Structure-based drug designing, scoring, and synthesis of some substituted sulphonylureas/guanidine-based derivatives as hypoglycemic agents

Article abstract of DOI:10.22159/ijpps.2017v9i12.21937

Objective: The present work deals with the designing, scoring, synthesis and, characterization of 1-(4-(2-(4-Substitutedphenylamino)-2-oxoethyl)phenylsulfonyl)-3-(4-substitutedbenzoyl)urea (5A-5B),1-(4-(2-(4-substitutedphenylamino)-2-oxoethyl)phenylsulfonyl)-3-(4-substituted-benzoyl)guanidine(5C-5E) and, 1-(4-Substitutedbenzoyl)-3-(4-(2-oxo-2-(piperazin-1-yl)ethyl)phenylsulfonyl)urea (5F-5H) based derivatives as hypoglycemic agents. Methods: Docking calculations were performed to predict the binding affinity between the AKR1C1 complexes and sulphonylureas compounds using the Glide docking program. Docking studies on LigPrep treated ligands were carried out to predict the binding pocket of protein 4YVP using the docking program. The QikProp program was used to predict the ADME/T properties of the analogues. All these newly synthesized compounds were screened for their in vivo hypoglycemic activity by most relevant animal models like alloxan-induced diabetic rats by measuring blood plasma concentration compared with reference drug glibenclamide. Results: Novel compounds 1-(4-(2-(4-Substitutedphenylamino)-2-oxoethyl)phenylsulfonyl)-3-(4-substitutedbenzoyl)urea (5A-5B), 1-(4-(2-(4-substitutedphenylamino)-2-oxoethyl)phenylsulfonyl)-3-(4-substitutedbenzoyl) guanidine (5C-5E), and 1-(4-Substitutedbenzoyl)-3-(4-(2-oxo-2-(piperazin-1-yl)ethyl)phenylsulfonyl)urea (5F-5H) were synthesised and characterized using spectral and analytical data. The results of molecular docking and in vivo hypoglycemic activity, all compounds have shown considerable activity with respect to glibenclimide, but compounds 5D (52.49±7.73) and 5E(48.18±4.22)are equipotent with respect to activity as compared to standard glibenclamide(55.97±3.19). Conclusion: Compounds 5D and 5E have exhibited good hypoglycemic activity,hence both the derivatives will consider as a lead molecule and further some modification in their structures to get a more potent anti-diabetic agent.

Full text of DOI:10.22159/ijpps.2017v9i12.21937

International Journal of Pharmacy and Pharmaceutical Sciences
ISSN- 0975-1491
Vol 9, Issue 12, 2017
Original Article
STRUCTURE-BASED DRUG DESIGNING, SCORING, AND SYNTHESIS OF SOME SUBSTITUTED
SULPHONYLUREAS/GUANIDINE-BASED DERIVATIVES AS HYPOGLYCEMIC AGENTS
ISHAN PANCHAL1, DHRUBO JYOTI SEN2, ARCHANA NAVLE3, UMANG SHAH4
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Parul University, Vadodara, Gujarat, India, 2Department of
Pharmaceutical Chemistry, Shri Sarvajanik Pharmacy College, Mehsana, Gujarat, India, 3Department of Pharmacology, Faculty of
Pharmacy, Parul University, Vadodara, Gujarat, India, 4Department of Pharmaceutical Chemistry, Ramanbhai Patel College of Pharmacy,
Charotar University of Science and Technology, Changa, Gujarat, India
Email: ishanpharma@gmail.com
Received: 19 Aug 2017 Revised and Accepted: 02 Nov 2017
ABSTRACT
Objective: The present work deals with the designing, scoring, synthesis and, characterization of 1-(4-(2-(4-Substitutedphenylamino)-2-
oxoethyl)phenylsulfonyl)-3-(4-substitutedbenzoyl)urea (5A-5B),1-(4-(2-(4-substitutedphenylamino)-2-oxoethyl)phenylsulfonyl)-3-(4-substituted-
benzoyl)guanidine(5C-5E) and, 1-(4-Substitutedbenzoyl)-3-(4-(2-oxo-2-(piperazin-1-yl)ethyl)phenylsulfonyl)urea (5F-5H) based derivatives as
hypoglycemic agents.
Methods: Docking calculations were performed to predict the binding affinity between the AKR1C1 complexes and sulphonylureas compounds
using the Glide docking program. Docking studies on LigPrep treated ligands were carried out to predict the binding pocket of protein 4YVP using
the docking program. The QikProp program was used to predict the ADME/T properties of the analogues. All these newly synthesized compounds
were screened for their in vivo hypoglycemic activity by most relevant animal models like alloxan-induced diabetic rats by measuring blood plasma
concentration compared with reference drug glibenclamide.
