Design and synthesis of novel diamide derivatives of glycine as antihyperglycemic agents

Article abstract of DOI:10.1080/00397911.2016.1203435

DPP-4 inhibition is one of the most extensively explored approaches for the management of type 2 diabetes (T2D). Most DPP-4 inhibitors in the market contain a proline mimetic active pharmacophore. Herein, we report the design, synthesis, and preliminary e

Full text of DOI:10.1080/00397911.2016.1203435

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Design and synthesis of novel diamide derivatives
of glycine as antihyperglycemic agents
Radhika Sharma & Shubhangi S. Soman
To cite this article: Radhika Sharma & Shubhangi S. Soman (2016): Design and synthesis of
novel diamide derivatives of glycine as antihyperglycemic agents, Synthetic Communications,
DOI: 10.1080/00397911.2016.1203435
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Date: 30 July 2016, At: 03:13

SYNTHETIC COMMUNICATIONS®
http://dx.doi.org/10.1080/00397911.2016.1203435
Design and synthesis of novel diamide derivatives of glycine
as antihyperglycemic agents
Radhika Sharma and Shubhangi S. Soman
Department of Chemistry, Faculty of Science, M. S. University of Baroda, Vadodara, Gujarat, India
ABSTRACT
ARTICLE HISTORY
Received 14 April 2016
DPP-4 inhibition is one of the most extensively explored approaches
for the management of type 2 diabetes (T2D). Most DPP-4 inhibitors in
the market contain a proline mimetic active pharmacophore. Herein,
we report the design, synthesis, and preliminary evaluation of a series
of novel diamide derivatives of glycine, devoid of the proline mimic, for
the treatment of T2D. As predicted from in silico studies, the diamide
derivatives of glycine exhibited comparable DPP-4 inhibition with the
standard as confirmed by the preliminary in vitro studies. Compound
6b was found to be the most potent (IC50 94.82 nM) DPP-4 inhibitor
among all the molecules synthesized in the series.
KEYWORDS
Diamide; DPP-4 inhibitor;
non-proline mimetic;
sulfonamide
GRAPHICAL ABSTRACT
Introduction
Diabetes mellitus is a chronic metabolic disorder symptomatically characterized by
hyperglycemia or high blood sugar.[1] The onset of hyperglycemic events can occur because
of either absence of insulin secretion (type 1 diabetes) or lack of insulin secretion and
insulin resistance both (T2D). In recent years, diabetes has become a severe and increasingly
prevalent disease due to urbanization and lifestyle changes.[2] About 415 million people
worldwide suffer from diabetes and this is projected to increase to 642 million by 2040.[3]
Type 2 diabetes (T2D) is the major contributor to the overall diabetic population. T2D
is linked to aging, hypertension, and obesity and often remains undetected until the micro-
vascular or macrovascular complications begin to show.[4] Long-term hyperglycemia is
associated with adverse cardiovascular complications, leading to high mortality rates.[5]
Most of the modern therapeutic interventions are directed toward decreasing the hypergly-
cemic events within the patients. A major drawback of this first-line therapy is the induction
CONTACT Shubhangi S. Soman
shubhangiss@rediffmail.com
Department of Chemistry, Faculty of Science, M. S.
University of Baroda, Vadodara, Gujarat, 390 002, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
© 2016 Taylor & Francis

2
R. SHARMA AND S. S. SOMAN
Figure 1. Some DPP-4 inhibitors.
of hypoglycemia and weight gain. To overcome these side effects, targets involving
glucose-dependent insulin secretion (GDIS) have gained importance. Glucagon-like
peptide-1 (GLP-1), an incretin hormone, plays an important role in GDIS.[6] GLP-1 acts
as a stimulator of endogenous insulin release, while inhibiting the glucagon secretion in
glucose-dependent manner, thereby reducing the risk of hypoglycemia.[7–9] However, the
GLP-1(7-36)amide is rapidly degraded, by a serine protease, dipeptidyl aminopeptidase-4
(DPP-4, EC 3.4.14.5), into its inactive form, GLP-1(9-36)amide, with no therapeutic
effects.[10,11] Hence DPP-4 is involved in pathogenesis of T2D and is an attractive target
for therapeutic intervention. Thus, inhibition of DPP-4 has gained importance, as it results
in increased half-life of endogenous GLP-1, thereby improving glucose exclusion in
diabetics.[12,13] The DPP-4 inhibitors tested in animal models and in clinical trials have
clearly demonstrated therapeutic potential for treatment of T2D (Fig. 1).
