, 121.41,
where Acontrol is the absorbance of the control and Asample
1
1
23.64, 126.40, 126.55, 128.40, 130.93, 133.03, 135.55,
is the absorbance of the tested microculture.
36.57, 150.70, 151.82, 153.18, 157.71, 195.68. HRMS
CONCLUSIONS
+
(m/z) calculated for C H ClN O S [M + H] : 398.0730,
20
16
3
2
found: 398.0704.
The present study presents the synthesis of ben-
zothiazolyl hydrazones 3a–3o and their preliminary
biological tests data for antidiabetic and antimicrobial
activities. Hydrazones 3a–3o have been synthesized
by condensation of 2-acyl-(1H)-indene-1,3(2H)-diones
(1) with 2-hydrazinylbenzothiazoles (2). Structures of
all the newly synthesized compounds are confirmed by
FT-IR, NMR and HRMS spectra. All the synthesized
Biological assay. In vitro antidiabetic activity. The
protocol reported by Xiao et al [11] was used for the
evaluation of in vitro α-amylase inhibition activity of
the synthesized hydrazones 3a–3o, and McCue’s proto-
col was utilized for evaluation of in vitro α-glucosidase
inhibitory activity [12]. Acarbose was used as a positive
control for comparative studies.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

SYNTHESIS, TYPE II DIABETES INHIBITORY ACTIVITY, AND ANTIMICROBIAL TESTS
1873
hydrazones 3a–3o exhibit significant in vitro α-amylase
and α-glucosidase inhibitory activity. Compounds 3e and
https://doi.org/10.1021/jm400556w
4. Mor, S., Mohil, R., Kumar, D., and Ahuja, M.,
Med. Chem. Res., 2012, vol. 21, p. 3541.
3
n are the most active against α-amylase enzyme, and 3j
against α-glucosidase enzyme.Antibacterial activity tests
of the products have been carried out by the agar well
diffusion method and antifungal activity was reported
on the basis of a quantitative microspectrophotometric
assay. Compound 3n demonstrates maximum inhibition
zone against B. subtilis equivalent to that of Streptomy-
cin. Compound 3b demonstrates inhibition of A. niger
comparable to that of Fluconazole. Hence, compounds
https://doi.org/10.1007/s00044-011-9859-y
5. Mor, S., Pahal, P., and Narasimhan, B., Eur. J.
Med. Chem., 2012, vol. 53, p. 176.
https://doi.org/10.1016/j.ejmech.2012.03.054
6. Mor, S., Pahal, P., and Narasimhan, B., Eur. J. Med.
Chem., 2012, vol. 57, p. 196.
https://doi.org/10.1016/j.ejmech.2012.09.003
7. Shapiro, S.L., Geiger, K., and Freedman, L., J. Org.
Chem., 1960, vol. 25, p. 1860.
3
n and 3b may be considered as potential antibacterial
https://doi.org/10.1021/jo01081a008
and antifungal agents for further studies.
8
. Dhawan, S.N., Dasgupta, S., Mor, S., and Gupta, S.C.,
FUNDING
Indian J. Heterocycl. Chem., 1993, vol. 2, p. 155.
9
. Dhawan, S.N., Mor, S., Sharma, M.K., Chawla, A.D.,
Saini, A., and Gupta, S.C., Indian J. Chem. Sect. B, 1994,
vol. 33, p. 38.
The authors are grateful to the Council of Scientific
and Industrial Research, New Delhi, India for providing
financial support [CSIR no. 09/752(0060)/2016-EMR-I].
1
0. Gupta, S.C., Quraishi, M., and Dhawan, S.N., Indian J.
Chem. Sect. B, 1979, vol. 18, p. 547.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019