Synthesis and antidiabetic performance of β-amino ketone containing nabumetone moiety

Article abstract of DOI:10.1016/j.bmc.2012.01.028

We wish to report the further design and improved synthesis that resulted in two series of target molecules, TM-1 and TM-2, with remarkably simplified structures containing β-amino ketone of discrete nabumetone moiety. These were obtained via a 'one-pot,

Full text of DOI:10.1016/j.bmc.2012.01.028

Bioorganic & Medicinal Chemistry 20 (2012) 2119–2130
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and antidiabetic performance of b-amino ketone containing
nabumetone moiety
Hang Wang a, Ju-fang Yan b, Xiao-li Song a, Li Fan a, Jin Xu a, Guang-ming Zhou a, Li Jiang c,
⇑
Da-cheng Yang a,
⇑
a School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
b Drug Screening Center, Chengdu DiAo Pharmaceutical Group Co., Ltd, Chengdu 610041, China
c Schlumberger Technology Corporation, 110 Schlumberger Drive, Sugar Land, TX 77478, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We wish to report the further design and improved synthesis that resulted in two series of target mole-
cules, TM-1 and TM-2, with remarkably simplified structures containing b-amino ketone of discrete nab-
umetone moiety. These were obtained via a ‘one-pot, two-step, three-component’ protocol of Mannich
reaction with yield up to 97%. A total of 28 out of 31 new compounds were characterized using 1H
NMR, 13C NMR, ESI MS and HRMS techniques. Studies on their antidiabetic activities, screened in vitro
Received 1 December 2011
Revised 14 January 2012
Accepted 17 January 2012
Available online 2 February 2012
at 10
and
l
a
g mLÀ1 level, indicate that TM-2 possesses peroxisome proliferator-activated receptor activation
-glucosidase inhibition activity significantly stronger than that of TM-1, and also that of the series
Keywords:
Diabetes mellitus
B compounds that were previously synthesized by the group. Analysis of the structure–activity relation-
ship points to the sulfanilamide unit as the most probable potent group of b-amino ketone and, on the
basis of which, a tangible strategy is presented for the development of new antidiabetic drugs.
Ó 2012 Elsevier Ltd. All rights reserved.
a-Glucosidase
Peroxisome proliferator-activated receptor
Mannich reaction
b-Amino ketone
Nabumetone
1. Introduction
b-Amino ketones are well accepted as key synthetic intermedi-
ates of numerous drugs and natural products such as b-amino
Diabetes mellitus is a metabolic disorder caused by a variety of
factors including genetic defects, endocrinopathy, exocrine pancre-
atitis and infection. Among the various forms, type 2 diabetes
mellitus (T2DM) takes account of over 90% of the total occurrence.
According to their mechanism of action, T2DM drugs can be cate-
gorized into the following seven groups: insulin secretagogues
(including sulfonylureas, phenylalanine derivatives and glucagon-
like peptides), insulin sensitizers (including metformin, thiazolid-
alcohols, b-amino acids, b-lactam, etc.2,3 As important bioactive
substances, they are widely used with functionalities spanning
from anti-inflammatory,4 anticancer,5–8 antibacterial,9 analgesia,10
anti-tuberculosis,11,12 antiandrogen13,14 and so on. As shown in
Figure 1 below, some marketed drugs also contain the structural
moiety of b-amino alcohol (Artane) or b-amino ketones (Dyclonine,
Ondansetron).
Benzenesulfonamide structural module has been widely incor-
inediones (TZDs) and b-receptor agonists), a-glucosidase inhibitors
porated into drugs such as antibacterial,15 diuretics,16 hypoglyce-
(such as acarbose, miglitol and voglibose), aldose reductase (AR)
inhibitors (such as tolrestat and epalrestat), simulation insulin
sensitizers (including insulin-like growth factors and vanadate
compounds), insulin medication (oral, injection and inhaled insulin
preparations) and traditional Chinese hypoglycemic medicine
(including single herbal medicine or composite formulation).1
Despite a great number of drugs available on the market, none of
them fully addresses the need for T2DM treatment. Therefore it
remains highly critical to develop target molecules of higher
efficacy and lower toxicity.
mic agents,17 -adrenergic receptor antagonist18 and precursor
a
molecules, as well as sulfonylurea drugs for insulin secretion,
including diabetoplex, gliclazide and glimepiride.19 Certain
benzenesulfonamide containing compounds also display HIV-1
protease inhibition effect.20 It was also revealed by the group that
certain molecules containing a sulfamethoxazole (SMZ) structural
O
O
OH
N
N
.HCl
N
.HCl
.HCl
N
N
O
Ondansetron
Dyclonine
Artane
⇑
Corresponding authors.
E-mail addresses: ljiang@slb.com (L. Jiang), hxydc@swu.edu.cn (D. Yang).
Figure 1. Examples of drugs containing structural moiety of b-amino alcohol or
b-amino ketones.
0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2012.01.028

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H. Wang et al. / Bioorg. Med. Chem. 20 (2012) 2119–2130
moiety exhibit remarkable peroxisome proliferator-activated
receptor (PPAR) activities21,22 (Fig. 2). All the evidence implies that
it is most likely the benzenesulfonamide structural module be an
important part of a new class of antidiabetic agents.
It was reported that naphthalene-containing compounds exhib-
ited more effective PPAR activation activities than benzene-
containing analogues.23 We subsequently designed new b-amino
ketones containing both nabumetone and SMZ moieties, anticipat-
ing enhanced performance due to the combined functionalities.
Some of the compounds showed significant antidiabetic activities.
two-step, three-component’ protocol (Scheme 2), that is, first allow
the reaction between aldehyde and amine; but instead of separat-
ing, and purifying, the resultant Schiff base as would normally en-
sue, ketone and catalyst are added to the same reaction vessel to
continue the reaction till the end.35–37 In essence, this protocol
inherits the simplicity of the ‘one-pot’ analogue but with a bonus
of clearly defined endpoint. In the present article, we synthesized
a total of thirty one b-amino ketone target molecules using the
aforementioned protocol with yield up to an outstanding 97%. Up
to 28 target compounds were comprehensively characterized using
1H NMR, 13C NMR, ESI MS and HRMS techniques. In addition, their
antidiabetic performances were screened in vitro.
For example, the
reached a remarkable level of 70.5% (IC50 = 3.24
a
-glucosidase inhibition (
a
-GI) of compound B-m
l
g mLÀ1), closely
resemble that of Acarbose whose effective concentration is 10
times higher. The PPAR relative activity of compounds B-n, B-b
and B-j approached 83.30%, 81.78% and 78.17%, respectively (see
Fig. 3).24,25 These data represent a new class of antidiabetic agents
of high performances.
3. Results and discussion
It is fairly easy to produce b-amino ketone target molecules in
the presence of the three starting materials plus catalyst. However,
to achieve high purity product requires delicate optimization of the
experimental parameters.
It is unfortunate, though, such potent compounds have fairly
large molecular weights (over 500) and exert only limited solubil-
ity in water. In order to develop target molecules of higher efficacy,
from the Lipinski’s Rule of Five,26 it is favorable to enhance the
solubility in water and reduce the molecular weight. One of prac-
tical optimizations, for this purpose, is to disconnect the mother
molecule into relative small chemical entity. We took a strategy
to retaining the nabumetone fragment (for building the b-amino
ketone) and dividing SMZ into sulfanilamide and isoxazole frag-
ment, both are potent and contain the amino group to participate
in the Mannich reaction. As such the two series of target molecules
TM-1 and TM-2 were designed (Scheme 1). The new class of b-ami-
no ketones consists of hydrophobic nabumetone, sulfanilamide or
5-methylisoxazole, the latter two being known potent agents,
bridged via an aldehyde component. This strategy has proven
effective in achieving the dual objectives of reducing molecular
weight and enhancing solubility in water. In addition, it allows
the pharmacological effects of SMZ, sulfanilamide and 5-methylis-
oxazole be probed within different molecular entities.
3.1. Optimal temperatures
It was observed that for both TM-1 and TM-2 series the reac-
tions were able to proceed in the temperature range of 25–30 °C.
The same applies at expanded range of aldehydes when most of
the reactions complete within 22–47 h. On the other hand, change
of temperature did not show any apparent improvement for those
relatively low yield reactions such as TM-1a(4-NO2). In addition,
change of temperatures in the range of 5–45 °C could not activate
those reactions did not occur under normal conditions, such
as those involving isonicotinaldehyde, 2-chlorobenzaldehyde,
3-hydroxylbenzaldehyde,
and 4-hydroxy-3-methoxybenzaldehyde. Therefore it can be
concluded that temperature is not a key governing parameter.
3-hydroxy-4-methoxybenzaldehyde
3.2. Selection of solvent
2. Chemistry
Small alcohol in particular ethanol is often the primary choice
due to its high solubility differential from reactant against product,
and ready availability. But ethanol solvent resulted in fairly limited
yield involving 4-methylbenzaldehyde starting material. Further at-
tempts covered methanol, benzene, dichloromethane (DCM),
chloroform, and binary mixtures of ethanol–DCM, ethanol–chloro-
form, etc. It was found that the reactions tended to be stopped at
the Schiff base stage without proceeding further in methanol or
benzene solvent, but finished with the highest yield of b-amino
ketones as the final product in ethanol–chloroform mixed solvent.
In addition, it was also found advantageous of using different
solvents at different stages of the reaction. For example, mixed alde-
hyde and amine in the single solvent of ethanol to form Schiff base;
and then added the solution of nabumetone in chloroform to
continue the reaction in ethanol–chloroform mixed solvents till
the final product of b-amino ketone was formed. These combina-
tions were also applicable for the Mannich reactions involving other
aldehydes, sulfanilamide or 5-methylisoxazole and nabumetone.
The Mannich reaction is one of the most important basic
reactions in organic chemistry commonly used in the synthesis
of numerous pharmaceuticals and natural products.27–30 Recent
developments also show stringent chemoselectivity, stereoselec-
tivity, diastereoselectivity of the products,31 greatly expands the
validity of this classic reaction.
It is common to adopt either a two-step, or ‘one-pot’, protocol
for direct Mannich reaction.32 The former approach allows
aldehyde reacting with amine first to form Schiff base, which then
in turn reacts with ketone to yield the final product.33 On the other
hand, the latter method mixes all the three components, namely,
aldehyde, ketone and amine, plus catalyst, in the same reaction
vessel from beginning to the end.34 This method is very simple
to set up, but it is difficult to monitoring the reaction process
and determining the endpoint. Subsequent to years of research
and successive modifications, the authors established a ‘one-pot,
Me
Me
OMe
O
OMe
O
O
S
O
O
S
O
N
O
N
H
N
O
N
H
N
H
N
H
HO
Br
PPAR activation 69.75%
PPAR activation 66.35%
Figure 2. Two representative compounds with strong PPAR activation activities.

