Synthesis of novel 1-substituted triazole linked 1,2-benzothiazine 1,1-dioxido propenone derivatives as potent anti-inflammatory agents and inhibitors of monocyte-to-macrophage differentiation

Article abstract of DOI:10.1039/c5md00171d

A series of novel 1-substituted-triazole linked 1,2-benzothiazine 1,1-dioxido propenone derivatives 8a-s & 12a-l were prepared from 1-substituted 1,2,3-triazol-4-aldehydes 6 & 11 with N-methyl-3-acetyl-4-hydroxybenzothiazine-1,1-dioxide 7 by condensation.

Full text of DOI:10.1039/c5md00171d

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CONCISE ARTICLE
Synthesis of novel 1-substituted triazole linked
1,2-benzothiazine 1,1-dioxido propenone
derivatives as potent anti-inflammatory agents
and inhibitors of monocyte-to-macrophage
differentiation†
Cite this: DOI: 10.1039/c5md00171d
Malla Reddy Gannarapu,ab Sathish Babu Vasamsetti,ac Nagender Punna,ab
ac
ab
*
*
Srigiridhar Kotamraju
and Narsaiah Banda
A series of novel 1-substituted-triazole linked 1,2-benzothiazine 1,1-dioxido propenone derivatives 8a–s &
12a–l were prepared from 1-substituted 1,2,3-triazol-4-aldehydes 6 & 11 with N-methyl-3-acetyl-4-
hydroxybenzothiazine-1,1-dioxide 7 by condensation. Final compounds 8 and 12 were evaluated for their
anti-inflammatory activity and ability to inhibit monocyte-to-macrophage transformation, a process pivotal
during the development and progression of atherosclerosis. Among all the compounds, 12e, 12g, 12i, 12j,
12k and 12l showed impressive anti-inflammatory activity against TNF-α, IL-1β and MCP-1 cytokines
released in a dose-dependent manner. The most promising compounds 12g, 12i and 12l further signifi-
cantly inhibited phorbol 12-myristate 13-acetate (PMA)-induced MMP-9 activity and PMA-induced
monocyte-to-macrophage differentiation.
Received 22nd April 2015,
Accepted 11th June 2015
DOI: 10.1039/c5md00171d
www.rsc.org/medchemcomm
implicated in impaired neurogenesis, atherosclerosis, rheu-
Introduction
matoid arthritis (RA), Alzheimer's disease etc.4 Tumor necro-
Inflammation is a complex physiological response of multi-
cellular organisms to various infections and tissue injuries as
part of the defense mechanism of a host.1 Under normal con-
ditions, this process is auto-regulated by limiting the expres-
sion levels of pro-inflammatory cytokines. However, in meta-
bolic disorders like diabetes mellitus, obesity, hypertension,
aging etc., immune cells become hypersensitive and trigger
the continuous production of diverse range of inflammatory
mediators even in the absence of infections and tissue inju-
ries.2 This unrestrained generation of low-grade chronic
inflammation is the main cause and consequence of manifes-
tation of diverse clinical diseases.3 Interleukin (IL)-1β is a
multi-potent, inflammatory cytokine of many acute, chronic
non-infectious diseases and its prolonged release is
sis factor (TNF)-α has both immune-regulatory and pro-
inflammatory functions as seen in several auto-immune disor-
ders including systemic lupus erythematosus.5 Monocyte
chemoattractant protein-1 (MCP-1) is an important chemo-
kine which recruits circulating leukocytes into the sites of
inflammation, a process known to be enhanced in various
disorders like RA, insulin-resistance, diabetes, atherosclerosis
etc.6 Substantial evidence implicates that macrophages act as
predominant sources of inflammation responsible for all the
aforementioned disorders.7 Particularly in vascular disorders,
macrophages ingest lipid moieties that have accrued in the
surroundings of the vessel wall by expressing scavenger recep-
tors elaborating accumulation of fatty streaks which consti-
tute the bulky atherosclerotic lesion.8 Moreover, matrix meta-
lloproteinases (MMPs) secreted by macrophages contribute to
disease progression by promoting atherosclerotic plaque rup-
ture.9,10 All these events lead to the narrowing of the lumen
of the artery which ultimately leads to ischemia/stroke and
myocardial infarction. Monocyte-to-macrophage differentia-
tion plays a predominant role in the development of several
vascular disorders including atherosclerosis by eliciting a
plethora of inflammation-promoting events11 and restraining