Results: Novel compounds 1-(4-(2-(4-Substitutedphenylamino)-2-oxoethyl)phenylsulfonyl)-3-(4-substitutedbenzoyl)urea (5A-5B), 1-(4-(2-(4-
substitutedphenylamino)-2-oxoethyl)phenylsulfonyl)-3-(4-substitutedbenzoyl) guanidine (5C-5E), and 1-(4-Substitutedbenzoyl)-3-(4-(2-oxo-2-
(piperazin-1-yl)ethyl)phenylsulfonyl)urea (5F-5H) were synthesised and characterized using spectral and analytical data. The results of molecular
docking and in vivo hypoglycemic activity, all compounds have shown considerable activity with respect to glibenclimide, but compounds 5D
(52.49±7.73) and 5E(48.18±4.22)are equipotent with respect to activity as compared to standard glibenclamide(55.97±3.19).
Conclusion: Compounds 5D and 5E have exhibited good hypoglycemic activity,hence both the derivatives will consider as a lead molecule and
further some modification in their structures to get a more potent anti-diabetic agent.
Keywords: Diabetes mellitus, Sulphonylureas, ADME/T, AKR1C1, QikProp, Alloxan
© 2017 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
DOI: http://dx.doi.org/10.22159/ijpps.2017v9i12.21937
INTRODUCTION
antidiabetic therapy for many years. Thus, it was thought to develop
new antidiabetic agents with higher efficacy and lower toxicity for the
long-term treatment of type II diabetes mellitus. Searching for new,
safer anti-diabetic agents are still a challenge for medicinal chemists.
Hui-bin Zhang et al. has reported1-(4-(2-(4-substituted phenyl
sulfonamide) ethyl) phenylsulfonyl)-3-(4-substituted phenyl)
thiourea/ urea derivatives with benzene sulfonamide groups as
potential hypoglycemic agents [15]. Abbas Ahmadi et al. has reported
the synthesis and investigating hypoglycemic and hypolipidemic
activities of some glibenclamide analogues in rats [18].
Diabetes mellitus (DM) is a major degenerative disease in the today’s
world. It is a group of disorders of carbohydrate metabolism resulting
from body's failure to produce insulin in Type 1 and insulin resistance
in Type 2 diabetes mellitus through altered secretion, decreased
insulin activity, or a combination of both factors and characterized by
hyperglycaemia [1]. In Type 1 diabetes, the cause is an absolute
deficiency of insulin secretion caused by pancreatic beta cell
destruction. In
Type 2 diabetes, which is a much more prevalent category, the cause is
a combination of resistance to insulin action and an inadequate
compensatory insulin secretory response [2]. Several epidemiological
S
HN
S
O
C
O
HN
R2
and clinical studies indicate
a direct relationship between
hyperglycemia and long-term complications such as retinopathy,
nephropathy, neuropathy like micro and macro vascular
complications. This disease is associated with reduced life expectancy
significant morbidity due to specific diabetes-related microvascular
complications that diminish the quality of life. India became the
diabetic capital of the world with over 20 million diabetics and this
number is set to increase to 57 million by 2025 [3].
H
H
O
N
N
H2
O
C
S
15
O
CH2
O
O
R1
S
NH
N
H
O
R
18
R1
C
O
X
Numerous drugs such as sulfonylureas and biguanides are presently
available to reduce hyperglycemia in diabetes mellitus. These drugs
have side effects and thus searching for a new class of compounds is
essential to overcome this problem [4]. The onset of insulin in the
body, which causes an abnormal effect on glucose metabolism, is
related not only to the development of Type II diabetes but also to
cardiovascular disease [5]. Sulfonylureas [6-18] are the backbone of
O
NH
O
S
NH
C
C
HN
O
R2
5A-5E
Fig. 1: Structures of lead compound and (5A-5E) synthesized a
compound

Panchal et al.
Int J Pharm Pharm Sci, Vol 9, Issue 12, 226-232
Based on extensive literature review, we have designed and
synthesized the compounds and subjected to In silico docking
studies. The best-scored compounds further explored for In vivo
biological activity and In silico ADMET study. Fig. 1 shows the lead
compounds and targeted derivatives.
docking studies on LigPrep treated legends were carried out to predict
the binding pocket of protein 4YVP using the glide docking program.
In silico ADME/T property analysis
The QikProp program of maestro was used to predict the ADME/T
properties of the analogues. All the analogues were neutralized
before being used by QikProp (V4.6, 2015). QikProp helps in
analyzing the pharmacokinetics and pharmacodynamics of the
legend by accessing the drug-like properties. Lipinski’s rule of five
provides a method of assessing the likelihood that a given molecule
could be orally bioavailable based on a series of physicochemical
requirements, not more than one of which should be violated.