H. Wang et al. / Bioorg. Med. Chem. 20 (2012) 2119–2130
2121
Me
Me
O
B-m
Me
O
O
B-n
O
O
S
O
S
O
N
O
N
H
N
O
N
H
N
H
N
H
MeO
MeO
a-GI 70.5% (IC50=3.24 ug.mL-1
)
PPAR activation 83.30%
Me
O
Me
O
NO2
O
OMe
O
B-j
B-b
S
S
N
O
N
H
N
O
N
H
O
O
N
H
N
H
MeO
MeO
PPAR activation 81.78%
PPAR activation 78.17%
Figure 3. Structures and biological activities of compound B-m, B-n, B-b and B-j.
Me
O
Me
O
Me
OMe
OMe
O
S
O
O
S
O
O
S
O
R
R
O
N
N
O
N
H
O
N
H
N
O
N
H
N
H
N
H
N
H
R"
A
MeO
HO
B
Me
O
O
S
O
R
R
SO NH
2
2
O
O
N
O
N
Me
H
N
H
N
H
N
O
N
H
MeO
MeO
Br
TM-2
TM-1
Scheme 1. Design of target molecules.
R
O
Me
O
Me
N
O
H N
H2N
H2N
O
MeO
N
CHO
MeO
TM-1a~TM-1p
R
+
R
SO2NH2
O
SO2NH2
N
H
MeO
2a R=4-NO2
2b R=3-NO2
2c R=3,4-diCl
2e R=3-F
TM-2a~TM-2r
1a R=4-NO2
1b R=3-NO2
1c R=3,4-diCl
1d R=2,4-diCl
1e R=3-F
1l R= 4-Me
1m R= 3-Me
1n R= 4-C4H9O
1o R= 3,4-OCH2O
1p R= 4-OH
1g R=3-Cl
2g R=3-Cl
2h R=4-Br
2j R=3-MeO
2k R=H
2n R=4-C4H9O
2o R=3,4-OCH2O
2p R=4-OH
2q RC6H4 is 6-methoxy-2-naphthyl
2r RC6H4 is 2-C4H4O
1h R=4-Br
1i R= 4-MeO
1j R=3-MeO
1k R= H
2m R=3-Me
2f R=4-Cl
1f R=4-Cl
Scheme 2. Synthetic routes to the target molecules.
3.3. Selection of catalyst
TM-1f(4-Cl), required a lower pH range of 3–4 in order to obtain
the final products.
There are numerous species that may be used as catalysts for
the Mannich reaction, including Lewis38–40 or Brönsted41,42 acids,
and transitional metal salts.43 In a model reaction system involving
furaldehyde, sulfanilamide and nabumetone starting materials, a
number of potential catalysts were screened including concen-
trated hydrochloric acid, phosphoric acid, nitric acid, acetic acid,
ironic chloride and aluminum chloride. It was observed that con-
centrated hydrochloric acid exerted the best catalytic performance
among the candidates examined, while nitric acid showed literally
no enhancement in reaction rate at all. In addition, the effect of pH
was also investigated. While most of the reactions proceeded as
expected in the domain of pH 4–5, a few of the TM-1 series mole-
cules, such as TM-1a(4-NO2), TM-1b(3-NO2), TM-1d(2,4-diCl) and
3.4. Yield-substituent relationship
In the TM-1 series, reactions using 3,4-dichlorobenzaldehyde,
4-chlorobenzaldehyde as starting materials reached yields over
85%, while that using 3-chlorobenzaldehyde only had a yield of
48.8%, indicating the impact of the number and location of chloro
atom on the yield. Specifically, substitution at the 4-position ap-
peared to be able to significantly enhance the yield. However, both
3- and 4-nitrobenzaldehydes only led to yields (1b) below the 50%
mark, showing a moderate effect of strong electron-withdrawing
group on the yield. On the other hand, strong electron-donating
groups such as 3,4-OCH2O led to an excellent yield (1o) of 96.3%.

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H. Wang et al. / Bioorg. Med. Chem. 20 (2012) 2119–2130
of insulin sensitivity and lipid concentration, as well as the gene
expressions of multiple metabolisms.47 Glycosidase exerts a num-
ber of critical activities such as promoting hydrolysis of glycosides
in a wide range of substrates including microorganisms, plants and
animals. Both
a- and b-glucosidases are associated with a variety
of biochemical processes relevant to diabetes, viral and/or bacterial
infection, and cancer. Studies of their inhibitors are of great impor-
tance to the in-depth understanding of the physiochemical pro-
cesses and in turn guide the development of new medications.48
The present work probes the target molecules’ antidiabetic per-
formances by measuring their PPAR activation and
a-glucosidase
inhibition in vitro. Table 1 depicts the bioactivity of all the target
molecules. Among them, TM-2p(4-OH) reaches a remarkable level
of PPAR in 73.37%, and TM-2h(4-Br)’s
a-GI goes up to 79.70%.
Table 2 presents the EC50 and IC50 values of a few selected target
molecules.
3.5.1. PPAR agonist activity
As presented in Table 1 and Fig. 6a, there is only 1 molecule(TM-
1j), out of 16, in TM-1 whose PPAR relative activation is greater than
40%; for TM-2, that ratio is 9 out of 14, while for previously made
series B, the ratio is 8 out of 14. Therefore the PPAR relative activa-
tion takes an order as: TM-2 > B > TM-1. However, 3 molecules in
the B series show even stronger PPAR relative activation, culmi-
nated by B-b and B-n. In addition, most of the active target
molecules are 4-substituted; least active counterparts are either
3-substituted or 4-substituted with bulky functional group, for
example OC4H9(TM-2n), or other aldehydes such as 6-methoxy-
2-naphthaldehyde(TM-2q) or furan-2-carbaldehyde(TM-2r). For
identical substituent at identical location, TM-2 is almost invariably
more active than their TM-1 counterparts. Further analysis of the
structural features also transpires that both TM-2 and B series con-
tain the benzenesulfonamide moiety, which is categorically absent
from TM-1. It naturally prompts a plausible hypothesis of benzene-
sulfonamide being the potent pharmacophore. In general, the
molecular weight of TM-2 is smaller than its B counterpart, which
in turn led the benzenesulfonamide moiety more accessible from
the external environment. This could well be the key to its superior
bioactivity. Also, for the weaker molecules, they tend to carry small
4-substituent, for example Cl (B-f), H (B-k) and HO (B-p). In
comparison, those weak TM-2 counterparts carry more bulky
4-substituent, for example OC4H9 (TM-2n). Thus, it can be reason-
ably speculated that the spatial hindrance of the SMZ moiety in B
series is significantly greater than that of the sulfonamide moiety
in TM-2 series because of the presence of methylisoxazole
fragment. The bulky substituent might have squeezed the SMZ frag-
ment in order to achieve effective integration with its ligand(s). But
for TM-2 series, the molecules contained bulky substituent cannot
achieve a reasonable three dimensional conformation to integrate
with ligand. It is exactly such a spatial effect dictates that the
sulfonamide structure cannot be abnormally bulky (Fig. 7).
Figure 4. Yield–substituent relationships.
For TM-2 series, the yield of reactions involving double substituted
benzaldehyde by chloro atom tend to be lower than the single
substituted counterpart, for example, 2c(3,4-diCl) < 2f(4-Cl). For
different substitution groups at the identical location of benzalde-
hyde, the yield is in line with the trend of the electron-donating
ability of the substituent, for example, 2b(3-NO2) ꢀ 2e
(3-F) < 2g(3-Cl). These results highlight the remarkable impact on
the final yield by the electron density distribution and the number
of substituent on the benzaldehyde ring (Fig. 4).
In addition, the modifications made on TM-1 and TM-2 series
rendered considerably higher solubilities in both aqueous and
organic solvents, compared to previously reported B series. This
presents a significant advantage in the subsequent characteriza-
tion and investigation in their antidiabetic performances.
3.5. Biological activities
Among the numerous antidiabetic targets being investigated,
most of the on-going efforts focus on dipeptidyl peptidase-IV
(DPP-4), protein tyrosine phosphatase 1B (PTP1B) and PPARs, while
works on
a-glucosidase inhibitor lack of appreciable progress. At
present, the traditional Chinese hypoglycemic medicines, and car-
bohydrate-analogous, are the main clinical drugs. While there are
reports about PTP1B research, no chemical entity has reached the
clinical stage.21,22 DPP-4 family drugs have been outstanding in re-
cent years with a few new products, for example of the Saxagliptin
(OnglyzaÒ, marketed in 2009),44 Alogliptin (approved in Japan in
2010),45 and Linagliptin (approved by US FDA in 2011)46 (Fig. 5),
perhaps due to their relatively low acute toxicities, but their
chronic toxicities remain to be determined. As a member of the nu-
clear receptor superfamily, PPAR targets received considerable
attention for their involvement in a wide range of gene expression
affecting lipid and carbohydrate metabolisms. Among the three
3.5.2.
It is apparent from Table 1 and Fig. 6b that TM-1 only possesses
very weak -GI activities, and there is hardly any appreciable dis-
a-Glucosidase inhibition activity
a
parity in
a-GI activities among individual TM-1 series molecules.
subtypes, PPAR
a
, PPAR
c
and PPARd, PPAR
c
takes part in the tuning
O
O
H
NH2
N
O
NH2
N
N
N
N
N
N
N
N
H
N
NH2
NC
HO
O
N
O
CN
Alogliptin
Linagliptin
Saxagliptin
Figure 5. DPP-4 family drugs marketed in recent years.

