PPAR gamma targeted molecular docking and synthesis of some new amide and urea substituted 1, 3, 4-thiadiazole derivative as antidiabetic compound

Article abstract of DOI:10.1002/jhet.3941

The PPAR-γ agonist enhances the insulin sensitivity and avoids the disorganized hyperglycemic by promoting the insulin guided cellular uptake of blood glucose. Therefore, in the present work PPAR-γ has chosen as the target for the molecular docking study to design an effective agonist of the same. By this research work an effort has been made to prepare amide and urea series of 1, 3, 4-thiadiazole derivatives as 4-substituted-N-(5-(4-(1-piperidino)1-piperidinyl)-1,3,4-(2-thiadiazolyl)benzamide (4a-f) and 1-(4-substitutedphenyl)-3-(5-(4-(1-piperidino)1-piperidinyl)-1,3,4-(2-thiadiazolyl)urea (6a-f). Both the docking score as well as the pharmacological animal study data has been suggested that the electron donating group containing compound 4f and 6f are most potent molecules for the antidiabetic activity close to the standard drug pioglitazone. It was further observed that the unsubstituted aromatic ring containing derivatives have also considerable effect (4a and 6a) than the electron withdrawing containing derivatives. After the comparison of biological data for amide and urea series, it was concluded that the urea (6a-f) series is more effective than the amide series.

Full text of DOI:10.1002/jhet.3941

Received: 1 November 2019
DOI: 10.1002/jhet.3941
Revised: 29 January 2020
Accepted: 2 February 2020
A R T I C L E
PPAR gamma targeted molecular docking and synthesis
of some new amide and urea substituted 1, 3, 4-thiadiazole
derivative as antidiabetic compound
1
1
1
Yogesh Vaishnav
| Dhansay Dewangan
| Shekhar Verma
|
1
2
3
Achal Mishra
| Alok Singh Thakur | Pranita Kashyap
|
4
Santosh Kumar Verma
1
Shri Shankaracharya Technical Campus,
Abstract
Shri Shankaracharya Group of
Institutions, Bhilai, India
The PPAR-γ agonist enhances the insulin sensitivity and avoids the disorganized
hyperglycemic by promoting the insulin guided cellular uptake of blood glucose.
Therefore, in the present work PPAR-γ has chosen as the target for the molecular
docking study to design an effective agonist of the same. By this research work an
effort has been made to prepare amide and urea series of 1, 3, 4-thiadiazole deriv-
atives as 4-substituted-N-(5-(4-(1-piperidino)1-piperidinyl)-1,3,4-(2-thiadiazolyl)
benzamide (4a-f) and 1-(4-substitutedphenyl)-3-(5-(4-(1-piperidino)1-piperidinyl)
2
Department of Pharmaceutical
Chemistry, Shri Rawatpura Sarkar
Institute of Pharmacy, Kumhari, India
3
Department of Pharmaceutical
Chemistry, Dr. R.G. Bhoyar Institute of
Pharmaceutical Education and Research,
Wardha, India
4
School of Chemistry and Chemical
-1,3,4-(2-thiadiazolyl)urea (6a-f). Both the docking score as well as the pharma-
Engineering, Yulin University, Yulin, P.R.
China
cological animal study data has been suggested that the electron donating group
containing compound 4f and 6f are most potent molecules for the antidiabetic
activity close to the standard drug pioglitazone. It was further observed that the
unsubstituted aromatic ring containing derivatives have also considerable effect
Correspondence
Yogesh Vaishnav, Shri Shankaracharya
Technical Campus, Shri Shankaracharya
Group of Institutions, Junwani, Bhilai,
(4a and 6a) than the electron withdrawing containing derivatives. After the com-
4
90020, Chhattisgarh, India.
Email: yogesh446688@gmail.com
parison of biological data for amide and urea series, it was concluded that the
urea (6a-f) series is more effective than the amide series.
1
| INTRODUCTION
nerve tissues, and heart. A person suffering from diabe-
tes is more prone to heart attack as compared to
Diabetes is one the major intimidation in the 21st cen-
tury which affects the health of people globally. Diabe-
tes affected 210 million in the year 2010 and projected
to be augmented around 300 million by the year
nondiabetic patient. Insulin dependent and noninsulin
dependent or types-2 diabetes were the two main clas-
ses of diabetes. Due to obesity and inactive lifestyle,
[
2]
type 2 diabetes was observed in many cases.
[1]
2
025. Rise of glucose level in the blood causes diabe-
After the exhaustive study of literatures, it was found
that the 1, 3, 4-thiadiazole derivatives are potential anti-
tes. In diabetes, production of insulin is affected and
this may be due to many reasons such as genetically or
may be due to inappropriate lifestyle. Now a day's peo-
ple suffering from diabetes more due to depraved life-
style. The surplus blood sugar in diabetes can cause
disorder of blood vessels throughout the body which
causes complications. Diabetic condition can harm dif-
ferent body parts and organs such as kidneys, eyes,
[
2–6]
diabetic pharmacophore.
It is known that thiadiazole
and its derivatives efficiently bind with the PPAR-γ
[7]
(Peroxisome Proliferator Activating Receptor gamma).
PPAR-γ genes are well studied as they contributed toward
reducing the endoplasmic reticulum stress which is
[
8,9]
responsible for insulin resistance.