The DPP-4 acts by cleaving the N-terminal dipeptides with L-proline or L-alanine at the
penultimate position.[14–17] Several classes of DPP-4 inhibitors have been reported from
many laboratories and most of them are derived from a- or β-amino acids mimicking
the N-terminal dipeptide residues of the incretin hormones. In view of all these studies
and with the aim of identifying it for DPP-4 inhibition, studies were carried out in our
laboratory by preparing diamide derivatives of glycine (Fig. 2).
Figure 2. General structure of glycine derivatives.

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Results and discussion
A series of novel, non-proline mimetic, diamide derivatives of glycine 6a–k were designed
by substituting 1-(phenylsulfonyl)piperidine-3-carboxamide at the P2 site and various sec-
ondary or tertiary amides at the P1 site. From the in silico studies it was predicted that the
binding affinity of the diamide derivatives of glycine (6b ¼ À 8.5 kcal/mol) for the DPP-4
enzyme was comparable with that of the marketed drug (Vildagliptin ¼ À 6.7 kcal/mol)
and hence was expected to show comparable potency. To synthesize diamide derivatives
of glycine, commercially available boc-protected glycine 1 was at first reacted with amine
in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI),
1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine (DMAP) to yield various
C-substituted amide derivatives of glycine 2a–k as shown in Scheme I.
However, when dicyclohexyl carbodiimide (DCC) was used in place of EDCI and HOBt
for the reaction, a very strong ester bond was formed between the carboxylate of glycine and
carbodiimide carbon, which rendered it unreactive for further reaction with the amines, and
it was isolated by column chromatography as a nonpolar compound. Also, EDCI, in itself,
could not sufficiently activate the carboxylic acid group of glycine and thus addition of
HOBt was necessary for this coupling reaction. On the other hand, reaction of piperi-
dine-3-carboxylic acid with benzene sulfonyl chloride, in the presence of sodium carbonate
as a base, in a mixture of dichloromethane (DCM)/water (1:1) yielded 1-(phenylsulfonyl)
piperidine-3-carboxylic acid 5 on acidification. Infrared (IR) spectrum of 5 showed bands
at 1693 and 1352 cmÀ 1 for the carbonyl group of carboxylic acid and sulfonamide group
respectively while the 1H NMR showed a multiplet from δ 7.56 to 7.79 for the five aromatic
protons and a broad singlet at δ 8.98, indicating the proton of the carboxylic acid group and
thereby confirming the formation of 5. Compounds 2a–k were converted into their salts
3a–k by addition of 10% trifluoroacetic acid (TFA) in DCM. The salts 3a–k, on further
Scheme 1. Synthesis of diamide derivatives of glycine, reagents and conditions: (i) EDCI, HOBt, DMAP,
amine, DCM, 25°C, 16h; (ii) 10% TFA in DCM; (iii) PhSO2Cl, Na2CO3, DCM/H2O (1:1), 25°C, 16h, (iv) HCl,
pH 2; (v) EDCI, HOBt, DMAP, 3a–k, DCM, 25°C, 10 h.

4
R. SHARMA AND S. S. SOMAN
reaction with acid 5 in the presence of peptide coupling agents EDCI, HOBt, and DMAP,
gave the desired diamide derivatives of glycine 6a–k as shown in Scheme 1. The structures
of 6a–k were confirmed by their IR, 1H NMR, 13C NMR, and ESI-MS analyses. While the IR
spectra of compounds 6a–k exhibited one strong band at ∼3300 cmÀ 1 for the –NH (amide),
two strong bands between 1730 and 1600 cmÀ 1 for amide carbonyls and a strong band
1
∼1350 cmÀ 1 for the sulfonamide group were found. In the H NMR of 6a–k, a multiplet
at δ ∼ 4.00 for the methylene group of glycine is observed due to the interactions with the
neighboring amide group protons. The IR spectrum of compound 6b exhibited five strong
bands: two bands at 3329, 3303 cmÀ 1 for the two –NH (amide), another two bands 1679 and
1644 cmÀ 1 for amide carbonyls, and a band at 1355 cmÀ 1 for the sulfonamide group. In the
1H NMR spectrum of 6b, the methylene group of glycine exhibited a multiplet at δ 3.84–3.86
due to the interactions with the neighboring amide group protons and a multiplet from δ
7.36 to 7.74 representing the aromatic protons. In the 13C NMR spectrum two peaks at
168.26 and 173.16 for the carbonyl carbons of the amide groups, six peaks from 24.14 to
48.63 for the piperidyl and glycyl carbons, and eight peaks ranging from 121.10 to 138.25
for the aromatic carbons confirmed the formation of 6b, which was also supported by its
ESI-MS spectrum with a peak at m/z 435.9 for [M þ H]þ. The molecular docking studies
were performed by selecting binding site residues of the A chain of DPP-4 (PDB ID:
3W2T) at a distance of 4.5 Å from NVP-LAF237.[18] To carry out the docking studies, chain
Figure 3. Binding of 6b at the active site of DPP-4. All the images have been generated using PyMOL.