H. Wang et al. / Bioorg. Med. Chem. 20 (2012) 2119–2130
2123
Table 1
Antidiabetic activity of target molecules
TM
a
-Glucosidase
PPAR relative
activation (%)
TM
a
-Glucosidase
PPAR relative
activation (%)
B
a
-Glucosidase
PPAR relative
activation (%)
inhibition (%)
inhibition (%)
inhibition (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
24.57
24.40
22.30
13.00
13.27
26.30
26.27
1.42
4.18
9.11
5.37
11.48
30.08
6.32
4.86
2.87
3.13
41.56
5.83
11.52
12.65
6.33
12.64
5.30
2a
2b
2c
2f
2g
2h
2j
2k
2m
2n
2o
2p
2q
2r
31.65
32.66
34.75
66.26
40.77
79.70
15.68
41.73
14.09
À4.69
-4.32
52.81
6.39
46.75
14.75
45.77
71.87
58.68
67.32
60.31
60.98
57.32
17.98
9.87
B-b
B-c
B-d
B-e
B-f
B-g
B-i
B-j
B-k
B-l
B-m
B-n
B-o
B-p
41.57
53.71
20.31
24.71
44.23
47.08
50.75
12.67
14.95
15.83
70.51
14.33
19.18
7.07
81.78
22.38
64.52
36.67
3.92
19.55
48.38
78.17
17.83
58.52
68.41
83.30
43.05
13.77
10.76
15.75
7.36
7.23
73.37
19.05
6.64
10.25
10.97
0.35
À9.77
21.38
Note: PPAR relative activation is the average of four measurements at a constant concentration of 10
rosiglitazone, respectively.
l
gÁmLÀ1; positive controls of
a
-GI and PPAR were acarbose and
Table 2
EC50 and IC50 of some active compounds
Entry
R
Object ID
Max Concn (
l
g/mL)
IC50
(
lg/mL)
EC50 (lg/mL)
TM-2f
TM-2h
TM-2p
4-Cl
4-Br
4-OH
DIAO-000003638
DIAO-000003633
DIAO-000003636
10
10
10
4.07
2.92
4.14
6.74
8.21
5.56
Rosiglitazone
Acarbose
0.974
100
0.043
/
Figure 6a. PPAR relative activation-substituent diagram.
Figure 6b. a-GI-substituent diagram
in the TM-2 series. The fact that TM-2 and B series show clear dis-
tinction in their -GI activities, despite of the common feature of
sulfonamide moiety, implies the multiple factors involved in the
competitive inhibition of -GI activity, including perhaps spatial
hindrance, charge density distribution, solubility and other func-
tional groups. Both TM-2f(4-Cl) and TM-2p(4-HO) show significant
The fact that TM-1 does not show any significant
corroborates well with the notion of sulfonamide being the likely
potent pharmcophore. For TM-2 whose -GI activities are greater
than 40%, their activities follow this order: TM-2h(4-Br) >
TM-2f(4-Cl) > TM-2p(4-OH) > TM-2k(H) > TM-2g(3-Cl). Again,
4-substitution results in stronger -GI activity. In comparison, B
series follow different order of activity: B-m(3-Me) > B-c
(3,4-diCl) > B-i(4-OMe) > B-g(3-Cl) > B-f(4-Cl) > B-b(3-NO2). The
disparity in -GI activities among B series is not as great as those
a-GI activity
a
a
a
a
a-GI activities, the former maybe due to the optimal size of chloro
a
atom, and in turn electron density distribution, plus a fair lipo-
hydro distribution coefficient (see Fig. 12); the latter maybe
a

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H. Wang et al. / Bioorg. Med. Chem. 20 (2012) 2119–2130
Figure 7. Three dimensional structures of B-n and TM-2p.
attributed to its hydrophilicity. TM-2h(4-Br) and B-m(3-CH3) are
most active in -GI in the three series, their three dimensional
a
structures show that the naphthalene ring does not share its plane
with any other ring moieties. Despite drastically different three
dimensional structures (Fig. 8), the two molecules show little dis-
parity in their activities. This may point to the three dimensional
conformation not being the decisive factor of its activity.
Comparison of the overall antidiabetic activities, as outlined in
Figures 9, 10 and 11, shows considerable fluctuations in PPAR
Figure 10. PPAR and a-GI of TM-2.
among TM-1, but their overall levels of
and constant; on the other hand, TM-2 displays the common fea-
ture of high PPAR and -GI performances, an invaluable pattern
of multiple target activities. It is also noteworthy that the B-series
a-GI are fairly moderate
a
exhibits diverse trends of PPAR and
structure–activity relationship.
a-GI, indicating an intriguing
It is interesting to note, as shown in Figure 12, that the lipo-hy-
dro distribution coefficients (calculated by Chemdraw Ultra 12.0)
for TM-1, TM-2 and B series against individual substituent show
to a great extent similar trend, which once again corroborates from
Figure 11. PPAR and a-GI of B series.
Figure 8. Threedimensional structures of B-m and TM-2h.
Figure 9. PPAR and
a-GI of TM-1.
Figure 12. Relationship of lipo-hydro distribution coefficient-substituent.

H. Wang et al. / Bioorg. Med. Chem. 20 (2012) 2119–2130
2125
a unique aspect the critical roles played by the substituent. Under
the condition of identical substituent, the magnitude of the lipo-
hydro distribution coefficient takes the following order: TM-
2 < TM-1 < B, which indicates improved hydrophilicity for the
new target molecules as reported in the present study. This also
endorsed our approach to enhance the hydrophilicity by simple
mass reduction without touching the key functional groups.
Furthermore, the coincidence of trends of lipo-hydro distribution
coefficient and biological activities against individual substituent
shows a close correlation between the two parameters. Therefore
the impact of the lipo-hydro distribution coefficient should be
rightly taken into consideration in any further optimization of
the target molecules.
product. Melting point was determined, and the structure was con-
firmed by 1H NMR, 13C NMR, ESI MS and HRMS techniques.
TM-1a~TM-1p
Ar2
R
O
Me
N
Ar1
O
H
N
H3CO
In conclusion, implementation of our strategy to systematically
tuning the size of the SMZ fragment has successfully led to novel b-
amino ketone target molecules with significantly enhanced antidi-
abetic activities than their predecessors. In particular, novel target
molecules TM-2f, -2h and -2p have demonstrated outstanding
antidiabetic performances in all the tests conducted. The current
results unambiguously pinpoint to the benzenesulfonamide moi-
ety as the potent pharmacophore in the target molecules. This
overall approach should have set important guidelines to the
further development of antidiabetic drugs.
4.2.1. TM-1a 5-(6-Methoxynaphthalen-2-yl)-1-(5-
methylisoxazol-3-ylamino)-1-(4-nitrophenyl)pentan-3-one
Yield: 33.9%, mp: 166–168 °C. 1H NMR (300 MHz, CDCl3, ppm)
d: 2.23 (3H, s, CH3), 2.77 (2H, q, J = 7.8 Hz, CH2), 2.93–3.02 (4H,
m, 2ÂCH2), 3.92 (3H, s, OCH3), 4.95–5.01 (1H, m, ⁄CH), 4.99 (1H,
s, NH), 5.41 (1H, s, O–C(Me)@CH), 7.09 (1H, s, Ar1-H), 7.12 (1H, d,
J = 9.0 Hz, Ar1-H), 7.17 (1H, d, J = 8.8 Hz, Ar1-H), 7.39 (2H, d,
J = 8.6 Hz, Ar2-H), 7.44 (1H, s, Ar1-H), 7.61 (2H, d, J = 8.5 Hz, Ar1-
H), 8.03 (2H, d, J = 8.5 Hz, Ar2-H). 13C NMR (75 MHz, CDCl3, ppm)
d: 12.5, 29.5, 44.9, 48.6, 53.7, 55.4, 93.5, 105.8, 119.1, 123.9
(2ÂC), 126.4, 127.1, 127.3 (2ÂC), 128.1, 128.9, 129.0, 133.2,
135.4, 147.2, 149.4, 157.6, 163.4, 169.1, 208.1. MS (m/z, %): 460
([M+H]+,100), 482 ([M+Na]+, 10). HRMS: formula: C26H25N3NaO5,
calcd: 482.1686, found: 482.1671.
4. Experimental section
4.1. Reagents and instrumentation
Melting points were determined by an electrothermal X-6
apparatus. FT-IR spectra were carried out on Perkin-Elmer,
Spectrum GX, USA, using KBr pellets in the 400–4000 cmÀ1 range.
1H NMR and 13C NMR spectra were recorded on a Bruker AV 300
spectrometer using TMS as an internal standard. The chemical
shifts were reported in parts per million (ppm), the coupling con-
stants (J) are expressed in hertz (Hz) and signals were described as
singlet (s), doublet (d), triplet (t), quartet (q), as well as multiplet
(m). ESI-MS were obtained on an Agilent 1946B instrument. High
resolution mass spectra (HRMS) analyse were conducted on a
Daltonics Data Analysis 3.2 (Bruker) using ESI (electrospray ioniza-
tion) techniques. The purity of the compounds was examined by
thin-layer chromatography (TLC) on silica gel plate using petro-
leum ether and ethyl acetate. All chemical reagents and solvents
were commercially available, and were used without further
purification.
4.2.2. TM-1b 5-(6-Methoxynaphthalen-2-yl)-1-(5-
methylisoxazol-3-ylamino)-1-(3-nitrophenyl)pentan-3-one
Yield: 47.8%, mp: 173–174 °C. 1H NMR (300 MHz, CDCl3, ppm)
d: 2.16 (3H, s, CH3), 2.72 (2H, dd, J = 7.4, 15.4 Hz, CH2), 2.86–2.91
(3H, m, CH2 and CH2⁄CH), 2.99 (1H, dd, J = 6.2, 16.9 Hz, CH2⁄CH),
3.85 (3H, s, OCH3), 4.92–4.97 (1H, m, ⁄CH), 5.36 (1H, s, O–
C(Me)@CH), 7.02 (1H, s, Ar1-H), 7.04 (1H, d, J = 8.9 Hz, Ar1-H),
7.12 (1H, d, J = 8.3 Hz, Ar1-H), 7.29–7.32 (1H, m, Ar2-H), 7.38 (1H,
s, Ar1-H), 7.50–7.57 (3H, m, Ar2-H and 2Ar1-H), 7.95 (1H, d,
J = 8.4 Hz, Ar2-H), 8.10 (1H, s, Ar2-H). 13C NMR (75 MHz, CDCl3,
ppm) d: 12.6, 29.5, 44.9, 48.7, 53.5, 55.4, 93.6, 105.7, 119.0,
121.3, 122.5, 126.4, 127.1, 127.3, 127.4, 129.0, 129.6, 133.0,
133.3, 135.5, 144.3, 148.5, 157.5, 163.4, 169.1, 208.2. MS (m/z,
%): 460 ([M+H]+, 100), 482 ([M+Na]+, 8). HRMS formula
C26H25N3NaO5, calcd 482.1686, found 482.1693.