Thus, PPAR-γ ago-
nist enhances the insulin sensitivity and avoids the
J Heterocyclic Chem. 2020;1–12.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
VAISHNAV ET AL.
disorganized hyperglycemic by promoting the insulin
guided cellular uptake of blood glucose.
protein and ligand interaction and for the calculation of
[14]
drug score.
To understand the comprehensive percep-
Earlier a quantitative structure activity relationship
QSAR) studies were performed in search of new 1, 3,
tion of ligand and protein structure in this study, X-ray
crystal of PPAR-γ having PDB ID: 3et0 was utilized which
was obtained from RCSB protein data bank.
(
4
-thiadiazole derivatives. Finest models were developed
[10,11]
by the help of QSAR analysis.
Here in the current
work some novel substituted 1, 3, 4-thiadiazole com-
pounds were developed by the aid of QSAR analysis.
Through different QSAR parameters, synthetic scheme
was developed and the synthesized compounds were
screened for antidiabetic activity.
2.2 | Synthesis
2.2.1 | Synthesis of 4-substituted-N-
(5-(4-(1-piperidino)1-piperidinyl)-
1,3,4-(2-thiadiazolyl)ben-zamide (4a-f) and
1-(4-substitutedphenyl)-
3-(5-(4-(1-piperidino)1-piperidinyl)-
1,3,4-(2-thiadiazolyl)urea (6a-f) analogues
To find the authenticity of the biological result and to
claim molecular level mechanism of action of synthesized
derivatives, molecular docking tool is the best option. The
molecular docking study helps to predict the mode of inter-
action of synthesized ligand molecule with amino acid resi-
dues at the binding site of target protein on the basis of
docking score. The docking score suggests the binding
energy of ligand and targeted protein interaction. The
higher negative value of docking score defines the strong
The synthetic scheme was depicted in Figure 1, in which
synthesis was started by taking 2-amino-1, 3, 4-thiadiazole
(1) which was available commercially. Compound (1)
undergoes bromination reaction in the presence of sodium
acetate after stirring at room temperature for 12 hours
using bromine solution in acetic acid that resulted the
[12]
interaction of ligand with the residues at the target site.
5-bromo-1,3,4-thiadiazol-2-amine (2). After the condensa-
2
| MATERIALS AND METHODS
tion of compound 2 with 4-piperidinopiperidine in the pres-
ence of N, N- diisopropyethylamine, it was given
5-(4-(1-piperidino) 1-piperidinyl)-1, 3, 4-thiadiazol-2-amine
(3). In the later step of reaction, benzoylation was done by
using Schotten Baumann reaction, where the benzoyl chlo-
ride was reacted with free amine group of compound 3 in
the presence of sodium hydroxide which give compound
(4a-f). The scheme was further extended to prepare urea
containing compounds. The effort was made by the con-
densation of compound (3) with ethylchloroformate to pro-
duce carbamate compound (5). Further, the ester
hydrolysis was made byamine group of anilines individu-
ally to produce urea containing compounds (6a-f).The list
of substituents for compounds 4a-f, 6a-f along with physi-
cal characterization, yield and melting point of synthesized
compounds were depicted in Table 1.
The chemicals used were synthetic and analytical grade,
procured from HiMedia laboratories, molychem, Merck
Pvt. Ltd, India. Open capillary method was used to mea-
sure melting point of synthesized compounds and are
uncorrected. The purity of synthesized compounds and the
progress of reactions were observed by using thin layer
chromatography using readily available plate of Silica gel
G (E. Merck) with appropriate solvent systems. Carlo Erba
EA 1108 elemental analyzer was used for elemental analy-
sis (C, H, N, O, and S) of synthesized compounds. All
molecular structures were sketched in the 2-Dimensional
Draw application option which was present in device
menu of QSAR plus and the model were developed in V-
[13]
Life Molecular Design Suite (VlifeMDS).
2.1 | In silico studies
2.2.2 | Procedure for synthesis of
5
-bromo-1, 3, 4-thiadiazol-2-amine (2)
In silico methodology is done to explain binding mode of
compound with the target location. In present study, 1, 3,
2-amino-1, 3, 4-thiadiazolesolution (1) (10 g, 99 mmol) was
prepared in acetic acid (140 mL). To the above solution
3.2 g of sodium acetate was added and stirred well. In the
above mixture bromine (0.2 M in acetic acid, 52 mL) was
added drop wise over 2 hours under ice cooled condition.
The mixture was stirred at room temperature for about
12 hours by addition of acetic acid at different time interval
to maintain the consistency. The mixture became solidified
after 12 hours. After the addition of 100 mL of water fur-
ther, the mixture was agitated and filtered followed by
4-thiadiazole scaffolds was considered based on its expected
interaction with PPAR-γ receptor as per the earlier reported
[6]
literature. For docking studies the structures of synthe-
sized compounds were drawn with the aid of Chem Draw
ultra of version 10.0 and have been converted from .mol file
to .pdb file. Docking software “Argus Lab” of version 4.0.1
was applied to examine the binding mode and allied con-
nections of the synthesized compounds with the target.
Pymol software tool having version 1.3 was applied to study

VAISHNAV ET AL.