Molecules violating any of these rules may have problems with
bioavailability. [22] It was also evaluated the acceptability of
analogues based on Lipinski’s rule of five which was essential to
ensure drug-like properties. The number of physical descriptors as
well as pharmaceuticals relevant properties of all sulphonylureas
analogues using QikProp was analyzed, amongst that the significant
descriptors were reported and are important for predicting the
drug−like properties of molecules. The properties include H−bond
Donor (0.0−6.0), H−bond Acceptor (2.0−20.0), Predicted water/gas
partition coefficient. (QPlogpw) (5.0−48.0), Predicted octanol/water
partition coefficient (QPlogPo/w) (–2.0 to 6.5), Predicted aqueous
solubility (QPlogS) (–6.0 to 0.5). The values represented in the
bracket are standard values for each parameter [23-25].
Fig. 2: Influences of structural components in determining the
structure-activity relationship: A) halogen atoms enhancing
binding affinity and insulin secretion; B) acid amide moiety
enhancing binding affinity by the factor 1000 in comparison to
tolbutamide; C) acidic sulfonylurea group essential for binding;
[19] D) benzene moiety increasing lipophilicity) nitro group at
the para position in compound to produce significant blood
glucose lowering activity [20]
Experimental section
Chemistry–Scheme 1 and 2
General procedure for Synthesis of 1-(4-(2-(4-Substitutedphenyl-
amino)-2-oxoethyl)
urea (5A-5B)
phenylsulfonyl)-3-(4-substituted-benzoyl)
MATERIALS AND METHODS
Materials
The compounds (5A-5B) were prepared by following the literature
method. [26] The novelty of all of the compounds was checked by Sci
finder report [27].
Laboratory grade chemicals and reagents were collected from Sigma
Alderich and Loba Chemie. The reactions were monitored by thin
layer chromatography on TLC silica gel 60 F254 plates for completion
of the reaction; mobile phase solvents were selected as n-hexane:
ethyl acetate (7:3). Melting points of all the synthesized compounds
were checked in capillary tubes by using a melting point apparatus
(VEEGO melting point apparatus).
Synthesis of 5A-5B was achieved by fridalcraft alkylation of 1-(4-
substituted benzoyl)-3-(phenylsulfonyl)urea (0.1 mmol) and N-(4-
substituted phenyl)-2-chloroacetamide (1 mmol) kept on reflux for
7 h in the presence of anhydrous AlCl3 and dry DCM (50 ml) as a
solvent. A reaction mixture was monitored by TLC. The resultant
mixture was poured onto crushed ice. The separated solid was
filtered and recrystallized with rectified spirit.
All the compounds were characterized by FT-IR spectrometer
(Bruker); 1H NMR, 13C NMR spectra were obtained from 400 MHz
NMR Spectrometer (Brüker Biospin, Switzerland) CoE Rajkot,
Gujarat. The molecular mass of synthesized compounds was
performed in Mass spectrophotometer (O2h discovery, Ahmedabad
and synzeal research Pvt Ltd, Gandhinagar).
General procedure for Synthesis of 1-(4-(2-(4-substituted
phenylamino)-2-oxoethyl) phenylsulfonyl)-3-(4-substituted benzoyl)
guanidine (5C-5E):
Synthesis of 5C-5E was achieved by fridal craft alkylation of 1-(4-
Substituted benzyl)-3-(phenylsulfonyl) guanidine (0.1 mmol) and N-
(4-substituted phenyl)-2-chloroacetamide (1 mmol) kept on reflux
for 7 h in the presence of anhydrous AlCl3 and dry DCM (50 ml) as a
solvent. A reaction mixture was monitored by TLC. The resultant
mixture was poured onto crushed ice. The separated solid was
filtered and recrystallized with rectified spirit.
Molecular docking study
The Crystal structure of alpha ketoreductase (AKR1C1) complexes
with glibenclamide complexes with hypoglycemic drug glibenclamide
(PDB ID: 4YVP) was imported and prepared by a multistep process
through the protein preparation wizard of Maestro (version 10.4,
Schrodinger, LLC, New York, NY) from protein data bank. The protein
preparation was done by protein preparation wizard of the maestro.
During protein preparation, hydrogen atoms were added and water
molecules within 5A ° of the co-crystallized ligand were removed. The
Protonation states of entire systems were adjusted to the pH range of
7.0±2.0 using Epik v3.4 and the geometry optimization was performed
to a maximum root mean square deviation (RMSD) of 0.3 A ° with the
OPLS (Optimized Potentials for Liquid Simulation) 2005 force field.