4.2.3. TM-1c 1-(3,4-Dichlorophenyl)-5-(6-methoxynaphthalen-
2-yl)-1-(5-methylisoxazol-3-ylamino)pentan-3-one
4.2. Chemistry
Yield: 85.7%, mp: 179–181 °C. 1H NMR (300 MHz, CDCl3, ppm)
d: 2.23 (3H, s, CH3), 2.75 (2H, t, J = 7.9 Hz, CH2), 2.92–2.98 (4H,
m, 2ÂCH2), 3.91 (3H, s, OCH3), 4.85 (1H, s, NH), 4.86–4.89 (1H,
m, ⁄CH), 5.48 (1H, s, O–C(Me)@CH), 7.09–7.12 (2H, m, Ar1-H),
7.16–7.29 (3H, m, 2 Ar2-H and 1Ar1-H), 7.40 (1H, s, Ar2-H), 7.46
(1H, s, Ar1-H), 7.63 (2H, d, J = 8.6 Hz, Ar1-H). 13C NMR (75 MHz,
CDCl3, ppm) d: 12.7, 29.5, 45.8, 49.8, 53.2, 55.7, 105.4, 118.6,
126.5, 126.8, 127.1, 128.0, 128.7, 129.0, 129.5, 129.8, 131.1,
132.5, 133.9, 136.0, 136.9, 144.8, 157.4, 158.4, 163.8, 208.7. MS
(m/z, %): 483 ([M+H]+, 100), 505 ([M+Na]+, 10). HRMS formula
General procedure for synthesis of the target molecules: Aromatic
aldehyde (2 mmol) and aromatic amine were added to the mixed
solvent of anhydrous ethanol–chloroform (5–10 mL, v/v = 3:1).
This mixture was stirred vigorously until the appearance of the
precipitate, and then ketone (2 mmol) was added followed by a
few droplets (0.1–0.2 mL) of concentrated hydrochloric acid as cat-
alyst. Stirred continuously at 20–32 °C, and if necessary, additional
amount of anhydrous ethanol was added. The reaction progress
was monitored by TLC. Upon completion, the suspension was
cooled in the refrigerator for about 2–5 h. The solid was subse-
quently collected by filtration. The filter cake was dispersed in
95% ethanol (4–10 mL), adjusting to pH 7–8 with 10% K2CO3 and
stirring for approximately 2 h. Subsequently, the suspension was
filtered with suction on a sintered glass funnel, the filter cake ob-
tained was washed thoroughly with water (2 Â 5 mL) and cool
absolute ethanol (2 Â 1.5 mL), and then dried in vacuo overnight
to afforded the crude product. Recrystallising from ethanol, meth-
anol, chloroform, or ethanol–acetone affords analytically pure
C26H24Cl2N2NaO3, calcd 505.1056, found 505.1055.
4.2.4. TM-1d 1-(2,4-Dichlorophenyl)-5-(6-methoxynaphthalen-
2-yl)-1-(5-methylisoxazol-3-ylamino)pentan-3-one
Yield: 74.6%, mp: 161–163 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.17 (3H, s, CH3), 2.70–2.90 (6H, m, CH2CH2, ⁄CHCH2),
3.85 (3H, s, OCH3), 5.19 (1H, dd, J = 6.8, 13.9 Hz, ⁄CH), 5.99 (1H, s,
O–C(Me)@CH), 6.75 (1H, d, J = 6.6 Hz, Ar1-H), 7.12 (1H, d,
J = 8.5 Hz, Ar1-H), 7.26 (1H, s, Ar2-H), 7.31 (1H, d, J = 7.8 Hz, Ar1-

2126
H. Wang et al. / Bioorg. Med. Chem. 20 (2012) 2119–2130
H), 7.38 (1H, d, J = 7.5 Hz, Ar2-H), 7.46 (1H, d, J = 7.7 Hz, Ar2-H),
7.55–7.58 (2H, m, NH, Ar1-H), 7.69–7.72 (2H, m, Ar1-H). 13C NMR
(75 MHz, DMSO-d6, ppm) d: 12.0, 28.8, 43.6, 47.6, 49.8, 55.1,
93.5, 105.8, 118.5 (2ÂC), 125.9, 126.7, 127.5, 127.6, 128.6, 128.7,
128.8, 132.1, 132.8, 136.2, 139.8, 156.8 (2ÂC), 163.0, 167.8,
206.5. MS (m/z, %): 483 ([M+H]+, 100), 484 ([M+2]+, 27), 485
([M+3]+, 67), 505 ([M+Na]+, 5). HRMS formula C26H24Cl2N2NaO3,
calcd 505.1056, found 505.1042.
MS (m/z, %): 493 ([M+H]+, 100), 515 ([M+Na]+, 5). HRMS formula
26H25BrN2NaO3, calcd 515.0941, found 515.0923.
C
4.2.9. TM-1i 5-(6-Methoxynaphthalen-2-yl)-1-(4-
methoxyphenyl)-1-(5-methylisoxazol-3-ylamino)pentan-3-one
Yield: 88.5%, mp: 163–165 °C. 1H NMR (300 MHz, CDCl3, ppm)
d: 2.15 (3H, s, CH3), 2.67–2.69 (2H, m, CH2), 2.84–2.89 (3H, m,
CH2, CH2⁄CH), 2.98 (1H, dd, J = 6.7, 16.0 Hz, CH2⁄CH), 3.69 (3H, s,
Ar2-OCH3), 3.84 (3H, s, OCH3), 4.79–4.82 (1H, m, ⁄CH), 5.33 (1H,
s, O–C(Me)@CH), 6.73 (2H, d, J = 8.5 Hz, Ar1-H), 7.04 (2H, d,
J = 9.8 Hz, Ar2-H), 7.10–7.14 (3H, m, 2Ar2-H and 1Ar1-H), 7.39
(1H, s, Ar1-H), 7.58 (2H, d, J = 8.5 Hz, Ar1-H). 13C NMR (75 MHz,
CDCl3, ppm) d: 12.5, 29.4, 45.2, 49.3, 54.0, 55.3, 55.4, 93.6, 105.7,
114.1 (2ÂC), 118.9, 126.3, 127.0, 127.6, 128.9 (2ÂC), 129.0, 130.1,
133.2, 133.9, 136.0, 157.4, 159.0, 164.0, 168.7, 208.6. MS (m/z, %):
445 ([M+H]+, 51), 467 ([M+Na]+, 8). HRMS formula C27H28N2NaO4,
calcd 467.1941, found 467.1959.
4.2.5. TM-1e 1-(3-Fluorophenyl)-5-(6-methoxynaphthalen-2-
yl)-1-(5-methylisoxazol-3-ylamino)pentan-3-one
Yield: 71.2%, mp: 150–153 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.17 (3H, s, CH3), 2.81 (1H, dd, J = 6.7, 15.7 Hz, ⁄CHCH2),
2.86 (4H, m, CH2), 2.99 (1H, dd, J = 7.0, 15.8 Hz, ⁄CHCH2), 3.85
(3H, s, OCH3), 4.88 (1H, dd, J = 6.8, 13.9 Hz, ⁄CH), 5.65 (1H, s, O–
C(Me)@CH), 6.65 (1H, d, J = 7.7 Hz, Ar1-H), 7.03 (1H, d, J = 7.5 Hz,
Ar2-H), 7.11–7.19 (2H, m, Ar2-H), 7.26–7.31 (4H, m, Ar1-H), 7.56
(1H, s, NH), 7.70 (2H, d, J = 7.5 Hz, Ar1-H). 13C NMR (75 MHz,
DMSO-d6, ppm) d: 12.0, 28.8, 43.5, 49.4, 52.7, 55.1, 93.7, 105.7,
118.5, 122.7, 125.9, 126.7, 127.7, 128.6, 128.8, 130.1, 130.2,
132.8, 136.2, 146.6, 156.8, 160.6, 163.4, 163.7, 167.6, 207.1. HRMS
formula C26H25FN2NaO3, calcd 455.1741, found 455.1731.
4.2.10. TM-1j 5-(6-Methoxynaphthalen-2-yl)-1-(3-
methoxyphenyl)-1-(5-methylisoxazol-3-ylamino)pentan-3-one
Yield: 81.3%, mp: 185–187 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.17 (3H, s, CH3), 2.80 (1H, dd, J = 5.7, 16.7 Hz, ⁄CHCH2),
2.83–2.88 (4H, m, 2ÂCH2), 3.05 (1H, dd, J = 5.9, 16.5 Hz, ⁄CHCH2),
3.71 (3H, s, Ar2-OCH3), 3.85 (3H, s, OCH3), 4.83 (1H, dd, J = 6.8,
13.9 Hz, ⁄CH), 5.63 (1H, s, O–C(Me)@CH), 6.59 (1H, d, J = 7.9 Hz,
Ar1-H), 6.77 (1H, d, J = 7.3 Hz, Ar1-H), 6.92 (1H, s, Ar2-H), 6.93
(1H, d, J = 8.0 Hz, Ar2-H), 7.10–7.30 (4H, m, NH, Ar1-H and 2Ar2-
H), 7.56 (1H, s, Ar1-H), 7.70 (2H, d, J = 8.0 Hz, Ar1-H). 13C NMR
(75 MHz, DMSO-d6, ppm) d: 12.0, 28.8, 43.6, 49.8, 53.2, 55.0,
55.1, 93.7, 105.7, 112.0, 112.3, 118.5, 118.7, 125.9, 126.7, 128.6,
128.8, 129.3, 132.8, 136.2, 145.2, 156.8, 159.2, 163.6, 163.7,
167.5, 207.3. MS (m/z, %): 445 ([M+H]+, 100), 446 ([M+Na]+, 23).
HRMS formula C27H28N2NaO4, calcd 467.1941, found 467.1923.
4.2.6. TM-1f 1-(4-Chlorophenyl)-5-(6-methoxynaphthalen-2-
yl)-1-(5-methylisoxazol-3-ylamino)pentan-3-one
Yield: 88.1%, mp: 169–171 °C. 1H NMR (300 MHz, CDCl3, ppm)
d: 2.22 (3H, s, CH3), 2.74 (2H, dd, J = 6.8, 14.1 Hz, CH2), 2.93 (3H,
d, J = 7.4 Hz, CH2, CH2⁄CH), 3.10 (1H, dd, J = 6.7, 16.5 Hz, CH2⁄CH),
3.91 (3H, s, OCH3), 4.85 (1H, s, NH), 4.89–4.92 (1H, m, ⁄CH), 5.39
(1H, s, O–C(Me)@CH), 7.12–7.16 (2H, m, Ar1-H), 7.19–7.23 (5H,
m, 4Ar2-H and Ar1-H), 7.45 (1H, s, Ar1-H), 7.63 (2H, d, J = 8.5 Hz,
Ar1-H). 13C NMR (75 MHz, CDCl3, ppm) d: 12.8, 29.8, 45.2, 49.7,
53.2, 55.3, 93.6, 105.6, 118.9, 127.2, 127.4, 128.0, 128.7 (2ÂC),
129.0 (2ÂC), 129.2, 129.5, 132.5, 133.8, 136.1, 144.6, 157.2,
158.3, 163.8, 208.6. MS (m/z, %): 449 ([M+H]+, 100), 471
([M+Na]+, 4). HRMS formula C26H25ClN2NaO3, calcd 471.1446,
found 471.1434.