3
FIGURE 1 Scheme for synthesis of some new amide and urea substituted 1, 3, 4-thiadiazole derivative
washing with distilled water and dried it. Then the pre-
pared compound was purified by recrystallization with eth-
anol. Yield 81% and m.p. 114 C to 116 C.
the resulting mixture refluxed with stirring at temperature
of 120 C for 2 hours and cooled to the normal (room) tem-
ꢀ
ꢀ
ꢀ
perature. On cooling, compound (3) becomes solidified.
Then filtered the solidified compound and wash it with
distilled water. Ethanol was used for recrystallization of
ꢀ ꢀ
2.2.3 | Procedure for synthesis of
5-(4-(1-piperidino) 1-piperidinyl)-1,
3, 4-thiadiazol-2-amine (3)
the compound. Yield78% and m.p. 120 C to 121 C.
2
.2.4 | 5-(4-(1-piperidino) 1-piperidinyl)-
A
solution of compound 2(8 g, 45 mmol) and
1, 3, 4-thiadiazol-2-amine (3)
4
-piperidinopiperidine (7 g, 42 mmol) was prepared by
−
1
using 1, 4- dioxane (150 mL) as a solvent. To the above
mixture N,N-diisopropylethylamine (8 mL) was added and
IR vmax (KBr, in cm ): 1630 (C N), 2360 (C S C),
3106 (CH ), 3448 ( NH ), NMR (300 MHz, DMSO-d ,
2
2
6

4
VAISHNAV ET AL.
ꢀ
TABLE 1 List of substituents and
physical properties of compounds
Compounds
R
M.p. ( C)
Yield (%)
Rf
λmax (nm)
4
4
4
4
4
4
6
6
6
6
6
6
a
b
c
d
e
f
H
154-155
154-158
146-148
164-168
152-153
154–155
157-159
159-160
158-160
148-150
166-167
178-180
81
78
74
72
70
85
76
80
69
67
78
71
0.7
0.8
0.8
0.8
0.7
0.6
0.7
0.7
0.8
0.8
0.6
0.7
248, 287
236, 281
228
(
4a-f, 6a-f)
Cl
OH
NO
2
264, 436
244, 277
255, 454
285
OCH
3
CH
3
a
b
c
d
e
f
H
Cl
257, 428
271, 472
354
OH
NO
2
OCH
3
289
CH
3
281
δ): 4.36 (2H, s,
-piperidinopiperidine), FAB-MS (m/z): 267 [M ];
Anal. Calcd for C H N S: C, 53.90; H, 7.92; N,
NH ), 1.60 to 2.51 (19H, m,
2.2.7 | 4-chloro-N-(5-(4-(1-piperidino)
1-piperidinyl)-1,3,4-(2-thiadiazolyl)
benzamide (4b)
2
+
4
1
2
21
5
2
2
6.19; S, 11.99. Found: C, 53.78; H, 7.99; N,
6.24; S, 11.74.
−1
IR vmax (KBr, in cm ): 1647 (C Nstr), 2984 (Ar C H
str), 3340 (CH str), 3423 ( NH str), 2363 (C S Cstr), 1710
2
2
(>C O str), 1062 (N N str of thiadiazole), NMR (300 MHz,
2
.2.5 | Procedure for synthesis
DMSO-d , δ): 8.14 (1H, s, NH C O), 7.43 to 7.82 (4H, m,
6
of 4-substituted-N-(5-(4-(1-piperidino)1-
piperidinyl)-1,3,4-(2-thiadiazolyl)
benzamide (4a-f)
Ar-CH)1.51 to 2.79 (19H, m, 4-piperidinopiperid -ine), FAB-
+
MS (m/z): 405 [M ]; Anal. Calcd for C H ClN OS: C,
19
24
5
56.22; H, 5.96; Cl, 8.73; N, 17.25; O, 3.94; S, 7.90. Found: C,
6.27; H, 5.88; Cl, 8.77; N, 17.19; O, 3.92; S, 7.87.
5
The compound 3 (5 g, 18 mmol) was benzoyl chloride
(
(
3
7 mL), dissolved in 50 mL of sodium hydroxide solution
10%). The solution was stirred for 30 minutes. After
0 minutes, the solution was added to the water (ice cold)
2.2.8 | 4-hydroxy-N-(5-(4-(1-piperidino)
1-piperidinyl)-1,3,4-(2-thiadiazolyl)
benzamide (4c)
to get the precipitate of compound. The product then fil-
tered and washed with cold water. Recrystallization was
done with cold ethanol.
−1
IR vmax (KBr, in cm ): 1635 (C Nstr), 3010 (Ar C H
str), 3280 ( OH str), 3374 (CH2 str), 3428 ( NH2
str),2358 (C S C str), 1721 (>C O str), 1055 (N N str
2
1
.2.6 | N-(5-(4-(1-piperidino)
-piperidinyl)-1,3,4-
of thiadiazole), NMR (300 MHz, DMSO-d , δ): 8.06 (1H,
s, NH C O), 5.10 (1H, s, OH), 6.85 to 7.82 (4H, m,
6
(
(
2-thiadiazolyl)benzamide
4a)
Ar-CH) 1.41 to 2.76 (19H, m, 4-piperidinopiperidine),
+
FAB-MS (m/z): 387 [M ]; Anal. Calcd for
C H N O S: C, 58.89; H, 6.50; N, 18.07; O, 8.26; S, 8.27.