SYNTHETIC COMMUNICATIONS®
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A of 3W2T was considered for analysis. The molecular docking was carried out using
AutoDock (version 4.2) for predicting the mode of binding.[19] The binding affinity of
the most potent compound in the series, 6b, for DPP-4 enzyme was calculated to be À 8.5
kcal/mol. The list of residues interacting with the ligand were also obtained from AutoDock
Tools.[19] Pymol[20] was used to visualize the structures (the protein and the docked
compound 6b) and align the ligands to highlight the interactions as seen in Fig. 3.
Several potent diamide and sulfonamide derivatives with peptidomimetics pharmaco-
phore (proline mimic) as DPP-4 inhibitors have been reported but the aim of this study
was to recognize the DPP-4 inhibition potential of this new series of nonproline mimetic,
diamide derivatives of glycine.[21,22] Preliminary in vitro DPP-4 inhibition assay was
performed to screen test compounds 6a–k and to study the effect of different amides
at the P1 site, for the DPP-4 enzyme inhibition potential. The IC50 values were then
determined for those compounds that exhibited greater than 50% enzyme inhibition at
3 µM concentration, as shown in Table 1.
Among the substituted secondary amide analogs 6a–f (at the P1 site), the effect of
fluoro, chloro, and methyl substituents on the benzamide was studied and it was observed
that the p-chloro benzamide derivative 6b (IC50 94.82 nM) was six-fold more potent than
p-fluoro benzamide derivative 6a (IC50 573.74 nM) and about three-fold more potent than
m-fluoro benzamide derivative 6d (IC50 205.40 nM), but p-methyl benzamide derivative
6c was relatively inactive. Also, 6d was found to be twice as potent as 6a but a similar
trend was not observed in 6e, 6f, and 6b. While among the substituted tertiary
amide analogs (at the P1 site) 6g–k, the simplest tertiary amide, N,N-dimethyl amide
derivative 6g (IC50 188.97 nM), was three times more potent than N-methyl benzamide
derivative 6k (IC50 592.56 nM) and twice as potent as the tetrahydroisoquinoline
amide derivative 6j (IC50 444.60 nM). Cyclic aliphatic amide derivatives 6h and 6i were
reported inactive. Thus the calculated IC50 values, obtained from the in vitro analysis
of the diamide derivatives of glycine 6a–k, clearly demonstrated 6b (IC50 94.82) as the most
potent DPP-4 inhibitor.
Table 1. In vitro DPP-4 inhibition by diamide derivatives of glycine.
Compound
Inhibition of DPP-4 (%)a
IC50 (nM)b
6a
55.0
69.5
14.4
58.5
14.1
14.4
51.3
12.4
10.1
51.6
50.5
91.7
573.74
94.82
ND
205.40
ND
ND
188.97
ND
ND
444.60
592.56
5.37
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
Sitagliptin phosphate
aThe DPP-4 inhibitory activity determined by fluorescence-based assay was measured using Spectra Max fluorometer
(Molecular Devices, CA). Values of inhibition are mean of three independent determinations at 3 µM concentration of the
test samples.
bIC50 values were determined using Graph Pad Prism software. Values of DPP-4 inhibition (expressed as IC50) are mean of
the three independent determinations.
Note. ND, not determined.

6
R. SHARMA AND S. S. SOMAN
Conclusion
A novel series of diamide derivatives of glycine devoid of a proline mimic has been
designed and synthesized, and its application as DPP-4 enzyme inhibitor for treatment
of T2D has been evaluated. Compound 6b (IC50 ¼ 94.82 nM) was found to be the most
potent compound in the series, which is in agreement with the molecular docking studies.
An extension of this approach to other scaffolds is in progress in our laboratory.