4.2.11. TM-1k 5-(6-Methoxynaphthalen-2-yl)-1-(5-
methylisoxazol-3-ylamino)-1-phenylpentan-3-one
Yield: 63.8%, mp: 177–179 °C. 1H NMR (300 MHz, CDCl3, ppm)
d: 2.22 (3H, s, CH3), 2.68–2.72 (2H, m, CH2), 2.88–2.95 (3H, m,
CH2, CH2⁄CH), 3.06 (1H, dd, J = 6.7, 16.0 Hz, CH2⁄CH), 3.91 (3H, s,
OCH3), 4.91–4.95 (1H, m, ⁄CH), 5.41 (1H, s, O–C(Me)@CH), 7.08–
7.10 (2H, m, Ar1-H), 7.14–7.16 (1H, m, Ar1-H), 7.22–7.29 (5H, m,
Ar2-H), 7.45 (1H, s, Ar1-H), 7.63 (2H, d, J = 8.5 Hz, Ar1-H). 13C
NMR (75 MHz, CDCl3, ppm) d: 12.5, 29.6, 45.7, 49.2, 53.7, 55.2,
93.6, 105.8, 118.9, 126.7, 126.8, 127.0, 127.4 (2ÂC), 128.7, 129.0
(2ÂC), 129.9, 130.1, 133.0, 133.8, 141.2, 157.1, 158.4, 163.8,
208.5. MS (m/z, %): 415 ([M+H]+, 100), 437 ([M+Na]+, 5). HRMS for-
mula C26H26N2NaO3, calcd 437.1836, found 437.1833.
4.2.7. TM-1g 1-(3-Chlorophenyl)-5-(6-methoxynaphthalen-2-
yl)-1-(5-methylisoxazol-3-ylamino)pentan-3-one
Yield: 48.8%, mp: 154–156 °C. 1H NMR (300 MHz, CDCl3, ppm)
d: 2.23 (3H, s, CH3), 2.75 (2H, t, J = 7.9 Hz, CH2), 2.92–2.97 (3H,
m, CH2 and CH2⁄CH), 3.00 (1H, dd, J = 6.5, 16.6 Hz, CH2⁄CH), 3.91
(3H, s, OCH3), 4.79 (1H, d, J = 7.1 Hz, NH), 4.87–4.91 (1H, m, ⁄CH),
5.40 (1H, s, O–C(Me)@CH), 6.91 (1H, s, Ar1-H), 7.15–7.23 (5H, m,
3Ar2-H and 2Ar1-H), 7.30 (1H, s, Ar2-H), 7.47 (1H, s, Ar1-H), 7.63
(2H, d, J = 8.5 Hz, Ar3-H). 13C NMR (75 MHz,CDCl3,ppm) d: 12.8,
29.8, 45.2, 49.8, 53.8, 55.4, 93.5, 105.4, 118.7, 126.4, 126.8, 127.1,
127.4, 127.5, 128.6, 129.3, 129.5, 131.6, 132.8, 133.8, 136.1,
145.2, 157.3, 158.3, 163.9, 208.6. MS (m/z, %): 449 ([M+H]+, 100),
471 ([M+Na]+, 5). HRMS formula C26H25ClN2NaO3, calcd
471.1446, found 471.1431.
4.2.12. TM-1l 5-(6-Methoxynaphthalen-2-yl)-1-(5-
methylisoxazol-3-ylamino)-1-p-tolylpentan-3-one
Yield: 61.2%, mp: 144–147 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.16 (3H, s, Ar3-CH3), 2.24 (3H, s, Ar2-CH3), 2.74 (1H, dd,
J = 9.3, 15.1 Hz, ⁄CHCH2), 2.84 (4H, m, 2ÂCH2), 2.97 (1H, dd,
J = 8.0, 15.4 Hz, ⁄CHCH2), 3.85 (3H, s, OCH3), 4.79 (1H, dd,
J = 6.8 Hz, 13.9 Hz, ⁄CH), 5.61 (1H, s, O–C(Me)@CH), 6.55 (1H, d,
J = 7.8 Hz, Ar1-H), 7.07 (2H, d, J = 6.6 Hz, Ar2-H), 7.11 (1H, d,
J = 7.7 Hz, Ar1-H), 7.21 (2H, d, J = 6.6 Hz, Ar2-H), 7.23–7.26 (2H,
m, Ar1-H), 7.54 (1H, s, NH), 7.69 (2H, d, J = 7.0 Hz, Ar1-H). 13C
NMR (75 MHz, DMSO-d6, ppm) d: 12.0, 20.7, 28.8, 43.6, 49.7,
53.0, 55.1, 93.8, 105.7, 118.5, 125.9, 126.4 (2ÂC), 126.7, 127.7,
128.6, 128.8 (2ÂC), 132.8, 135.9, 136.2, 136.3, 140.4, 156.8,
163.6, 167.4, 207.4. MS (m/z, %): 429 ([M+H]+, 100), 451
([M+Na]+, 7). HRMS formula C27H28N2NaO3, calcd 451.1992, found
451.1993.
4.2.8. TM-1h 1-(4-Bromophenyl)-5-(6-methoxynaphthalen-2-
yl)-1-(5-methylisoxazol-3-ylamino)pentan-3-one
Yield: 67.5%, mp: 188–190 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.17 (3H, s, CH3), 2.76–2.81 (1H, m, ⁄CHCH2), 2.84–2.89
(4H, m, 2ÂCH2), 2.99 (1H, dd, J = 8.5, 16.3 Hz, ⁄CHCH2), 3.85 (3H,
s, OCH3), 4.82 (1H, dd, J = 8.0, 13.9 Hz, ⁄CH), 5.62 (1H, s, O–
C(Me)@CH), 6.65 (1H, d, J = 7.9 Hz, Ar1-H), 7.12 (1H, d, J = 8.4 Hz,
Ar1-H), 7.26–7.30 (4H, m, NH, Ar1-H and 2 Ar1-H), 7.45 (2H, d,
J = 8.2 Hz, Ar2-H), 7.55 (1H, s, Ar1-H), 7.68–7.72 (2H, m, Ar1-H).
13C NMR (75 MHz,CDCl3, ppm) d: 12.0, 28.8, 43.5, 49.3, 52.6, 55.1,
93.7, 105.7, 118.5, 119.8, 125.9, 126.7, 127.7, 128.6(2ÂC), 128.7
128.8, 131.0(2ÂC), 132.8, 136.2, 142.9, 156.8, 163.4, 167.5, 207.1.

H. Wang et al. / Bioorg. Med. Chem. 20 (2012) 2119–2130
2127
4.2.13. TM-1m 5-(6-Methoxynaphthalen-2-yl)-1-(5-
TM-2a~TM-2r
methylisoxazol-3-ylamino)-1-m-tolylpentan-3-one
O
O
Yield: 51.3%, mp: 158–160 °C. 1H NMR (300 MHz, CDCl3, ppm)
d: 2.22 (3H, s, CH3), 2.30 (3H, s, Ar2-CH3), 2.72 (2H, t, J = 7.3 Hz,
CH2), 2.89–2.95 (3H, m, CH2 and ⁄CHCH2), 3.03 (1H, dd, J = 6.8,
A:
Ar2
H3CO
R
O
R
O
S
B:
C:
D:
H3CO
Ar3
N
H
NH2
Ar1
N
H
SO
2NH2
⁄
15.9 Hz, CH2⁄CH), 3.90 (3H, s, OCH3), 4.68–4.72 (1H, m, CH), 4.89
O
R
H3CO
SO2NH2
HN
(1H, d, J = 5.9 Hz, NH), 5.41 (1H, s, O–C(Me)@CH), 7.09 (5H, m,
4Ar2-H and 1Ar1-H), 7.19 (2H, d, J = 8.4 Hz, Ar1-H), 7.46 (1H, s,
Ar1-H), 7.62 (2H, d, J = 8.4 Hz, Ar1-H). 13C NMR (75 MHz, CDCl3,
ppm) d: 12.4, 21.4, 28.3, 45.1, 49.4, 53.9, 55.3, 93.4, 105.7, 119.0,
124.5, 127.3, 127.4, 127.9, 128.2, 128.5, 128.8, 129.0, 129.1,
133.0, 133.9, 137.0, 142.3, 157.1, 158.7, 163.9, 208.4. MS (m/z, %):
429 ([M+H]+, 100), 451 ([M+Na]+, 7). HRMS formula C27H28N2NaO3,
calcd 451.1992, found 451.1993.
4.2.17. TM-2a 4-(5-(6-Methoxynaphthalen-2-yl)-1-(4-
nitrophenyl)-3-oxopentylamino)benzenesulfonamide
Yield: 82.8%, mp: 167.2–169.0 °C. 1H NMR (300 MHz, DMSO-
d6, ppm) d: 2.84–2.95 (5H, m, CH2CH2, CH2⁄CH), 3.01 (1H, dd,
J = 8.8, 16.7 Hz, CH2⁄CH), 3.85 (3H, s, OCH3), 5.12 (1H, dd,
J = 8.1, 12.5 Hz, ⁄CH), 6.60 (2H, d, J = 8.5 Hz, Ar3-H), 6.91 (2H, s,
NH2), 7.05 (1H, d, J = 7.7 Hz, Ar1-H), 7.11 (1H, dd, J = 2.1,
8.9 Hz, Ar1-H), 7.25 (1H, s, Ar1-H), 7.30 (2H, d, J = 8.5 Hz, Ar2-
H), 7.44 (2H, d, J = 8.5 Hz, Ar3-H), 7.56 (1H, s, Ar1-H), 7.64–7.70
(3H, m, Ar1-H), 8.14 (2H, d, J = 8.5 Hz, Ar2-H). 13C NMR
(75 MHz, DMSO-d6, ppm) d: 28.8, 43.4, 49.5, 51.9, 55.2, 105.8,
111.9(2ÂC), 118.6, 123.7, 125.9, 126.8, 127.3, 127.7, 127.9,
128.6, 128.8(2ÂC), 131.2, 132.8, 136.1, 146.6, 150.0, 151.3,
156.8, 206.5. ESI MS (m/z, %): 213 (A, 63), 361 (B, 17), 305 (C,
8), 171 (D, 36), 534 ([M+H]+, 9), 556 ([M+Na]+, 72). HRMS calcd
for C28H27N3NaO6S 556.1518, found [M+Na]+ 556.1507, [M+K]+
572.1240.