19
25 5 2
−
1
IR vmax (KBr, in cm ): 1697 (C Nstr), 3029 (Ar C H
str), 3337 (CH str), 3449 ( NH str), 2341 (C S Cstr),
Found: C, 58.82; H, 6.47; N, 18.11; O, 8.22; S, 8.32.
2
2
1
749 (>C O str), 1054 (N N str of thiadiazole), NMR-
(
300 MHz, DMSO-d , δ): 8.08 (1H, s, NH C O), 7.40
2.2.9 | 4-nitro-N-(5-(4-(1-piperidino)
1-piperidinyl)-1,3,4-(2-thiadiazolyl)
benzamide (4d)
6
to 7.99 (4H, m, Ar-CH) 1.54 to 2.82 (19H, m,
4
Calcd for C H N OS: C, 61.43; H, 6.78; N, 18.85; O,
4
4
+
-piperidinopiperid -ine), FAB-MS (m/z): 371 [M ]; Anal.
19
25 5
−
1
.31; S, 8.63. Found: C, 61.40; H, 6.71; N, 18.81; O,
.25; S, 8.58.
IR vmax (KBr, in cm ): 1642 (C N str), 2994 (Ar C H
str), 1540 and 1354 ( NO str), 3351 (CH str), 3430
2
2

VAISHNAV ET AL.
5
(
(
NH str),2361 (C S C str), 1715 (>C O str), 1064
washing with water. Ethanol was used for recrystallization
of the product. Yield 85% and m.p. 132 to 135 C.
2
ꢀ
N N str of thiadiazole), NMR (300 MHz, DMSO-d , δ):
6
8
.00 (1H, s, NH C O), 7.85 to 8.47 (4H, m, Ar-CH) 1.6
to 2.85 (19H, m, 4-piperidinopiperidine), FAB-MS (m/z):
+
4
5
5
16 [M ]; Anal. Calcd for C H N O S: C, 54.79; H,
2.2.13 | 5-(4-(1-piperidino)1-piperidinyl)-
1,3,4-(2-thiadiazolyl)carbamate (5)
19
24 6 3
.81; N, 20.18; O, 11.52; S, 7.70. Found: C, 54.75; H,
.76; N, 20.22; O, 11.47; S, 7.67.
−1
IR vmax (KBr, in cm ): 1647 (C N), 2359 (C S C),
029 (CH ), 3449 ( NH ),2980 (C H, alkyl) NMR
3
2
2
2
1
.2.10 | 4-methoxy-N-(5-(4-(1-piperidino)
-piperidinyl)-1, 3,4-(2-thiadiazolyl)
(300 MHz, DMSO-d , δ): 8.00 (1H, s, NH), 4.20 (2H, m,
6
CH of ethyl), 1.39 (3H, t, CH of ethyl) 1.51 to 2.27 (19H,
2
3
+
benzamide (4e)
m, 4-piperidinopiperidine), FAB-MS (m/z): 267 [M ];
Anal. Calcd for C H N S: C, 53.90; H, 7.92; N, 26.19; S,
12
21 5
−
1
IR vmax (KBr, in cm ): 1624 (C Nstr), 3033 (Ar C H
str), 1485 and 1325 ( OCH str), 3344 (CH str), 3424
11.99. Found: C, 53.78; H, 7.99; N, 26.24; S, 11.74.
3
2
(
(
8
NH str), 2360 (C S C str), 1707 (>C O str), 1063
2
N N str of thiadiazole), NMR (300 MHz, DMSO-d , δ):
2.2.14 | Procedure for synthesis of
1-(4-substituted phenyl)-
3-(5-(4-(1-piperidino)1-piperidinyl)-1,
3,4-(2-thiadiazolyl)urea (6a-f)
6
.06 (1H, s, NH C O), 6.74 to 7.90 (4H, m, Ar-CH)
1
.40 to 2.72 (19H, m, 4-piperidinopiperidine), FAB-MS
+
(m/z): 401 [M ]; Anal. Calcd for C H N O S: C,
20
27 5 2
5
5
9.83; H, 6.78; N, 17.44; O, 7.97; S, 7.99. Found: C,
9.80; H, 6.75; N, 17.34; O, 7.92; S, 7.91.
In hot toluene (50 mL) the carbamate derivative (5) (6.6 g,
20 mmol) was dissolved. The corresponding substituted
aniline was added slowly in the above solution and refluxed
for 4 to 5 hours. The precipitate of desired compound was
obtained on cooling of refluxed solution. Ethanol was used
for washing of product and it was recrystallized by the help
of toluene and methanol mixture.