Docking calculations were performed to predict the binding affinity
between the AKR1C1 complexes and sulphonylureas compounds
using the Glide docking program [21]. The chemical structures of
designing compounds were built using Maestro 10.4. Ligand
structures were submitted to the energy minimization using the OPLS
force field until the energy difference between subsequent structures
was 0.001 KJ/Mol A °. The possible tautomers of legends maintaining
original stereochemistry were explored using Lig Prep (version 3.0,
Schrodinger, LLC, New York, NY. Lig Prep generated multiple
conformations using confusion, and ionization states were generated
for all the compounds by using Epik 3.4. A single legend was searched
for multiple conformations based on torsional angles. Molecular
General procedure for Synthesis of 1-(4-Substituted benzyl)-3-(4-(2-
oxo-2-(piperazin-1-yl) ethyl) phenylsulfonyl) urea (5F-5H):
Synthesis of 5F-5H was achieved by fridal craft alkylation of 1-(4-
Substituted benzyl)-3-(phenylsulfonyl) urea (0.1 mmol) and 2-
Chloro-1-(piperazin-1-yl)ethanone(1 mmol) kept on reflux for 7 h in
the presence of anhydrous AlCl3 and dry DCM (50 ml) as a solvent. A
reaction mixture was monitored by TLC. The resultant mixture was
poured onto crushed ice. The separated solid was filtered and
recrystallized with rectified spirit.
Spectral data
1-(4-(2-(4-Bromophenylamino)-2-oxoethyl) phenylsulfonyl)-3-
(4-nitrobenzoyl) urea (5A)
Yield: 55%, M. P 140-142 °C; Rf = 0.70 (ethyl acetate: hexane 2:8 v/v)
IR (KBr) (cm1): 3648(N-H)str, 2973(C-H), 1169(S=O), 1568(C-C,Ar),
848(C-Br).
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Int J Pharm Pharm Sci, Vol 9, Issue 12, 226-232
1H NMR (DMSO): δ (ppm) 3.40(s,2H,CH2), 7.12(d,2H,ArH), 7.60
In vivo biological evaluation
(d,6H,ArH),8.36(d,2H,ArH),8.21(d,2H,ArH),8.18(s,1H,NH),10.41(s,1
H,NH); MS: m/z: 561(M+1); 13C NMR (DMSO):157.04, 43.45, 164,
116.31,120.2,120.3,124.6,124.6,130.11,125
Albino wistar rats (Parul University, Vadodara) were used for in vivo
biological evalution of novel hypoglycemic agents. Experiments
were carried out in male rats have weight between 150-200 g. They
were housed (six per cage) in plastic cages (47 cm × 34 cm × 18 cm)
lined with husk renewed every 24 h under standard laboratory
conditions maintained at 25±10 °C and under 12/12 hour light/dark
cycle. The rats were fed on pelletdiet (Hindustan Lever, India).
Drinking water was allowed ad libitum. The experimental protocol
was approved by the institutional animal ethics committee (Protocol
No: PIPH 03/16) and by the animal regulatory body of the Indian
Government (Registration No: 921/PO/EReBi/S/ 05/CPCSEA/
PIPH03).
1-Benzoyl-3-(4-(2-oxo-2-(phenylamino) ethyl) phenylsulfonyl)
urea (5B)
Yield: 75%; gray crystalline powder; M. P=164-166 °C; ; Rf = 0.75
(ethyl acetate: hexane 2:8 v/v) IR (KBr) (cm-1):3263(N-H)
str,2973(C-H),1190(S=O),1590(C-C, str Ar);1HNMR(DMSO): δ(ppm)
3.42(s,2H,CH2),7.16(d,2H,ArH), 7.26(d,2H,ArH), 7.60(d,6H, ArH),
8.32(d,2H,ArH),8.21(d,2H,ArH),8.14(s,1H,NH), 1.40(s,1H,NH); MS:
m/z: 439.2(M+2); 13C NMR (DMSO):43.45,164, 116.31,120.2, 120.3,
124.6,124.6,130.11,125,130
Diabetes was induced in the rats by a single intraperitoneal injection
of alloxan (150 mg kg-1 body weight). Since alloxan is capable of
producing fatal hypoglycaemia as a result of the massive pancreatic
insulin release, rats were treated with 20% glucose solution (15-20
ml) intraperitoneally after 6h. The rats were then kept for the next
24h on 5% glucose solution bottles in their cages to prevent
hypoglycaemia. [28] After 1 w, rats with moderate hyperglycaemia
with blood glucose range of 200-400 mg dl−1 were used for the
study. Blood was collected from the tail vein. All of the target
molecules were given to the diabetic rats orally in the form of a
suspension in carboxymethyl cellulose.