4.2.14. TM-1n 1-(4-Butoxyphenyl)-5-(6-methoxynaphthalen-2-
yl)-1-(5-methylisoxazol-3-ylamino)pentan-3-one
Yield: 72.3%, mp: 120–123 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 0.92 (3H, t, J = 7.3 Hz, CH2CH3), 1.37–1.44 (2H, m, CH2CH3),
1.63–1.68 (2H, m, CH2CH2CH3), 2.16 (3H, s, CH3), 2.75–3.01 (6H, m,
COCH2CH2, ⁄CHCH2), 3.85 (3H, s, OCH3), 3.90 (2H, d, J = 6.3 Hz,
OCH2), 4.77 (1H, dd, J = 6.8, 13.9 Hz, ⁄CH), 5.60 (1H, s, O–
C(Me)@CH), 6.50 (1H, d, J = 7.5 Hz, Ar1-H), 6.80 (2H, d, J = 6.3 Hz,
Ar2-H), 7.11 (1H, d, J = 8.3 Hz, Ar1-H), 7.21–7.25 (4H, m, 2Ar1-H,
2Ar2-H), 7.53 (1H, s, NH), 7.69 (2H, d, J = 8.4 Hz, Ar1-H). 13C NMR
(75 MHz, DMSO-d6, ppm) d: 12.0, 13.7, 18.8, 28.8, 30.8, 43.6,
49.7, 52.8, 55.1, 67.0, 93.8, 105.7, 114.0 (2ÂC), 118.5, 125.9,
126.7, 127.5, 127.6 (2ÂC), 128.6, 128.8, 132.7, 135.1, 136.2,
156.8, 157.6, 163.6, 167.4, 207.5. MS (m/z, %): 487 ([M+H]+, 91).
HRMS formula C30H34N2NaO4, calcd 509.2411, found 509.2394.
4.2.18. TM-2b 4-(5-(6-Methoxynaphthalen-2-yl)-1-(3-
nitrophenyl)-3-oxopentylamino)benzenesulfonamide
Yield: 79.2%, mp: 121.2–124.7 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.90–2.99 (5H, m, CH2CH2, CH2⁄CH), 3.09 (1H, dd, J = 8.6,
16.2 Hz, CH2⁄CH), 3.85 (3H, s, OCH3), 5.08 (1H, m, ⁄CH), 6.64 (2H,
d, J = 8.6 Hz, Ar3-H), 6.91 (2H, s, NH2), 7.06–7.13 (2H, m, NH and
Ar1-H), 7.25–7.31 (2H, m, Ar2-H), 7.45 (2H, d, J = 8.6 Hz, Ar3-H),
7.54–7.62 (2H, m, Ar1-H), 7.66–7.71 (2H, m, Ar1-H), 7.88 (1H, d,
J = 7.6 Hz, Ar1-H), 8.05 (1H, d, J = 8.0 Hz, Ar2-H), 8.31 (1H, s, Ar2-
H). 13C NMR (75 MHz, DMSO-d6, ppm) d: 28.6, 43.6, 49.3, 51.4,
55.2, 105.8, 111.6 (2ÂC), 118.4, 119.9 (2ÂC), 125.8, 126.8, 127.2
(2ÂC), 127.6, 128.5, 128.7 (3ÂC), 130.8, 132.7, 134.5, 145.8,
147.5, 150.1, 156.7, 207.0. ESI MS (m/z, %): 213 (A, 54), 361 (B,
23), 305 (C, 9), 171 (D, 38), 534 ([M+H]+,4), 556 ([M+Na]+, 68).
4.2.15. TM-1o 1-(Benzo[d][1,3]dioxol-5-yl)-5-(6-
methoxynaphthalen-2-yl)-1-(5-methylisoxazol-3-
ylamino)pentan-3-one
Yield: 96.3%, mp: 187–189 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.17 (3H, s, CH3), 2.76 (1H, dd, J = 5.4, 15.9 Hz, CH2⁄CH),
2.80–2.86 (4H, m, 2ÂCH2), 2.96 (1H, dd, J = 8.6, 15.7 Hz, CH2⁄CH),
3.85 (3H, s, OCH3), 4.74–4.79 (1H, m, ⁄CH), 5.63 (1H, s, O–
C(Me)@CH), 5.95 (2H, s, OCH2O), 6.53 (1H, d, J = 8.6 Hz, Ar1-H),
6.78–6.80 (2H, m, 2Ar2-H), 6.93 (1H, s, NH), 7.10–7.14 (1H, m,
Ar1-H), 7.25–7.30 (2H, m, Ar1-H and Ar2-H), 7.55 (1H, s, Ar1-H),
7.69–7.72(2H, m, Ar1-H). 13C NMR (75 MHz, DMSO-d6, ppm) d:
12.0, 28.8, 43.6, 53.1, 55.1, 56.1, 93.7, 105.7, 107.9, 112.1, 118.5,
119.8, 126.1, 126.7, 127.7, 128.6, 128.8, 129.5, 132.8, 136.2,
144.7, 146.0, 156.8, 157.5, 167.4, 207.1. MS (m/z, %):459 ([M+H]+,
100), 481 ([M+Na]+, 43). HRMS formula C27H26N2NaO5, calcd
481.1734, found 481.1741.
HRMS calcd for
C
28H27N3NaO6S 556.1518, found [M+Na]+
556.1528, [M+K]+ 572.1289.
4.2.19. TM-2c 4-(1-(3,4-Dichlorophenyl)-5-(6-
methoxynaphthalen-2-yl)-3-oxopentylamino)benzene-
sulfonamide
4.2.16. TM-1p 1-(4-Hydroxyphenyl)-5-(6-methoxynaphthalen-
2-yl)-1-(5-methylisoxazol-3-ylamino)pentan-3-one
Yield: 68.5%, mp: 164.0––166.7 °C. 1H NMR (300 MHz, DMSO-
d6, ppm) d: 3.00 (2H, t, CH2CO, J = 7.1 Hz), 3.12 (2H, t, J = 7.1 Hz,
CH2), 3.29–3.35 (2H, m, J = 6.9 Hz, CH2⁄CH), 3.85 (3H, s, OCH3),
4.96 (1H, dd, J = 7.9, 13.7 Hz, ⁄CH), 6.78–6.83 (2H, m, Ar3-H), 7.05
(1H, s, Ar1-H), 7.13 (2H, d, J = 8.4 Hz, Ar-H), 7.20–7.27 (3H, m, Ar-
H), 7.40 (1H, d, J = 8.2 Hz, Ar1-H), 7.33–7.59 (1H, m, Ar1-H), 7.67
(1H, s, Ar1-H), 7.74 (2H, d, J = 8.6 Hz, Ar3-H). 13C NMR (75 MHz,
DMSO-d6, ppm) d: 28.8, 43.5, 50.1, 51.9, 55.1, 105.8, 111.8 (2ÂC),
111.9, 118.5, 125.6, 126.8, 127.3 (3ÂC), 127.8, 128.8, 129.1,
130.7, 130.5, 131.2, 131.8, 132.6, 136.2, 144.6, 150.1, 156.8,
207.3. ESI MS (m/z, %): 213 (A, 100), 385 (B, 33), 329 (C, 4), 171
(D, 10), 557 ([M+H]+, 68), 579 ([M+Na]+, 4). HRMS calcd for
Yield: 82.2%, mp: 174–176 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.16 (3H, s, CH3), 2.74 (1H, dd, J = 5.4, 15.5 Hz, CH2⁄CH),
2.80–2.86 (4H, m, 2ÂCH2), 2.96 (1H, dd, J = 8.5, 15.7 Hz, CH2⁄CH),
3.85 (3H, s, OCH3), 4.73 (1H, q, J = 6.3 Hz, ⁄CH), 5.60 (1H, s, O–
C(Me)@CH), 6.48 (2H, d, J = 8.4 Hz, Ar1-H), 6.66 (2H, d, J = 8.2 Hz,
Ar2-H), 7.10–7.14 (2H, m, Ar1-H), 7.27 (2H, d, J = 8.6 Hz, Ar2-H),
7.54 (1H, s, NH), 7.70 (2H, d, J = 8.9 Hz, Ar1-H), 9.28 (1H, s, OH).
13C NMR (75 MHz, DMSO-d6, ppm) d: 11.9, 28.7, 43.6, 49.7,
52.8, 55.1, 93.7, 105.7, 114.8 (2ÂC), 118.4, 125.8, 126.5, 126.6,
127.5 (2ÂC), 128.5, 128.7, 132.7, 133.5, 136.2, 156.2, 156.7,
163.6, 167.2, 207.5. MS (m/z, %): 431 ([M+H]+, 67), 453
([M+Na]+, 37). HRMS formula C26H26N2NaO4, calcd 453.1785,
found 453.1770.
C
28H26Cl2N2NaO4S 579.0883, found [M+Na]+ 579.0863, [M+K]+
595.0619.

2128
H. Wang et al. / Bioorg. Med. Chem. 20 (2012) 2119–2130
4.2.20. TM-2e 4-(1-(3-Fluorophenyl)-5-(6-methoxynaphthalen-
2-yl)-3-oxopentylamino)benzenesulfonamide
4.2.24. TM-2j 4-(5-(6-Methoxynaphthalen-2-yl)-1-(3-
methoxyphenyl)-3-oxopentylamino)benzenesulfonamide
Yield: 77.2%, mp: 121.6–124.3 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.84 (1H, dd, J = 4.3, 16.3 Hz CH2⁄CH), 2.88–2.93 (4H, m,
CH2CH2), 3.01 (1H, dd, J = 9.3, 16.3 Hz, CH2⁄CH), 3.70 (3H, s, Ar2-
OCH3), 3.85 (3H, s, OCH3), 4.99 (1H, m, ⁄CH), 6.59 (2H, d,
J = 8.8 Hz, Ar3-H), 6.78 (1H, d, J = 8.8 Hz, Ar2-H), 6.88 (2H, s, NH2),
6.91–6.96 (2H, m, NH and Ar-H), 6.96 (1H, s, Ar1-H), 7.12–7.31
(4H, m, Ar-H), 7.43 (2H, d, J = 8.4 Hz, Ar3-H), 7.56 (1H, s, Ar1-H),
7.66–7.71 (2H, m, Ar1-H). 13C NMR (75 MHz, DMSO-d6, ppm) d:
27.8, 43.5, 50.3, 52.2, 55.1, 60.2, 105.7, 111.3, 116.4, 119.3 (2ÂC),
125.7, 126.2, 126.3, 127.2, 127.6 (2ÂC), 128.2 (2ÂC), 128.6, 128.8,
131.0, 132.3, 133.2, 143.6, 149.3, 157.8, 159.8, 207.1. ESI MS (m/z,
%): 213 (A, 100), 347 (B, 39), 291 (C, 4), 171 (D, 7), 519 ([M+H]+, 63),
541 ([M+Na]+, 18). HRMS calcd for C29H30N2NaO5S 541.1768, found
[M+Na]+ 541.1794, [M+K]+ 557.1583.