Experimental
Chemistry
Reagent-grade chemicals and solvents were purchased from commercial supplier and used
after purification. Thin-layer chromatography (TLC) was performed on silica-gel F254
plates (Merck). Merck silica gel (60–120 mesh) was used for column chromatographic
purification. All reactions were carried out in a nitrogen atmosphere. Melting points are
uncorrected and were measured in open capillary tubes, using a Rolex melting-point
apparatus. IR spectra were recorded as KBr pellets on a Perkin-Elmer RX 1 spectrometer
1
and the wave numbers are reported in cmÀ 1. H NMR and 13C NMR spectral data were
recorded on Advance Bruker 400 spectrometer (1H 400 MHz/13C 100 MHz) with CDCl3
or DMSO-d6 as solvent and tetramethylsilane (TMS) as internal standard and reported in
δ (ppm). J values are in hertz (Hz). Mass spectra were determined by ESI-MS, using a
Shimadzu LCMS 2020 apparatus. Elemental analyses were recorded on ThermoFinnigan
Flash 11-12 series EA. All reactions were carried out under a nitrogen atmosphere. Purity
of all the tested compounds was greater than 97%.
Inhibitory activity
In vitro enzyme (DPP-4) inhibitory activity was determined using fluorescence based
assay. Gly-ProAminomethylcoumarin (AMC) was used as a substrate to measure DPP-4
activity. Cleavage of the peptide bond by DPP-4 releases the free AMC group, resulting
in fluorescence that is analysed using an excitation wavelength of 350–360 nm and
emission wavelength of 450–465 nm. Human recombinant DPP-4 enzyme was procured
from Enzo Life Science (batch no. BML-SE434-9091), substrate H-Gly-Pro-AMC was
procured from Enzo Life Science (batch no. BML-P189-9091), and assay buffer of pH
7.8 was used in the assay. DPP-4 activity was measured by mixing reagents in a 96-well
plate (order of addition of reagents: assay buffer, enzyme, solvent/inhibitor, and finally
substrate). Both the enzyme and 96-well plate were incubated for 30 min and the resulting
fluorescence was measured using Spectra Max Fluorometer (Molecular Devices, Sunnyvale
CA) by exciting at 360 nm and emission at 460 nm with the excitation filter at 360 nm and
emission filter at 460 nm at sensitivity of 45.
General procedure for the preparation of compounds 2a–k
A mixture of boc-glycine 1 (1.11 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (EDCI) (1.67 mmol), 1-hydroxybenzotriazole (HOBt) (1.11 mmol),
4-dimethylaminopyridine (DMAP) (1.34 mmol), and amine (10 and 20) (1.22 mmol) in
dichloromethane (DCM) (50 mL) was stirred at room temperature for 16 h. The reaction

SYNTHETIC COMMUNICATIONS®
7
was monitored using TLC. On completion of the reaction, it was washed with water
(2 � 20 mL) and brine (1 � 10 mL), dried over anhydrous sodium sulfate, and the solvent
was evaporated under reduced pressure to give the crude product, which was then purified
by column chromatography using silica gel as stationary phase and methanol/
dichloromethane (5:95) as eluent to yield desired N-boc glycine amide 2a–k, as a white solid.
1-(Phenylsulfonyl)piperidine-3-carboxylic acid (5)
Benzene sulfonyl chloride (1.1 mmol) was added to a mixture of piperidine-3-carboxylic
acid 4 (1.0 mmol) and sodium carbonate (3.0 mmol) in 25 mL DCM/water (1:1), and the
reaction mixture stirred at room temperature for 16 h or until the completion of reaction,
as monitored by TLC. On completion of reaction, the reaction mixture was washed with
petroleum ether (20 mL) and then acidified with concentreated HCl, to pH 2. The white
solid thus separated was filtered, washed with water several times, and then dried to yield
the desired product as white solid.
1
Yield: 91%; white solid; mp: 115–117°C; IR (KBr): 2940, 1693, 1352 cmÀ 1; H NMR
(400 MHz, CDCl3): δ 1.41–1.50 (m, 1H), 1.65–1.73 (m, 1H), 1.80–1.85 (m, 1H), 1.99–2.04
(m, 1H), 2.41 (dt, 1H, J1 ¼ 2.8 Hz, J2 ¼ 11.2 Hz), 2.57 (t, 1H, J ¼ 10.8 Hz), 2.65–2.71
(m, 1H), 3.59 (br d, 1H, J ¼ 11.6 Hz), 3.83 (dd, 1H, J1 ¼ 3.2 Hz, J2 ¼ 7.2 Hz), 7.54–7.58
(m, 2H), 7.61–7.63 (m, 1H), 7.77–7.79 (m, 2H), 8.98 (br s, 1H); 13C NMR (100 MHz,
CDCl3): δ 23.88, 26.21, 40.73, 46.26, 47.35, 127.62, 129.18, 132.94, 135.96, 178.63.