1-benzoyl-3-(4-(2-oxo-2-(phenylamino) ethyl) phenylsulfonyl)
guanidine (5C)
Yield: 80%; gray crystalline powder; M. P=156-158 °C; Rf = 0.65
(ethyl acetate: hexane 2:8 v/v) IR (KBr) (cm-1): 3449(N-H)
str,1691(C=O) str, 2989(C-H), 1187(S=O), 1590(C-C,Ar),1HNMR
(DMSO): δ (ppm)3.44(s,2H,CH2),2.51(s,1H,NH), 7.98(s,1H,NH), 7.65
(d,2H,ArH),7.16(d,2H,ArH),7.60(d,6H,ArH)8.17(d,4H,ArH); MS: m/z:
437.2(M+1);13C NMR (DMSO):43.45,164, 118.31, 122,126, 130.11
1-(4-(2-(3-Fluorophenylamino)-2-oxoethyl) phenylsulfonyl)-3-
(4-nitrobenzoyl) guanidine (5D)
Experimental design
Yield: 65%;M. P: 116-118 °C. Rf = 0.65 (ethyl acetate: hexane 3:7
v/v) IR (KBr) (cm-1): 3274(C-H),1724(C-O),1625(C-H,Ar), 1157
(S=O),1568(N-O) str,1355(N-O) str,1102(S=O); MS: (m/z):
500[M+1]; 1H NMR (δ ppm): 3.45(s,2H,CH2), 2.50(s,1H,NH),
7.98(s,1H,NH),7.65(d,2H,ArH),7.16(d,2H,ArH),7.60(d,6H,ArH),8.20(
d,2H,ArH); 13C NMR (DMSO):157.04,38.81, 40.07,164.53, 115.31,
134.88
In the experiment, a total of 66 rats (60 diabetic surviving rats+6
normal rats) were used. One week before starting the treatment,
diabetes was induced in rats. The rats were divided into eleven
groups as follows.
Group I: Normal-Normal controlled rats fed with 0.5 ml of normal saline.
Group II: Diabetic control (DC) rats; fed with 0.5 ml of normal saline.
1-(4-Nitrobenzoyl)-3-(4-(2-oxo-2-(phenylamino) ethyl) phenyl-
sulfonyl) guanidine (5E)
Group III: Diabetic rats treated with standard drug Glibenclamide 5
mg/kg body wt.
Yield: 55%; M. P=112-114 °C. Rf value: 0.5 (ethyl acetate: hexane:
0.7:0.3). IR (KBr) (cm-1): 3361(N-H) str,1638(C=O) str,1474(C-
H,Ar),2974(C-H),1170(S=O),1560(N-O) str,1365(N-O) str; MS (m/z):
480.3[M]; 1HNMR (δ ppm) 2.31 (s, 2H, CH2), 10.41(s,1H,NH),
8.32(s,1H,NH),8.17(s,1H,NH),7.46-7.68(d,4H,ArH),7.0-7.46(d,5H,
ArH), 8.21-8.37(d,4H,ArH)
Group IV: Diabetic rats; treated with synthesized drug No 5A in 1%
CMC 50 mg/kg of body weight.
Group V: Diabetic rats; treated with synthesized drug No 5B in 1%
CMC 50 mg/kg of body weight
Group VI: Diabetic rats; treated with synthesized drug No 5C in 1%
CMC 50 mg/kg of body weight
1-(4-Nitrobenzoyl)-3-(4-(2-oxo-2-(piperazin-1-yl)ethyl)
phenylsulfonyl)urea(5F)
Group VII: Diabetic rats; treated with synthesized drug No 5D in 1%
CMC 50 mg/kg of body weight
Yield: 58%; M. P=122-126 °C. Rf value: 0.5 (mobile phase: ethyl
acetate: hexane: 0.3:0.7). IR (KBr) (cm-1): 3361(N-H),1638(C=O)
str,1574(N-O),1345(N-O)2974(C-H),1170(S=O);MS (m/z): 476
[M+1].1.71(s,1H,NH),7.6-8.02(d,4H,ArH),7.20-7.55(d,4H,ArH) 3.40
(s,2H,CH2),3.33(t,4H,H2 and H6piperazine), 1.92(t,4H, H3 and H5
piperazine)
Group VIII: Diabetic rats; treated with synthesized drug No 5E in 1%
CMC 50 mg/kg of body weight
Group IX: Diabetic rats; treated with synthesized drug No 5F in 1%
CMC 50 mg/kg of body weight
Group X: Diabetic rats; treated with synthesized drug No 5G in 1%
CMC 50 mg/kg of body weight
1-benzoyl-3-(4-(2-oxo-2-(piperazin-1-yl)ethyl)phenyl-sulfonyl)
urea(5G)
Group XI: Diabetic rats; treated with synthesized drug No 5H in 1%
CMC 50 mg/kg of body
Yield: 37%; M. P=148-152 °C. Rf value: 0.5 (mobile phase: ethyl
acetate: hexane: 0.3:0.7);IR (KBr) (cm-1):1719(C-O) str,1510(C-
H,Ar),2927(C-H),1275(S=O);MS(m/z):431(M+1);1HNMR (δ ppm):
1.75(s,1H,NH),8.03(d,2H,ArH),7.35(d,2H,ArH)3.41(s,2H,CH2),3.34(t,
4H,H2 and H6 piperazine),1.95(t,4H, H3 and H5 piperazine)
The dose for the newly synthesized compounds was decided on the
basis of literature survey. [29] Glibenclamide was taken as the
standard. The blood glucose level was determined at 0 and 3 h after
administration of test compound using glucometer (Johnson and
1-(4-Fluorobenzoyl)-3-(4-(2-oxo-2-(piperazin-1-yl) ethyl) phenyl-
sulfonyl) urea(5H)
Johnson Pvt. Ltd.)