2
1
.2.11 | 4-methyl-N-(5-(4-(1-piperidino)
-piperidinyl)-1,3,4-(2-thiadiazolyl)
benzamide (4f)
−1
IR vmax (KBr, in cm ): 1630 (C Nstr), 3029 (Ar C H
str), 2771 (ali, C H str, of CH ), 3334 (CH str), 3448 ( NH
2
3
2
str), 2360 (C S C str), 1706 (>C O str), 1062 (N N str of
2.2.15 | 1-phenyl-3-(5-(4-(1-piperidino)
thiadiazole), NMR (300 MHz, DMSO-d , δ): 8.12 (1H, s,
1-piperidinyl)-1,3,4-(2-thiadiazolyl)urea (6a)
6
NH C O), 2.32 (3H, s, Ar CH ), 7.24 to 7.90 (4H, m,
3
−1
Ar CH) 1.10 to 2.99 (19H, m, 4-piperidinopiperidine), FAB-
IR vmax (KBr, in cm ): 1648 (C N str), 3058 (Ar C H
str), 3197 (CH str), 3288 ( NH str), 2360 (C S C str),
+
MS (m/z): 385 [M ]; Anal. Calcd for C H N OS: C,
20
27
5
2
2
6
7
2.31; H, 7.06; N, 18.17; O, 4.15; S, 8.32. Found: C, 62.25; H,
.10; N, 18.12; O, 4.11; S, 8.30.
1745 (>C O str), 1034 (N N str of thiadiazole), NMR
(300 MHz, DMSO-d , δ): 6.41 (2H, s, NH CO NH), 7.04
6
to 7.92 (5H, m, Ar CH) 1.54 to 2.63 (19H, m,
+
4
-piperidinopiperidine), FAB-MS (m/z): 386 [M ]; Anal.
2
5
1
.2.12 | Procedure for synthesis of ethyl
-(4-(1-piperidino)1-piperidinyl)-
,3,4-(2-thiadiazolyl)carbamate (5)
Calcd for C H N OS: C, 59.04; H, 6.78; N, 21.74; O, 4.14; S,
19 26 6
8.30. Found: C, 59.10; H, 6.72; N, 21.69; O, 4.11; S, 8.26.
The corresponding amine derivative (3) (5.6 g, 20 mmol)
was added to the solution of ethyl chloroformate (20 mL,
2.2.16 | 1-(4-chlorophenyl)-
3-(5-(4-(1-piperidino)1-piperidinyl)-1,
3,4-(2-thiadiazolyl)urea (6b)
2
0 mmol) and anhydrous potassium carbonate (4 g) in
anhydrous acetone (250-300 mL) and the above mixture
was refluxed for 18 to 20 hours. By distillation process
excess of acetone was recovered. The above mixture was
left undisturbed for 12 to 16 hours at room temperature
then water (100-120 mL) was added. The solution was
neutralized with acetic acid to get precipitate of compound
−
1
IR vmax (KBr, in cm ): 1664 (C N str), 2853 (Ar C H
str), 3045 (CH str), 3255 ( NH str), 2360 (C S C str),
2
2
1712 (>C O str), 1012 (N N str of thiadiazole), NMR
(300 MHz, DMSO-d , δ): 6.12 (2H, s, NH CO NH),
6
7.26 to 7.61 (4H, m, Ar CH) 1.50 to 2.24 (19H, m,
4-piperidinopiperidine), FAB-MS (m/z): 420 [M ]; Anal.
+
5. The product was obtained after filtration followed by

6
VAISHNAV ET AL.
Calcd for C H ClN OS: C, 54.21; H, 5.99; Cl, 8.42; N,
52.88; H, 5.84; N, 22.72; O, 11.12; S, 7.43. Found: C, 52.82; H,
5.78; N, 22.75; O, 11.14; S, 7.48.
19
25
6
1
8
9.96; O, 3.80; S, 7.62. Found: C, 54.17; H, 5.91; Cl,
.45; N, 19.90; O, 3.82; S, 7.60.
2
.2.19 | 1-(4-methoxyphenyl)-
2
3
3
.2.17 | 1-(4-hydroxyphenyl)-
-(5-(4-(1-piperidino)1-piperidinyl)-1,
,4-(2-thiadiazolyl)urea (6c)
3-(5-(4-(1-piperidino)1-piperidinyl)-1,
3,4-(2-thiadiazolyl)urea (6e)
−1
IR vmax (KBr, in cm ): 1654 (C N str), 2933 (Ar C H
str), 1450 and 1314 ( OCH str), 3141 (CH str), 3324 ( NH
str),2360 (C S C str), 1728 (>C O str), 1043 (N N str of
−
1
IR vmax (KBr, in cm ): 1633 (C N str), 2917 (Ar C H
str), 3134 (CH str), 3351 ( NH str), 2359 (C S C str),
3
2
2
2
2
1
689 (>C O str), 3410 ( OH str.) 1042 (N N str of
thiadiazole), NMR (300 MHz, DMSO-d , δ): 6.10 (1H, s,
6
thiadiazole), NMR (300 MHz, DMSO-d , δ): 6.08 (2H, s,
NH C O), 6.90 to 7.62 (4H, m, Ar CH), 3.62 (3H, s,
6
NH CO NH), 7.15 to 7.74 (4H, m, Ar CH)1.52 to
CH ) 1.64 to 2.81, (19H, m, 4-piperidinopiperidine), FAB-
3
+
2
.61 (19H, m, 4-piperidinopiperidine), 5.02 (1H, s, OH),
MS (m/z): 416 [M ]; Anal. Calcd for C H N O S: C,
20 28 6 2
+
FAB-MS (m/z): 402 [M ]; Anal. Calcd for
C H N O S: C, 56.69; H, 6.51; N, 20.88; O, 7.95; S, 7.97.
57.67; H, 6.78; N, 20.18; O, 7.68; S, 7.70. Found: C, 57.62; H,
6.71; N, 20.21; O, 7.63; S, 7.74.