General procedure for the preparation of compounds 6a–k
Compounds 2a–k were deprotected by stirring in 10% trifluoroacetic acid (TFA) in DCM.
On completion of the reaction after an hour or as monitored by TLC, the solvent was
evaporated under reduced pressure and once again the product was dissolved in DCM
to give a solution of compounds 3a–k. To a solution of compound 5 (1.0 mmol) in
DCM (20 mL), EDCI (1.5 mmol), HOBt (1.0 mmol), and DMAP (1.0 mmol) were added
at 0–5°C, followed by the solution of compound 3a–k in DCM (5 mL), and the reaction
mixture was then stirred at room temperature for 10 h or until the completion of the
reaction as detected by TLC. After completion of the reaction, it was washed with water
(2 � 20 mL) and brine (1 � 10 mL) and dried over anhydrous sodium sulfate. The solvent
was evaporated under reduced pressure to give the crude product, which was then purified
by column chromatography using silica gel, employing ethylacetate/petroleum ether
(70:30) as eluent to give pure product 6a–k as a white solid.
N-(2-(4-Fluorophenylamino)-2-oxoethyl)-1-(phenylsulfonyl)piperidine-3-
carboxamide (6a)
Yield: 70%; white solid; mp 196–198°C; IR (KBr): 3324, 3298, 2967, 2934, 2843, 2865, 1677,
1654, 1643, 1355 cmÀ 1; 1H NMR (400 MHz, DMSO-d6): δ 1.23–1.27 (m, 1H), 1.46–1.49 (m,
1H), 1.72–1.79 (m, 2H), 2.10–2.20 (m, 2H), 2.50–2.51 (m, 1H), 3.58–3.63 (m, 1H), 3.66–3.72
(m, 1H), 3.82–3.85 (m, 2H), 7.15 (t, 2H, J ¼ 8.8 Hz), 7.56–7.60 (m, 2H), 7.66 (t, 2H, J ¼ 8.4
Hz), 7.72–7.74 (m, 3H), 8.39 (br s, 1H), 10.05 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ
24.14, 27.00, 41.93, 42.85, 46.52, 48.62, 115.68, 115.90, 121.31, 121.39, 127.85, 129.94,

8
R. SHARMA AND S. S. SOMAN
133.70, 135.59, 135.67, 157.23, 159.61, 168.00, 173.16. Anal. calc. for C20H22FN3O4S: C,
57.27; H, 5.29; N, 10.02; found: C, 57.42; H, 4.90; N, 9.97%. ESI-MS: m/z 420.0 [M þ H]þ.
N-(2-(4-Chlorophenylamino)-2-oxoethyl)-1-(phenylsulfonyl)piperidine-3-
carboxamide (6b)
Yield: 55%; white solid; mp 178–180°C; IR (KBr): 3329, 3303, 2931, 2863, 2843, 1679, 1644,
1614, 1355, 1334 cmÀ 1; 1H NMR (400 MHz, DMSO-d6): δ 1.22–1.27 (m, 1H), 1.46–1.49 (m,
1H), 1.75 (t, 2H, J ¼ 15 Hz), 2.10–2.20 (m, 2H), 2.50–2.54 (m, 1H), 3.60–3.69 (m, 2H),
3.84–3.86 (m, 2H), 7.36 (d, 2H, J ¼ 8.8 Hz), 7.59–7.67 (m, 4H), 7.72–7.74 (m, 3H), 8.41
(t, 1H, J ¼ 8.0 Hz), 10.14 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 24.14, 27.01, 41.93,
42.95, 46.52, 48.63, 121.10, 127.25, 127.85, 129.13, 129.93, 133.68, 135.62, 138.25, 168.26,
173.16. Anal. calc. for C20H22ClN3O4S: C, 55.11; H, 5.09; N, 9.64; found: C, 55.22; H,
5.01; N, 9.58%. ESI-MS: m/z 435.9 [M þ H]þ.