% reduction in plasma glucose level was
calculated for each animal.
Yield: 42%; M. P=112-114 °C. Rf value: 0.5 (mobile phase: ethyl
Statistical analysis
acetate: hexane: 0.3:0.7); IR (KBƛrv)al ( in cm
-1):1719
(C=O),1157(S=O),711(C-F),1510(C-H,Ar),2927(C-H); MS (m/z):
450(M+2); 1HNMR (δ ppm):1.72 (s,1H,NH), 8.12(d,2H,ArH),
7.32(d,2H,ArH)3.45(s,2H,CH2),3.38(t,4H,H2 and H6piperazine),
1.99(t,4H, H3 and H5 piperazine)
Measurement data were tabulated as means±SEM Data were analyzed
using One-Way Analysis of Variance (ANOVA) followed by Turkey's
multiple comparison post hoc tests [30] using the Graph Pad Prism
5.3, San Diego, CA and **P<0.01 as the level of significance.
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Int J Pharm Pharm Sci, Vol 9, Issue 12, 226-232
O
S
O
S
O
a
H
N
Cl
H2N
C
X
NH2
H2N
C
X
O
Benzenesulfonyl chloride
(1)
COCl
COOH
b
c
R1= NO2,H
X=O,NH
R1
C (2)
R1
O
N
R2= F,Br,H
X
O
S
C
NH
H
R1
O
(3)
R2
NH2
O
d
Cl
C
e
Cl
R2
HN
O
C
(4)
Cl
R2
O
X
O
C
HN
C
C
O
N
S
N
R1
H
H
O
(5)
5A;R1=NO2, R2=Br,X=O
5B;R1=H,R2=H,X=O
5C;R1=H,R2=H,H=NH
5D;R1=NO2,R2=F,X=NH
5E;R1=NO2,R2=H,X=NH
Scheme 1: Synthetic route for the preparation of the sulphonylureas/gaunidine derivatives Reagents and conditions, (a)
Pyridine,CH3CH2OH,Reflux (yield>75%); (b) SOCl2,reflux,3 h,(yield>60%); (c) Pyridine,CH3CH2OH,Reflux (yield>80%); (d) DRY THF,0
TO RT,Stirring,4 h, rt (yield>85%).(e) Nitrobenzene,FeCl3,reflux,6 h, (yield>60%)
O
S
O
S
O
a
H
Cl
N
H2N
C
X
NH2
H2N
C
X
O
Benzenesulfonyl chloride
(1)
COCl
COOH
b
c
R1= NO2,,F
X=O,NH
R1
(2)
R1
O
X
O
S
N
C
NH C
R1
Cl
H
O
(3)
H
N
O
C
N
O
d
e
Cl
C
Cl
N
H
N
H
(4)
O
X
HN
O
C
N
C
C
N
S
N
H
O
R1
H
O
(5)
5F;R1=NO2,X=NH
5G;R1=H,,X=O
5H;R1=F,X=O
Scheme 2: Synthetic route for the preparation of the sulphonylureas/gaunidine derivatives Reagents and conditions: (a)
Pyridine,CH3CH2OH,Reflux (yield>70%); (b) SOCl2,reflux,3 h,(yield>60%); (c) Pyridine,CH3CH2OH,Reflux (yield>80%); (d) DRY THF,0 TO
RT,Stirring,4 h, rt (yield>85%).(e) Nitrobenzene,FeCl3,reflux,7 h.(yield>60%)
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Int J Pharm Pharm Sci, Vol 9, Issue 12, 226-232
compounds also follow the Lipinski rule of five (LRoF) which proved the
drug-likeness properties based on ADME/T properties analysis of
designed and synthesized compounds by QuickPro software.