19
26 6 2
Found: C, 56.22; H, 6.48; N, 20.92; O, 7.97; S, 7.92.
2
.2.20 | 1-(5-(4-(1-piperidino)1-piperidi
2
(
1
.2.18 | 1-(4-nitrophenyl)-3-(5-(4-
1-piperidino)1-piperidinyl)-
,3,4-(2-thiadiazolyl)urea (6d)
nyl)-1,3,4-(2-thiadiazolyl)-3-p-tolylurea (6f)
−1
IR vmax (KBr, in cm ): 1632 (C N str), 2974 (Ar C H
str), 2801 (ali, C H str, of CH ), 3063 (CH str), 3428
( NH2 str),2358 (C S C str), 1708 (>C O str), 1065
3
2
−1
IR vmax (KBr, in cm ): 1647 (C N str), 2965 (Ar C H
str), 3074 (CH str), 3413 ( NH str), 2360 (C S C str), 1740
(N N str of thiadiazole), NMR (300 MHz, DMSO-d , δ):
2
2
6
(>C O str), 1055 (N N str of thiadiazole), NMR (300 MHz,
6.24 (1H, s, NH C O), 7.02 to 7.57 (4H, m, Ar CH),
DMSO-d , δ): 6.24 (2H, s, NH CO NH), 7.82 to 8.12 (4H,
2.42 (3H, s,
CH3) 1.50 to 2.62 (19H, m,
6
+
m, Ar CH) 1.60 to 2.74 (19H, m, 4-piperidinopiperidine),
4-piperidinopiperidine), FAB-MS (m/z): 400 [M ]; Anal.
Calcd for C H N OS: C, 59.97; H, 7.05; N, 20.98; O,
+
FAB-MS (m/z): 431 [M ]; Anal. Calcd for C H N O S: C,
19
25
7
3
20 28 6
TABLE 2 Antidiabetic study of compounds (4a-f, 6a-f)
Blood glucose level (mg/dL)
%
inhibition in the rise
Compounds
Control
R
Prior to fed (Fasting)
120.3 ± 2.3
82.6 ± 3.6
76.3 ± 3.4
74.3 ± 4.7
72.3 ± 3.6
74.2 ± 4.8
74.7 ± 3.6
78.5 ± 4.6
76.5 ± 3.7
79.4 ± 5.4
76.4 ± 4.2
72.3 ± 3.5
73.6 ± 5.6
78.2 ± 2.7
After 90 min of fed
157.9 ± 3.1
87.65 ± 3.8
82.4 ± 4.8
83.9 ± 4.7
80.7 ± 2.9
82.3 ± 5.5
81.7 ± 4.5
83.1 ± 5.1
82.3 ± 4.6
86.4 ± 4.7
83.9 ± 5.7
80.4 ± 2.8
80.2 ± 3.8
83.2 ± 4.7
of blood glucose level
—
—
H
—
Pioglitazone
86.3
83.5
73.9
77.3
78.1
81.0
87.5
84.3
77.8
79.7
78.1
82.1
89.7
4
4
4
4
4
4
6
6
6
6
6
6
a
b
c
d
e
f
Cl
OH
NO
2
OCH
3
CH
H
3
a
b
c
d
e
f
Cl
OH
NO
2
OCH
3
CH
3

VAISHNAV ET AL.
7
3
3
.99; S, 8.01. Found: C, 59.91; H, 7.10; N, 20.96; O,
.93; S, 8.07.
prepared by using 1% solution of tween 40 in distilled
water in a volume of 10 mL/kg and administered to
group-I. The standard drug pioglitazone of 50 mg/kg as
well as test compounds in the dose of 50 mg/kg were pre-
pared by suspended in vehicle which were given per oral
in a volume of 10 mL/kg to the animal groups. After a
period of 15 minute dosing, rats were fed with their nor-
mal food. The blood sample was obtained by tail bleed,
just prior to and 90 minutes after the normal fed loading.
The concentration of glucose was measured by glucose
oxidase method using commercially available blood glu-
cose monitoring kit (one touch ultra). Finally, the inhibi-
tion in increased blood glucose level was measured as
percent inhibition in streptozotocin rats. The results were
expressed as value of mean ± SEM. A schematic repre-
sentation of animal experiment was given below.
2
.3 | Antidiabetic study
The antidiabetic study was performed on animals (weight
50-225 g) of either sex by streptozotocin induced model.
1
In this study, wistar rats were used to perform anti-
diabetic study. The screening was done under the guide-
lines of Committee for the Purpose of Control and
Supervision of Experiments on Animals (CPCSEA) in
approved laboratory by the Institutional Animal Ethical
Committee (IAEC) with approval no. SRIP/
IAEC/2015-16/10 (registration no 1188/ac/08/CPCSEA).
2
.3.1 | Study of NIDDM (non-insulin
dependent diabetes mellitus)
3 | RESULT AND DISCUSSION
3.1 | Chemistry
The streptozotocin was used to induce acute NIDDM. The
streptozotocin (40 m/kg body weight) was prepared freshly
in citrate buffer having pH 4.5 which was given intraperito-
neally. The blood glucose for fasting glucose levels was mon-
itored. Rats were considered for antidiabetic study when
their fasting glucose level becomes more than 140 mg/dL
and above 200 mg/dL after 1 hour of normal fed.