Yield: 72.1%, mp: 183.9–186.2 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.73–3.07 (6H, m, CH2CH2COCH2), 3.85 (3H, s, OCH3),
4.99–5.02 (1H, m, ⁄CH), 6.61 (2H, d, J = 8.0 Hz, Ar3-H), 6.90–6.94
(3H, m, NH2 and NH), 7.03 (1H, t, J = 8.0 Hz, Ar2-H), 7.12 (1H, d,
J = 8.8 Hz, Ar2-H), 7.22–7.28 (3H, m, Ar1-H), 7.32 (2H, d,
J = 8.2 Hz, Ar1-H), 7.45 (2H, d, J = 8.0 Hz, Ar3-H), 7.57 (1H, s, Ar1-
H), 7.66–7.72 (2H, m, Ar2-H). 13C NMR (75 MHz, DMSO-d6, ppm)
d: 28.8, 43.4, 49.9, 51.8, 55.1, 105.7, 111.9 (2ÂC), 118.5, 122.6,
125.9, 126.7, 127.3, 127.7, 128.6, 128.8 (2ÂC), 130.3, 130.4,
130.9, 132.8, 136.2, 148.3, 146.4, 150.2, 156.8, 160.7, 206.8. ESI
MS (m/z, %): 213 (A, 61), 351 (B, 18), 295 (C, 17), 171 (D, 12), 507
([M+H]+, 100), 529 ([M+Na]+, 14). HRMS calcd for C28H27FN2NaO4S
528.9173, found [M+Na]+528.9192.
4.2.21. TM-2f 4-(1-(4-Chlorophenyl)-5-(6-methoxynaphthalen-
2-yl)-3-oxopentylamino)benzenesulfonamide
4.2.25. TM-2k 4-(5-(6-Methoxynaphthalen-2-yl)-3-oxo-1-
phenylpentylamino)benzenesulfonamide
Yield: 78.0%, mp: 178.8–181.2 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.84 (1H, dd, J = 4.5, 16.5 Hz, CH2⁄CH), 2.87–2.93 (4H, m,
CH2CH2), 3.01 (1H, dd, J = 8.9, 16.5 Hz, CH2⁄CH), 3.85 (3H, s,
OCH3), 4.96 (1H, dd, J = 8.1,14.2 Hz, ⁄CH), 6.58 (2H, d, J = 8.6 Hz,
Ar3-H), 6.89 (2H, s, NH2), 6.93 (1H, d, J = 8.6 Hz, NH), 7.14 (1H, d,
J = 8.9 Hz, Ar1-H), 7.25–7.38 (6H, m, Ar-H), 7.43 (2H, d, J = 8.9 Hz,
Ar3-H), 7.56 (1H, s, Ar1-H), 7.66–7.71 (2H, m, Ar1-H). 13C NMR
(75 MHz, DMSO-d6, ppm) d: 28.8, 43.5, 49.9, 51.7, 55.1, 105.7,
111.8 (2ÂC), 118.5, 125.8, 126.7, 127.2 (3ÂC), 127.6 (2ÂC), 128.4,
128.5 (2ÂC), 128.8, 130.8, 131.2, 132.7, 136.1, 142.1, 150.2,
156.8, 206.8. ESI MS (m/z, %): 213 (A, 100), 351 (B, 43), 295 (C,
5), 171 (D, 12), 523 ([M+H]+, 23), 545 ([M+Na]+, 5). HRMS calcd
for C28H27ClN2NaO4S 545.1272, found [M+Na]+ 545.1260, [M+K]+
561.1031.
Yield: 89.1%, mp: 181.5–183.8 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.83 (1H, dd, J = 4.4, 16.3 Hz, CH2⁄CH), 2.88–2.93 (4H, m,
CH2CH2), 3.02 (1H, dd, J = 9.1, 16.2 Hz, CH2⁄CH), 3.85 (3H, s,
OCH3), 4.95 (1H, dd, J = 8.1, 12.4 Hz, ⁄CH), 6.58 (2H, d, J = 8.6 Hz,
Ar3-H), 6.88 (2H, s, NH2), 6.93 (1H, d, J = 8.5 Hz, NH), 7.20 (1H, d,
J = 7.1 Hz, Ar-H), 7.29 (1H, d, J = 7.1 Hz, Ar-H), 7.26–7.31 (4H, m,
Ar-H), 7.36–7.44 (4H, m, Ar-H), 7.56 (1H, s, Ar1-H), 7.66–7.71
(2H, m, Ar3-H). 13C NMR (75 MHz, DMSO-d6, ppm) d: 28.8, 43.5,
50.2, 52.3, 55.1, 105.7, 111.8 (2ÂC), 118.5, 125.9, 126.4, 126.7,
126.9 (2ÂC), 127.2 (2ÂC), 127.7, 128.5, 128.6, 128.8 (2ÂC), 130.6,
132.8, 136.2, 143.1, 150.4, 156.8, 207.0. ESI MS (m/z, %): 213 (A,
100), 317 (B, 30), 261 (C, 7), 171 (D, 7), 489 ([M+H]+, 46), 511
([M+Na]+, 17). HRMS calcd for C28H28N2NaO4S 511.1667, found
[M+Na]+ 511.1745, [M+K]+ 527.1414.
4.2.22. TM-2g 4-(1-(3-Chlorophenyl)-5-(6-methoxynaphthalen-
2-yl)-3-oxopentylamino)benzenesulfonamide
4.2.26. TM-2m 4-(5-(6-Methoxynaphthalen-2-yl)-3-oxo-1-m-
tolylpentylamino)benzenesulfonamide
Yield: 81.8%, mp: 127.9–130.1 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.88–2.96 (5H, m, CH2CH2CO CH2⁄CH), 3.03 (1H, dd, J = 9.1,
16.5 Hz, CH2⁄CH), 3.85 (3H, s, OCH3), 4.99 (1H, dd, ⁄CH, J = 8.4,
12.7 Hz), 6.61 (2H, d, J = 8.7 Hz, Ar3-H), 6.90 (2H, s, NH2), 6.93
(1H, d, J = 8.7 Hz, NH), 7.09 (1H, d, J = 7.3 Hz, Ar-H), 7.25–7.35
(5H, m, Ar-H), 7.43–7.46 (3H, m, Ar-H), 7.57 (1H, s, Ar1-H), 7.66–
7.72 (2H, m, Ar3-H). 13C NMR (75 MHz, DMSO-d6, ppm) d: 28.8,
43.4, 49.9, 51.8, 55.1, 105.7, 111.8 (2ÂC), 118.5, 125.3, 125.9,
126.4, 126.7, 127.0, 127.3, 127.6 (2ÂC), 128.6, 128.8, 130.3,
130.9, 132.7, 133.2, 136.2, 145.9, 150.1, 156.8, 206.8. ESI MS (m/
z, %): 213 (A, 78), 351 (B, 18), 295 (C, 9), 171 (D, 6), 523 ([M+H]+,
100), 545 ([M+Na]+, 14). HRMS calcd for C28H27ClN2NaO4S
545.1272, found [M+Na]+ 545.1286, [M+K]+ 561.1022.
Yield: 77.7%, mp: 139.8–142.9 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.25 (3H, s, CH3), 2.78 (1H, dd, J = 4.2, 16.3 Hz, CH2⁄⁄CH),
2.82–2.89 (4H, m, CH2CH2), 3.00 (1H, dd, J = 9.2, ⁄16.3 Hz CH2⁄CH),
3.85 (3H, s, OCH3), 4.90 (1H, dd, J = 8.2, 12.6 Hz, CH), 6.58 (2H, d,
J = 8.6 Hz, Ar3-H), 6.89 (2H, s, NH2), 6.93 (1H, d, J = 8.5 Hz, NH),
7.02 (1H, s, Ar2-H), 7.10–7.19 (4H, m, Ar-H), 7.29 (2H, d,
J = 8.5 Hz, Ar1-H), 7.43 (2H, d, J = 8.5 Hz, Ar3-H), 7.56 (1H, s, Ar1-
H), 7.66–7.71 (2H, m, Ar1-H). 13C NMR (75 MHz, DMSO-d6, ppm)
d: 21.1, 28.8, 43.5, 50.3, 52.3, 55.1, 105.7, 111.7 (2ÂC), 118.5,
123.5, 125.8, 126.7, 126.9, 127.2, 127.6 (2ÂC), 128.3 (2ÂC), 128.5,
128.8, 130.5, 132.7, 133.2, 137.5, 143.1, 150.4, 156.8, 207.0. ESI MS
(m/z, %): 213 (A, 100), 331 (B, 48), 275 (C, 4), 171 (D, 11), 503
([M+H]+, 36), 525 ([M+Na]+, 8). HRMS calcd for C29H30N2NaO4S
525.1818, found [M+Na]+ 525.1804, [M+K]+ 541.1527.
4.2.23. TM-2h 4-(1-(4-Bromophenyl)-5-(6-methoxynaphthalen-
2-yl)-3-oxopentylamino)benzenesulfonamide
Yield: 97.5%, mp: 170.4–172.6 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.84 (1H, dd, J = 4.5, 16.5 Hz, CH2⁄CH), 2.88–2.95 (4H, m,
CH2CH2), 3.01 (1H, dd, J = 8.8, 16.4 Hz CH2⁄⁄CH), 3.85 (3H, s,
OCH3), 4.95 (1H, dd, J = 7.8, 12.8 Hz, ⁄CH), 6.57 (2H, d, J = 8.4 Hz,
Ar3-H), 6.89 (2H, s, NH2), 6.93 (1H, d, J = 8.7 Hz, NH), 7.12 (1H, d,
J = 8.7 Hz, Ar1-H), 7.25–7.32 (3H, m, Ar1-H), 7.35 (1H, s, Ar1-H),
7.43 (2H, d, J = 8.8 Hz, Ar3-H), 7.47 (2H, d, J = 8.4 Hz, Ar2-H), 7.56
(1H, s, Ar1-H), 7.66–7.71 (2H, m, Ar2-H). 13C NMR (75 MHz,
DMSO-d6, ppm) d: 28.7, 43.5), 49.8, 51.7, 55.1, 105.8, 111.8
(2ÂC), 118.5, 119.9, 125.8, 126.7, 127.2 (2ÂC), 127.6, 128.5, 128.7
(3ÂC), 130.8, 131.2 (2ÂC), 132.7, 136.1, 142.5, 150.1, 156.8, 206.5.