N-(2-Oxo-2-(p-tolylamino)ethyl)-1-(phenylsulfonyl)piperidine-3-carboxamide (6c)
Yield: 85%; white solid; mp 194–196°C; IR (KBr): 3331, 3327, 2956, 2929, 2846, 1678, 1657,
1
1644, 1358, 1332 cmÀ 1; H NMR (400 MHz, DMSO-d6): δ 1.23–1.27 (m, 1H), 1.46–1.49
(m, 1H), 1.72–1.79 (m, 2H), 2.10–2.20 (m, 2H), 2.24 (s, 3H), 2.50–2.56 (m, 1H),
3.66–3.69 (m, 2H), 3.77–3.85 (m, 2H), 7.10 (d, 2H, J ¼ 8.0 Hz), 7.45 (d, 2H, J ¼ 8.0 Hz),
7.64–7.68 (m, 2H), 7.72–7.75 (m, 3H), 8.36 (m, 1H), 9.90 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): δ 20.89, 24.15, 27.01, 41.94, 42.87, 46.53, 48.64, 119.58, 127.86, 129.59,
129.94, 132.64, 133.69, 135.60, 136.76, 167.80, 173.10. Anal. calc. for C21H25N3O4S: C,
60.70; H, 6.06; N, 10.11; found: C, 60.78; H, 6.18; N, 9.90%. ESI-MS: m/z 416.1 [M þ H]þ.
N-(2-(3-Fluorophenylamino)-2-oxoethyl)-1-(phenylsulfonyl)piperidine-3-
carboxamide (6d)
Yield: 62%; white solid; mp 186–188°C; IR (KBr): 3308, 3104, 2930, 2851, 1709, 1670, 1616,
1351, 1317 cmÀ 1; 1H NMR (400 MHz, DMSO-d6): δ 1.23–1.27 (m, 1H), 1.46–1.49 (m, 1H),
1.72–1.79 (m, 2H), 2.10–2.20 (m, 2H), 2.50–2.51 (m, 1H), 3.61 (d, 1H, J ¼ 10.8 Hz), 3.68 (d,
1H, J ¼ 10.8 Hz), 3.84–3.87 (m, 2H), 6.88–6.90 (m, 1H), 7.26–7.36 (m, 2H), 7.55–7.75 (m,
6h), 8.41 (br s, 1H), 10.22 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 24.14, 27.00, 41.92,
42.97, 46.52, 48.62, 106.18, 106.44, 110.08, 110.29, 115.27, 127.86, 129.93, 130.85, 130.95,
133.69, 135.61, 140.95, 141.06, 161.38, 163.78, 168.49, 173.17. Anal. calc. for C20H22FN3O4S:
C, 57.27; H, 5.29; N, 10.02; found: C, 57.42; H, 4.90; N, 9.97%. ESI-MS: m/z 420.2 [M þ H]þ.
N-(2-(3-Chlorophenylamino)-2-oxoethyl)-1-(phenylsulfonyl)piperidine-3-
carboxamide (6e)
Yield: 59%; white solid; mp 140–142°C; IR (KBr): 3412, 3303, 2948, 2843,1692, 1666, 1650,
1350, 1333 cmÀ 1; 1H NMR (400 MHz, CDCl3): δ 1.67–1.71 (m, 1H), 1.75 (s, 1H), 1.82–1.91
(m, 2H), 2.45–2.55 (m, 1H), 2.64–2.74 (m, 2H), 3.57 (d, 1H, J ¼ 11.6 Hz), 3.74 (d, 1H, J ¼ 9.2
Hz), 4.14 (d, 2H, J ¼ 5.2 Hz), 7.01–7.10 (m, 1H), 7.16–7.24 (m, 2H), 7.40–7.42 (m, 1H),
7.52–7.56 (m, 2H), 7.60–7.64 (m, 2H), 7.75–7.77 (m, 2H), 8.82 (s, 1H); 13C NMR

SYNTHETIC COMMUNICATIONS®
9
(100 MHz, CDCl3): δ 23.76, 26.90, 42.39, 44.34, 46.35, 48.22, 117.84, 119.92, 124.44, 127.56,
129.25, 130.03, 133.10, 134.51, 135.59, 138.78, 167.04, 173.90. Anal. calc. for C20H22ClN3
O4S: C, 55.11; H, 5.09; N, 9.64; found: C, 55.26; H, 4.98; N, 9.52%. ESI-MS: m/z 436.00
[M þ H]þ.