The structure of compound 3 was confirmed from the IR
spectra observed at 2360 cm− for C S C and 1630 cm
1
−1
for C N bonds of 1, 3, 4-thiadiazole ring along with the
peak around 3448 cm− for primary NH2 group present
as substituent in ring. The presence of this amine group is
1
1
The diabetic animals (rats) were divided into groups.
Each group contains six rats (n = 6). Control vehicle was
further supported from HNMR singlet peak at δ 4.36.
There is another substituent, that is, 4-piperidinopiperidine,
TABLE 3 Statistical significance of synthesized compounds (4a-f and 6a-f)
Pre-meal
Post-meal
Bonferroni's
multiple
comparisons test
Mean
diff.
95.00% CI
of diff.
Mean
95.00% CI
of diff.
Significant? Summary diff.
Significant? Summary
Piolglitazone vs
Control
−36.6
−45.4 to −27.9 Yes
****
−69.9
−78.6 to −61.1 Yes
****
4a vs control
4b vs control
4c vs control
4d vs control
4e vs control
4f vs control
6a vs control
6b vs control
6c vs control
6d vs control
6e vs control
6f vs control
−42.6
−45.2
−46.2
−44.6
−44.5
−39.8
−46.1
−41.1
−44.7
−49.4
−47.9
−43.1
−51.4 to −33.9 Yes
−53.9 to −36.4 Yes
−54.9 to −37.4 Yes
−53.3 to −35.8 Yes
−53.2 to −35.8 Yes
−48.5 to −31.1 Yes
−54.9 to −37.4 Yes
−49.8 to −32.3 Yes
−53.4 to −35.9 Yes
−58.2 to −40.7 Yes
−56.6 to −39.2 Yes
−51.8 to −34.4 Yes
****
****
****
****
****
****
****
****
****
****
****
****
−74.4
−74.4
−74
−83.1 to −65.6 Yes
−83.2 to −65.7 Yes
−82.7 to −65.2 Yes
−82.6 to −65.2 Yes
−83.5 to −66.0 Yes
−81.7 to −64.2 Yes
−83.5 to −66.0 Yes
−81.9 to −64.4 Yes
−81.8 to −64.4 Yes
−88.2 to −70.8 Yes
−88.4 to −70.9 Yes
−85.4 to −67.9 Yes
****
****
****
****
****
****
****
****
****
****
****
****
−73.9
−74.8
−73
−74.8
−73.2
−73.1
−79.5
−79.7
−76.7
*
***Very Significant.

8
VAISHNAV ET AL.
FIGURE 2 Ball and stick structure of compound 6f with best docking pose, bond distance and hydrogen bonding in red color line
present in the above heterocyclic ring was illustrated from
Diabetic animals (Rats)
the NMR multiplets peaks around δ 1.60 to 2.51 which was
−1
well established with the IR peak at 3106 cm for CH2
Divided into groups
group of 4-piperidinopiperidine ring. The appearance of IR
−1
−1
peak near 1740 cm for keto and 3029 cm for aromatic
Ar C H str) ring suggested the attachment of benzoyl
(
moiety (4a-f). This was further confirmed by the NMR
multiplets peaks around δ 7.40 to 7.99 for Ar-CH of ben-
zene ring of compound 4a-f. on the sequence of study of
Group I
Control)
Group II
(Standard)
Group III
(
(Test Compounds)
−1
spectra, the manifested peaks around 1274 cm ,
1
−1
1
095 cm− ( C O , str.), and 1740 cm (>C O) imply
Blood sample was collected
the addition of ester functional group in the form of carba-
mate (5). The formation of ethyl-ester was supported due to
emergence of multiplet at δ 4.20 for CH and 1.39 for CH3
2
Glucose concentration was measured by
Glucose oxidase method
of ethyl group from ethyl ester. The disappearance of peak
for aliphatic alkyl group in the IR and NMR spectra, con-
firmed the urea formation after amine hydrolysis in com-
pounds (6a-f). IR and NMR spectra of compounds can be
seen in Data S1.
Inhibition in increased blood glucose level was
measured
FIGURE 3 Solid surface cascade structure of compound 6f
docked at the binding site in best possible orientation
3.2 | Antidiabetic study
Blood glucose lowering study was performed for all the
synthesized compounds (4a-f, 6a-f) and compared with
standard compound pioglitazone and control which was
depicted in Table 2. There are two series of derivatives
were prepared, first series constitute the aromatic
amide,4-substituted-N-(5-(4-(1-piperidino)1-piperidinyl)-
hydrocarbon) containing derivatives viz. 4a, 4f, 6a and 6f
were very dominant in the series for blood glucose lower-
ing effect. On the further observation, it was found that
the compound 6f shown the most significant effect on
the percentage inhibition in rise of blood glucose level
(89.7%), even more than the standard compound
pioglitazone (86.3%). The second effective derivative was
found as compound 4f. Both of these derivatives 6f and
4f were containing the electron donating methyl
substituted aromatic group, which certainly enhancing
hydrophobicity property of the compound. On the other
hand, unsubstituted aromatic group containing com-
pound 4a and 6a were the next highly effective hypogly-
cemic in their respective series (Table 2) and Statistical
1
,3,4-(2-thiadiazolyl)benzamide(4a-f) and second series
constitute the aromatic urea, 1-(4-substitutedphenyl)-
-(5-(4-(1-piperidino)1-piperidinyl)-1,3,4-(2-thiadiazolyl)
3
urea (6a-f). From the in vivo study it was found that the
urea series (6a-f) was more effectively lowered the blood
glucose level than the amide derivatives (4a-f).