RESULTS AND DISCUSSION
In silico docking and ADME/T analysis
During the docking result analysis, it was found that most of the
compounds have shown significant binding interactions with enzyme
and from the binding interaction, it was observed that the benzene ring,-
F,-NO2,-SONH2 groups are important for binding but not only the
structural requirement to evoke AKR1C1 inhibition. The hydrogen bond
interactions and π-π stacking were also contributed to the strong
binding of these compounds to the binding site of AKR1C1. All
The results were obtained as docking score, i.e. binding energy which is
mentioned in table 1. The results of in silico toxicity studies mentioned in
table 2. The all designed compounds have shown a good binding affinity
in comparison with standard glibenclamide, out of this compound
5A,5D,5G, and 5H showed a more binding affinity in comparison with
glibenclamide. Binding cavity and interaction with the various amino
acid residues with the compound 5H were shown in fig. 3
Fig. 3: Interaction of AKR1C1 with a synthesized moiety
Table 1: Docking result of 5A-5H compounds
Comp id
5A
Docking score
-8.086
-9.237
-9.237
-9.035
-9.796
-9.738
10.7
Glide energy
-79.887
-72.041
-72.043
-58.063
-60.495
-65.251
-64.1
Glide emodel
-128.459
-126.811
-124.811
-105.037
-109.31
XP H Bond
0
-1.712
-1.732
-1.294
-0.631
-1.33
-0.86
-3.46
-2.331
XP PhobEn
-1.9
-1.783
-1.788
-2.236
-2.7
-2.386
-1.61
-1.45
-2.7
XP Electro
-0.663
-1.411
-1.413
-0.569
-0.139
-0.861
-1.175
0
5C
5B
5D
5E
5F
-118.19
5G
102.15
-98.146
-105.375
5H
-10.4
-63.86
Gli
-9.035
-58.063
-1.021
Table 2: Predicted ADME/T properties of compounds by using QikProp
Code
H-Bond donor
H-bond acceptor
Q PlogPoct
(8.0-43.0)*
25.033
Q PlogPw
(5.0-48.0)*
15.739
Q Plog Po/w
(-2.0-6.0)*
3.308
Q PlogS
(-6.0-0.5)*
-7.163
-7.457
-2.604
-2.907
-3.15
5A
5E
5F
5G
5H
Gli
1
1
1
1
3
2
7.5
5.5
9.5
8.5
7
22.783
11.908
4.123
23.132
18.606
0.051
22.805
16.81
0.853
21.849
10.714
1.160
6.75
24.972
13.782
4.289
-4.931
mixture was monitored by thin layer chromatography. Different
derivatives (NO2,H and F) of benzene carboxylic acid were
converted into benzene carbonyl chloride 2 with the help of SOCl2
under reflux condition for 3 h. Compound 1 was dissolved in
Chemistry
Compound
1 was synthesized by reacting benzene sulphonyl
chloride with an excess amount of urea/guanidine in the presence of
pyridine (0.2 ml) under reflux condition for 5 h. The reaction
absolute alcohol and reacted with compound
2
under reflux
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Panchal et al.
Int J Pharm Pharm Sci, Vol 9, Issue 12, 226-232
condition for 2 h. Pyridine (0.2 ml) was taken as a catalyst. The
reaction mixture was poured into ice-cold water; solid product was
isolated and recrystallizes with rectified spirit. Various derivatives
of aniline (F, and Br) were stirred with chloro acetyl chloride under
the cooling condition for 4 h in fuming hood. After addition of ice
cold water in a reaction mixture, solid crystals were isolated.
mass spectroscopy, we were getting M (5E), M+1(5D, 5G, 5F),
M+2(5H) for different target compounds.5H contain F atom at the
para position so M+2 peak obtain. In 1H NMR doublet was obtained
for aromatic hydrogen between 7 to 8 delta values. In the same way
singlet of NH of urea/guanidine derivatives is obtained between
7.98 to 10.41. The absorption band at 1691 cm-1(5C), 1724 cm-1(5D),
1719 cm-1(5G), and 1715 cm-1(5H) corresponds to C=O stretching of
carbonyl and amide. Also, single N-H stretching was observed at
3449 cm-1(5C), 3274 cm-1(5D), 3361 cm-1(5E), and 3263 cm-1(5B)
gives strong hint about secondary amine of targeted compounds.
Halogen stretching was present at 848 cm-1 (C-Br, 5A), and 1157 cm-
1(C-F, 5H).