N-(2-(2-Chlorophenylamino)-2-oxoethyl)-1-(phenylsulfonyl)piperidine-3-
carboxamide (6f)
Yield: 48%; white solid; mp 162–164°C; IR (KBr): 3373, 3257, 2953, 2936, 2863, 1707, 1649,
1583, 1386, 1323 cmÀ 1; 1H NMR (400 MHz, CDCl3): δ 1.58–1.76 (m, 2H), 1.80–1.93 (m, 2H),
2.41–2.48 (m, 1H), 2.63–2.70 (m, 2H), 3.61–3.64 (m, 1H), 3.75–3.82 (m, 1H), 4.13–4.14
(m, 2H), 7.01–7.10 (m, 2H), 7.26–7.30 (m, 1H), 7.36–7.39 (m, 1H), 7.53–7.57 (m, 2H),
7.61–7.65 (m, 1H), 7.76–7.78 (m, 2H), 8.30–8.35 (m, 2H); 13C NMR (100 MHz, CDCl3):
δ 23.84, 26.93, 42.59, 44.53, 46.33, 48.21, 121.86, 123.18, 125.16, 127.61, 127.75, 129.17,
129.25, 133.07, 134.06, 135.54, 167.23, 173.79. Anal. calc. for C20H22ClN3O4S: C, 55.11; H,
5.09; N, 9.64; found: C, 55.25; H, 5.12; N, 9.58%. ESI-MS: m/z 436.05 [M þ H]þ.
N-(2-(Dimethylamino)-2-oxoethyl)-1-(phenylsulfonyl)piperidine-3-
carboxamide (6g)
Yield: 80%; white solid; mp 128–130°C; IR (KBr): 3351, 3274, 2978, 2940, 1720, 1677, 1635,
1
1365, 1338 cmÀ 1; H NMR (400 MHz, CDCl3): δ 1.46–1.50 (m, 1H), 1.65–1.85 (m, 2H),
1.89–1.93 (m, 1H), 2.28–2.35 (m, 1H), 2.48–2.60 (m, 2H), 3.02 (d, 6H, J ¼ 9.6 Hz), 3.73
(d, 1H, J ¼ 11.6 Hz), 3.85 (d, 1H, J ¼ 9.6 Hz), 4.03 (d, 2H, J ¼ 8.4 Hz), 6.82 (br s, 1H),
7.53–7.57 (m, 2H), 7.60–7.64 (m, 1H), 7.77 (d, 2H, J ¼ 7.2 Hz); 13C NMR (100 MHz, CDCl3):
δ 24.02, 27.16, 35.68, 35.95, 41.22, 42.84, 46.26, 48.24, 127.66, 129.13, 132.85, 135.92, 167.65,
172.54; C16H23N3O4S; ESI-MS: m/z 354.0 [M þ H]þ.
N-(2-Oxo-2-(pyrrolidin-1-yl)ethyl)-1-(phenylsulfonyl)piperidine-3-
carboxamide (6h)
Yield: 66%; white solid; mp 138–140°C; IR (KBr): 3383, 3304, 2949, 2870, 1681, 1651,
1
1398 cmÀ 1; H NMR (400 MHz, CDCl3): δ 1.43–1.53 (m, 1H), 1.66–1.73 (m, 1H), 1.79–
1.84 (m, 2H), 1.90–1.94 (m, 2H), 1.98–2.03 (m, 2H), 2.27–2.33 (m, 1H), 2.49 (t, 1H, J ¼ 10.4
Hz), 2.55–2.60 (m, 1H), 3.39 (t, 2H, J ¼ 6.8 Hz), 3.53 (t, 2H, J ¼ 6.8 Hz), 3.84–3.85 (m, 1H),
3.86–3.87 (m, 1H), 3.95–3.99 (m, 2H), 6.86 (br s, 1H), 7.52–7.56 (m, 2H), 7.59–7.63 (m, 1H),
7.75–7.78 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 24.07, 24.14, 25.89, 27.04, 41.96, 42.66,
45.53, 46.13, 46.26, 48.36, 127.62, 129.11, 132.82, 135.88, 166.33, 172.73. Anal. calc. for
C18H25N3O4S: C, 56.97; H, 6.64; N, 11.07; found: C, 57.00; H, 6.82; N, 11.30%. ESI-MS:
m/z 380.1 [M þ H]þ.