After the study of the obtained blood glucose mea-
sures, it was found that all the hydrophobic group (aro-
matic hydrocarbon and methyl containing aromatic

VAISHNAV ET AL.
9
TABLE 4 Molecular docking study data
Docking score
(Kcal/mol)
RMSD value
(in A )
ꢀ
S. no.
Structure
1
−9.30
0.12
O
N N
S
N
H
N
N
H
N
4
a
2
−10.03
0.11
O
N N
S
N
Cl
H
N
N
N
4
b
3
4
−8.76
−8.48
0.17
0.09
O
N N
S
N
OH
N
N
H
4
c
O
N N
S
N
NO2
H
4
d
5
6
7
−9.07
−9.75
0.06
0.10
0.11
O
N N
S
N
OCH3
N
N
H
N
N
4
e
O
N N
S
N
CH3
H
4
f
−10.13
H
O
N N
S
N
N
H
N
H
N
6a
(
Continues)

10
VAISHNAV ET AL.
TABLE 4 (Continued)
Docking score
(Kcal/mol)
RMSD value
(in A )
ꢀ
S. no.
Structure
8
−10.70
0.07
Cl
O
N N
S
N
H
N
N
H
N
6b
9
−10.03
0.08
OH
O
N N
S
N
H
N
N
H
N
6c
1
0
−8.11
0.22
NO2
O
N N
S
N
H
N
N
H
N
6d
1
1
−9.77
0.20
OCH3
O
N N
S
N
H
N
N
H
N
6e
1
2
−10.88
0.08
CH3
O
N N
S
N
H
N
N
H
N
6f
significance of synthesized compounds (4a-f and 6a-f)
were depicted in Table 3.
contribute for hypoglycemic efficacy. While the strong
electron withdrawing group containing derivatives 4b, 6b
(chloro substituted phenyl) and 4c, 6c (hydroxyl
substituted phenyl) were least effective in the series. Out
of all the compounds, chloro derivative 4-chloro-N-
(5-(4-(1-piperidino)1-piperidinyl)-1,3,4-(2-thiadiazolyl)
benzamide (4a) found the least effective compound out
On the next level of interpretation of data in concern
of safer as well as effective compounds, methoxy
substituted phenyl derivatives 4e and 6e were also given
significant blood glucose lowering effective. This result
suggested the mild electron withdrawing group can also

VAISHNAV ET AL.
11
of all the derivatives of this series with 73.9% inhibition
in blood glucose.
designed and synthesized compounds in both biological
as well as in silico result.
3
.3 | Docking study using peroxisome
4 | CONCLUSION
proliferator activated receptor gamma
In the sequence of work 1, 3, 4-thiadiazole derivatives
were designed and synthesized. The docking was per-
formed by using docking software to predict the active
compounds and reduce the effort for synthesis of inactive
or less significant molecules. All the structures were
established by the spectroscopic analysis. The urea analog
6f was found to be most potent antidiabetic compound
where as the amide analog 4f also showed effective action
against diabetes. The result of antidiabetic study was well
synchronized with the docking result which rationalizes
the performance of in silico study. This research gives an
idea to synthesize new potent drugs for the treatment of
diabetes.
The binding domain for the standard drug pioglitazone
and designed derivatives (4a-f, 6a-f) containing 617 ARG,
7
7
7
22 ASP, 711 GLN, 716 ILE, 712 LEU, 713 LEU, 718 LYS,
23 MET, 542 PHE, 620 PHE, 623 PHE, 619 PRO, and
15 VAL amino acid residues. All the derivatives were
docked in stated binding site for comparing with stan-
dard drug through docking software by using peroxisome
proliferator-activated receptor gamma (PDB ID: 3et0)
protein by using Argus Lab docking software. The effec-
tiveness of docking were evaluated on the basis of dock-
ing score (binding energy in kcal/mol), the negative
value suggests the effective binding. The standard ligand
pioglitazone docked effectively (with −11.84 binding
energy) at the active binding site of the targeted protein
CONFLICT OF INTEREST
(PPARgamma).
The
nitrogen
heteroatom
of
The authors declare no conflicts of interest.
thiazolidinedione ring of pioglitazone was contributed
for the hydrogen bond formation with amino acid residue
of binding site. The designed compounds were predicted
active on the basis of docking score found after perfor-
mance of docking in the same site. After the study of
docking score, it was observed that compound 4f and 6f
were the most prominent in concerned series, that is,
amide (4a-f) and urea (6a-f) with docking score −9.75
and −10.88, respectively. The structure (boll and stick)
with hydrogen bond as well as the solid surface structure
of compound 6f docked with binding site was shown in
Figures 2 and 3.
ORCID
Yogesh Vaishnav https://orcid.org/0000-0002-1726-
5
318
Dhansay Dewangan https://orcid.org/0000-0003-4177-
216
4
Achal Mishra https://orcid.org/0000-0002-3196-3390
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.