Fridal crafts alkylation was performed to prepare1-(4-(2-(4-
Substitutedphenylamino)-2-oxoethyl) phenylsulfonyl)-3-(4-substi-
tutedbenzoyl)urea 5A-5B and 1-(4-(2-(4-substituted-phenylamino)-
2-oxoethyl) phenylsulfonyl)-3-(4-substituted benzoyl) guanidine
5C-5E as illustrated in scheme (1), an appropriate1-(4-Substituted
benzoyl)-3-(phenylsulfonyl) guanidine and N-(4-substituted
phenyl)-2-chloroacetamide. Nitrobenzene was used as a solvent and
anhydrous FeCl3 as a catalyst. Reflux was done for 6 h and the
mixture was poured in ice cold water to get final product 5. The
synthesis of piperazine derivatives 5F-5H was done as illustrated in
the scheme (2), by reflux between 1-(4-Substituted benzoyl)-3-
(phenylsulfonyl) urea and 2-Chloro-1-(piperazin-1-yl) ethanone for
7 h in the presence of anhydrous AlCl3 and dry DCM (50 ml) as a
solvent. The entire target compounds 5A-5H were purified by
recrystallization. The reaction of all targeted molecules was
monitored by thin layer chromatography. Ethyl acetate and hexane
was used as mobile phase.
Biological evaluation
Alloxan induces diabetes by damaging the insulin-secreting cells of
the pancreas leading to hyperglycaemia. The ability of target
molecules to bind with sulphonylureas receptor was determined by
testing them at an albino wistar rate for measurement of reduction
of blood sugar level. In our study, we have found that administration
of compounds 5A-5H to diabetic rats reversed their blood glucose.
The possible mechanism by which they brings about them
hypoglycemic action may be by potentiation of the insulin effect of
plasma by increasing either the pancreatic secretion of insulin from
β-cells of islets of Langerhans or its release from the bound form.
However, the Compound 5D and 5E contain NO2 group in a para
position of the benzene ring which shows better % reduction of
blood glucose level (table 3)) compare to other derivatives.
Spectral characterization
1
It was done with Infra-red spectroscopy, mass spectroscopy, and H
and 13C nuclear magnetic resonance for all target compounds. For
Table 3: In vivo hypoglycemic activity of compounds 5A-5H
% Reduction in plasma glucose level (mean±SEM)
Group
Diabetic control
0.29±1.05
Glibenclamide
55.97±3.19
45.88±3.17
52.49±7.73
46.40±6.1
5C
5D
5H
5A
5B
5E
5F
5G
39.24±2.08
43.25±4.11
48.18±4.22
39.07±1.88
41.26±2.78
Note: Values are given as mean±SD for six rats in each group. Experimental groups are compared with Glibenclamide. Values are statistically
significant at ∗∗P<0.01 as compared with diabetic control
CONCLUSION
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The docking study revealed that in all designed sulphonyl-
ureas/guanidine series of compounds 5D, and 5E were found to be most
potent compounds as per the binding energy compared to
glibenclamide. So, the 4th of derivatives substituted with F, NO2, and
which was shown better result compare to unsubstituted or substituted
with other derivatives. Based on Quick Pro analysis of the all the
analogues, it was proved that those compounds having better drug-like
properties and follow the Lipinski’ rule of five. Subsequently, in vivo
biological evaluation compound, 5D and 5E contain NO2 group which
gives more
% reduction of blood sugar level with compare to
glibenclamide. Finally, it was concluded that result obtained from in vitro
docking analysis and in vivo biological activity on rat are significantly
same and the compound 5D and 5E can be used as a lead molecule for
the further development of more potent sulphonylureas/guanidine-
based derivatives as oral hypoglycemic agents.
6.
Dhanaji V, Umesh R, Neha R, Arvind K, Ramrao A. Synthesis and
antihyperglycemic evaluation of new 2,4-thiazolidine dione
shaving biodynamic aryl sulfonylurea moieties. Bioorg Med
Chem Lett 2012;22:436–9.
7. Xiongyu W, Yiqian W, Bianca P, Milad B, Mathias A. Aryl
benzylimidazole having selective angiotensin II AT2 receptor
agonists activity. J Med Chem 2006;49:7160–8.
CONFLICT OF INTERESTS
Declared none
8. Satyanand T, Sachin K, Amit K, Mohit S. Synthesis of analogues
of sulphonylureas as antidiabetic drugs and their structure-
activity studies. Int J Pharm Res 2010;1:1-16.
9. Ean Yves W, Jean-Michel D, Angela C, Andrea S. Carbonic
anhydrase inhibitors having anti-diabetic activity. J Med Chem
2005;48:2121-4.
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