N-(2-Morpholino-2-oxoethyl)-1-(phenylsulfonyl)piperidine-3-carboxamide (6i)
Yield: 79%; white solid; mp 178–180°C; IR (KBr): 3311, 2963, 2922, 2856, 1670, 1655, 1640,
1
1351, 1332 cmÀ 1; H NMR (400 MHz, CDCl3): δ 1.49–1.56 (m, 1H), 1.66–1.74 (m, 1H),
1.80–1.91 (m, 2H), 2.33–2.39 (m, 1H), 2.52–2.58 (m, 2H), 3.41–3.44 (m, 2H), 3.66–3.74
(m, 7H), 3.81 (d, 1H, J ¼ 8.0 Hz), 4.03–4.10 (m, 2H), 6.81 (br s, 1H), 7.53–7.57 (m, 2H),

10
R. SHARMA AND S. S. SOMAN
7.60–7.64 (m, 1H), 7.76–7.78 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 23.95, 27.11, 41.04,
42.34, 42.77, 44.78, 46.28, 48.19, 66.31, 66.69, 127.65, 129.14, 132.87, 135.89, 166.39, 172.62.
Anal. calc. for C18H25N3O5S: C, 54.67; H, 6.37; N, 10.63; found: C, 54.75; H, 5.86; N,
10.32%. ESI-MS: m/z 396.1 [M þ H]þ.
N-(2-(1,2,3,4-Tetrahydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-(phenylsulfonyl)
piperidine-3-carboxamide (6j)
Yield: 62%; white solid; mp 142–144°C; IR (KBr): 3322, 2948, 2913, 2849, 1664, 1650, 1635,
1351, 1343 cmÀ 1; 1H NMR (400 MHz, CDCl3): δ 1.48–1.51 (m, 1H), 1.67–1.70 (m, 1H), 1.80–
1.85 (m, 1H), 1.90–1.93 (m, 1H), 2.30–2.36 (m, 1H), 2.50–2.60 (m, 2H), 2.90–2.96 (m, 2H),
3.64 (t, 1H, J ¼ 6.0 Hz), 3.72 (d, 1H, J ¼ 11.2 Hz), 3.83–3.89 (m, 2H), 4.11–4.16 (m, 2H), 4.57
(s, 1H), 4.78 (s, 1H), 7.11–7.13 (m, 1H), 7.16–7.20 (m, 2H), 7.22–7.25 (m, 2H), 7.53–7.57 (m,
2H), 7.60–7.64 (m, 1H), 7.76–7.78 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 24.01, 27.14,
28.28, 29.07, 40.24, 41.42, 41.57, 42.13, 42.81, 44.51, 46.01, 46.27, 48.23, 126.16, 126.62,
126.66, 126.85, 126.91, 127.28, 127.66, 128.39, 128.95, 129.13, 131.47, 132.64, 132.85,
133.70, 134.64, 135.90, 166.62, 166.64, 172.56, 172.62. Anal. calc. for C23H27N3O4S: C,
62.56; H, 6.16; N, 9.52; found: C, 62.46; H, 6.07; N, 9.49%. ESI-MS: m/z 442.2 [M þ H]þ.
N-(2-(Methyl(Phenyl)amino)-2-oxoethyl)-1-(phenylsulfonyl)piperidine-3-
carboxamide (6k)
Yield: 65%; white solid; mp 156–158°C; IR (KBr): 3322, 2944, 1673, 1635, 1347, 1333 cmÀ 1
;
1H NMR (400 MHz, CDCl3): δ 1.44–1.50 (m, 1H), 1.66–1.89 (m, 3H), 2.29–2.35 (m, 1H),
2.44–2.56 (m, 2H), 3.31 (s, 3H), 3.66–3.78 (m, 4H), 6.69 (br s, 1H), 7.20–7.23 (m, 2H),
7.38–7.48 (m, 3H), 7.51–7.55 (m, 2H), 7.59–7.63 (m, 1H), 7.73–7.76 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ 23.94, 27.00, 37.60, 42.04, 42.72, 46.26, 48.26, 127.18, 127.64, 128.77,
129.12, 130.27, 132.86, 135.78, 141.68, 168.06, 172.47. Anal. calc. for C21H25N3O4S: C,
60.70; H, 6.06; N, 10.11; found: C, 60.71; H, 5.85; N, 10.12%. ESI-MS: m/z 416.1 [M þ H]þ.
Acknowledgments
The author acknowledge the head of the Department of Chemistry, Faculty of Science, M. S.
University of Baroda for providing the analytical and laboratory facilities; P. D. Baloni and
R. Bhagawat, IISc, Bangalore, for the molecular docking studies; D. Mammen, for the HPLC analysis;
Zydus Research Centre, Ahmedabad, for the ESI-MS and in vitro analysis; and Sun Pharma Advanced
Research Centre, Vadodara, for the elemental analysis.
Funding
The authors are thankful to the University Grants Commission (UGC), New Delhi, for the funding
(UGC-MRP) to one of the authors, Radhika Sharma (SRF).
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