ESI MS (m/z, %): 213 (A, 100), 395 (B, 30), 341 (C, 2), 171 (D, 12),
567 ([M+H]+, 12), 589 ([M+Na]+, 8). HRMS calcd for
4.2.27. TM-2n 4-(1-(4-Butoxyphenyl)-5-(6-methoxynaphthalen-
2-yl)-3-oxopentylamino)benzenesulfonamide
Yield: 80.4%, mp: 173.5–175.6 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 0.90 (3H, t, J = 7.1 Hz, CH3), 1.36–1.43 (2H, m, CH2CH3),
1.62–1.67 (2H, m, CH2CH2CH3), 2.76–3.03 (6H, m, CH2CH2COCH2),
3.85 (3H, s, OCH3), 3.87–3.90 (2H, m, Ar2-OCH2), 4.88–4.91 (1H, m,
⁄CH), 6.59 (2H, d, J = 8.1 Hz, Ar3-H), 6.80–6.86 (3H, m, Ar-H), 6.89
(2H, s, NH2), 7.12 (1H, d, J = 8.7 Hz, NH), 7.25–7.28 (4H, m, Ar-H),
7.44 (2H, d, J = 8.2 Hz, Ar3-H), 7.55 (1H, s, Ar1-H), 7.66–7.71 (2H,
m, Ar1-H). 13C NMR (75 MHz, DMSO-d6, ppm) d: 13.7, 18.8, 28.8,
30.8, 43.6, 50.4, 51.8, 55.1, 67.0, 105.7, 111.8(2ÂC), 114.3, 118.5,
125.9, 126.7, 127.2, 127.6(2ÂC), 127.7(2ÂC), 128.6, 128.8, 130.5,
132.8, 134.6, 136.2, 150.4, 156.8, 157.7, 207.2. ESI MS (m/z, %):
213 (A, 100), 389 (B, 23), 583 ([M+Na]+, 8). HRMS calcd for
C
28H27BrN2NaO4S 589.0767, found [M+Na]+ 589.0745, [M+K]+
605.0556.

H. Wang et al. / Bioorg. Med. Chem. 20 (2012) 2119–2130
2129
C32H36N2NaO5S 583.2237, found [M+Na]+ 583.2213, [M+K]+
599.1937.
127.7, 128.6, 128.8, 130.9, 132.8, 136.2, 142.1, 150.3, 154.9,
156.8, 206.9. ESI MS (m/z, %): 478 ([M+H]+, 100), 501 ([M+Na]+,
28). HRMS calcd for C26H26N2NaO5S 501.1455, found [M+Na]+
501.1438, [M+K]+ 517.1197.
4.2.28. TM-2o 4-(1-(Benzo[d][1,3]dioxol-5-yl)-5-(6-
methoxynaphthalen-2-yl)-3-oxopentylamino)benzene-
sulfonamide
4.3. Biology
Yield: 78.2%, mp: 168.8–169.8 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.81 (1H, dd, J = 4.7, 16.1 Hz, CH2⁄CH), 2.83–3.02 (5H, m,
CH2CH2COCH2), 3.85 (3H, s, OCH3), 4.87–4.90 (1H, m, ⁄CH), 5.95
(2H, s, OCH2O), 6.60 (2H, d, J = 8.7 Hz, Ar3-H), 6.78–6.88 (3H, m,
Ar-H), 6.90 (2H, s, NH2), 6.96 (1H, s, Ar2-H), 7.12 (1H, d,
J = 8.9 Hz, Ar-H), 7.25–7.30 (2H, m, Ar-H), 7.44 (2H, d, J = 8.6 Hz,
Ar3-H), 7.56 (1H, s, Ar1-H), 7.66–7.71 (2H, m, Ar1-H). 13C NMR
(75 MHz, DMSO-d6, ppm) d: 28.8, 43.5, 50.4, 52.2, 55.1, 100.9,
105.8, 106.8, 108.1, 111.9(2ÂC), 118.5, 119.7, 125.9, 126.7,
127.2(2ÂC), 127.7, 128.6, 128.8, 130.7, 132.8, 136.2, 137.1, 146.1,
147.4, 150.4, 156.8, 207.1. ESI MS (m/z, %): 213 (A, 3), 215 (A,
98), 361 (B, 22), 171 (D, 38), 555 ([M+Na]+, 68). HRMS calcd for
C29H28N2NaO6S 555.1560, found [M+Na]+ 555.1551, [M+K]+
571.1297.
4.3.1. The determination of
-Glucosidase activity was determined in a 100
a
-glucosidase inhibition21,22,24
a
l
L reaction
mixer containing optimal rat-
a-glucosidase (extracted from the
rat small intestine), 67 mmol LÀ1 pH 6.8 sodium phosphate buffer
and different samples. Blank control (without enzyme and
samples) or negative control (without sample) was set as above.
After incubation at 37 °C for 10 min, 0.1 mol LÀ1 maltose was
added and incubated for another 10 min at room temperature.
The reaction was stopped with 200
lL of glucose and the OD values
at 490 nm recorded. The inhibition rate was calculated according to
the following equation: I% = [1À(ODSampleÀODBlank)/(ODNegative
À
ODBlank)] Â 100%. Based on the inhibition value, IC50 was calculated
using 4 Parameter Logistic Model in Xlfit.
4.2.29. TM-2p 4-(1-(4-Hydroxyphenyl)-5-(6-
methoxynaphthalen-2-yl)-3-
4.3.2. Inspection and test of PPAR activation21,22,24,25
HepG2 cells were cultured in low glucose DMEM supplement
with 100 U mLÀ1 streptomycin and penicillin. One day prior to
transfection, the cells were plated in 96-well plates with
1.5 Â 104 cells per well. When the cells grew at confluence of
70%, plasmid pPPRE-Luc with firefly luciferase reporter gene and
the control plasmid phRL-TK with renilla luciferase reporter gene
were transfected into the cells. Twenty four hours after the trans-
fection, the medium was replaced with fresh medium containing
either different samples, rosiglitazone (positive control) or without
sample (negative control). The cells without transfection were
used as blank control. After a further 24 h incubation, the expres-
sion of luciferases was measured with Dual-Luciferase Reporter
Gene Assay Kit (Promega). The sample activation time (T%) was cal-
culated using the following equation: T = [(L1 SampleÀL1 Blank)/(L1
NegativeÀL1 Blank)]/[(L2 SampleÀL2 Blank)/(L2 NegativeÀL2 Blank)] Â 100%.
Where, L1 represents the values of firefly luciferase and L2 the val-
ues of Renilla luciferase.
oxopentylamino)benzenesulfonamide
Yield: 87.3%, mp: 182.4–184.0 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.75 (1H, dd, J = 4.7, 15.9 Hz, CH2⁄CH), 2.86–2.91 (4H, m,
CH2CH2), 3.01 (1H, dd, J = 8.9, 16.1 Hz, CH2⁄CH), 3.85 (3H, s,
OCH3), 4.95 (1H, dd, J = 7.9, 12.8 Hz, *CH), 6.57 (2H, d, J = 8.7 Hz,
Ar2-H), 6.66 (2H, d, J = 8.4 Hz, Ar3-H), 6.73 (1H, d, J = 8.7 Hz, NH),
6.87 (2H, s, NH2), 7.12–7.17 (3H, m, Ar1-H), 7.25–7.26 (2H, m,
Ar1-H), 7.43 (2H, d, J = 8.6 Hz, Ar2-H), 7.55 (1H, s, Ar1-H), 7.66–
7.69 (2H, m, Ar3-H), 9.28 (1H, s, OH). 13C NMR (75 MHz, DMSO-
d6, ppm) d: 28.8, 43.6, 50.4, 51.9, 55.1, 105.7, 111.8 (2ÂC), 115.2
(2ÂC), 118.5, 125.8, 126.7, 127.2, 127.5 (2ÂC), 127.7 (2ÂC),
128.6, 128.8, 130.4, 132.8, 133.0, 136.2, 150.5, 156.3, 156.8,
207.3. ESI MS (m/z, %): 213 (A, 91), 333 (B, 36), 277 (C, 3), 171
(D, 100), 527 ([M+Na]+, 10). HRMS calcd for C28H28N2NaO5S
527.1611, found [M+Na]+ 527.1610, [M+K]+ 543.1347.
4.2.30. TM-2q 4-(1,5-Bis(6-methoxynaphthalen-2-yl)-3-
oxopentylamino)benzenesulfonamide
Yield: 72.6%, mp: 171.5–173.0 °C. 1H NMR (300 MHz, DMSO-d6,
ppm) d: 2.83–2.94 (4H, m, CH2CH2), 3.07–3.16 (2H, m, *CHCH2),
3.85 (6H, s, 2ÂOCH3), 5.05–5.08 (1H, m, *CH), 6.64 (2H, d,
J = 8.3 Hz, Ar3-H), 6.89 (2H, s, NH2), 7.02 (1H, d, J = 8.5 Hz, NH),
7.10–7.15 (2H, m, Ar-H), 7.27 (2H, d, J = 8.6 Hz, Ar-H), 7.43 (2H,
d, J = 8.3 Hz, Ar3-H), 7.48–7.51 (2H, m, Ar-H), 7.62–7.69 (2H, m,
Ar-H), 7.72–7.76 (2H, m, Ar-H), 7.80 (2H, s, Ar-H). 13C NMR
(75 MHz, DMSO-d6, ppm) d: 28.8, 43.7, 50.1, 52.6, 55.1, 55.2,
105.8, 105.9, 111.8(2ÂC), 118.5, 118.7, 124.9, 125.2, 125.8, 126.7,
127.2(2ÂC), 127.6(2ÂC), 128.3, 128.6, 128.8, 129.2, 130.6, 132.8,
133.5, 136.2, 138.1, 150.5, 156.8, 157.2, 207.1. ESI MS (m/z, %):
213 (A, 100), 397 (B, 12), 171 (D, 20), 591 ([M+Na]+, 41). HRMS
Acknowledgment
This research work was supported in part by a grant (No. CSTC,
2011AB5001) from the scientific and technological project in
Chongqing, China.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2012.01.028. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
calcd for
C
33H32N2NaO5S 591.1924, found [M+Na]+591.1902,
[M+K]+ 607.1631.
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