monocyte recruitment into the aortic wall attenuates the risk
of atherosclerosis.12 Hence, targeting bio-active compounds
a Academy of Scientific and Innovative Research, CSIR-Indian Institute of
Chemical Technology, Tarnaka, Hyderabad-500607, India.
E-mail: giridhar@iict.res.in, narsaiah@iict.res.in
b Fluoroorganic Division, CSIR-Indian Institute of Chemical Technology, Tarnaka,
Hyderabad-500607, India
c Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology,
Tarnaka, Hyderabad-500607, India
† Electronic supplementary information (ESI) available: Experimental
procedures, physicochemical properties and characterization data for all
synthesized compounds are provided. See DOI: 10.1039/c5md00171d
This journal is © The Royal Society of Chemistry 2015
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responsible for inducing inflammation and inflammation-
dependent signaling cascades are important strategies to
combat those disease pathologies wherein inflammation plays
a key role.
compounds 12e, 12g, 12i, 12j, 12k and 12l were selected for
further assessment of their dose-dependent inhibitory effects
against PMA-induced TNF-α, IL-1β and MCP-1 release, and
their effects on MMP-9 activity were also investigated. Finally,
compounds 12g, 12i and 12l imposed significant inhibition
on PMA-induced monocyte-to-macrophage differentiation
along with inhibition of MMP-9 activity, thereby suggesting
their potential to serve not only as new anti-inflammatory
agents, but also as novel molecules affecting monocyte-to-
macrophage differentiation.
Benzothiazine derivatives are known to possess a versatile
range of biological activities.13–17 Among these, 1,2-benzo-
thiazine-3-carboxamide-1,1-dioxide derivatives, such as
piroxicam (1), ampiroxicam (2) and meloxicam (3) which
belong to the oxicam class of NSAIDs, are promising anti-
inflammatory agents with proven therapeutic potential for
various inflammatory and immune disorders (Fig. 1). The
reported candidates disrupt the biosynthesis of prostaglan-
dins and thromboxanes by inhibiting the enzyme cyclooxy-
genase (COX). Recent findings describe the role of 1,2-benzo-
Results and discussion
Chemistry
N-Methyl-3-acetyl-4-hydroxybenzothiazine-1,1-dioxide
7 was
thiazine
1,1-dioxide
derivatives
as
excellent
anti-
microbial,14,15 anti-oxidant,13 anti-hepatitis C virus (HCV)16
and 11β-HSD1 inhibitors.17 During the past few decades, syn-
thetic modifications of 1,2-benzothiazine 1,1-dioxides have
been intensively studied to enhance their bioactivity and
develop better anti-inflammatory candidates.18,19
prepared in three steps starting from the sodium salt of sac-
charin.13,20 In order to construct a 1,2,3-triazole scaffold,
propargyl alcohol 4 was independently reacted with alkyl
azide and alkyl amide azide 9 (which were, in turn, synthe-
sized from the coupling of amines, chloroacetyl chloride and
sodium azide in one pot) in t-butanol in the presence of
CuIJOAc)2 produced (1-alkyl substituted-1H-1,2,3-triazol-4-yl)-
methanol 5 and 2-IJ4-IJhydroxymethyl)-1H-1,2,3-triazol-1-yl)-N-
substituted acetamide 10, respectively. Alcohols 5 and 10
were further oxidized to aldehydes 6 and 11 by using the
Jones reagent. Aldehydes 6 and 11 were reacted with com-
pound 7 in ethanol under reflux conditions and propenone
derivatives 8 and 12 were obtained, respectively. The details
of the reactions are outlined in Schemes 1 and 2. The purity
of all the products was determined by HPLC and pure com-
pounds (≥95%) were used for biological experiments.
More recently, we have reported 1,2-benzothiazine 1,1-
dioxide-3-ethanone oxime N-aryl acetamide ether derivatives
as potent anti-inflammatory agents and inhibitors of
monocyte-to-macrophage differentiation, where we have
explored the 3rd position of 1,2-benzothiazine 1,1-dioxide
and prepared acetamide derivatives by using an oxime ether
link.20 In continuation of our efforts to identify better anti-
inflammatory agents, the present work aimed to functionalize
the 3rd position of 1,2-benzothiazine 1,1-dioxide with a 1,2,3-
triazole moiety (Fig. 2).
Thus, we have synthesized 1,2-benzothiazine 1,1-dioxide
derivatives 8a–s and 12a–l, evaluated them against TNF-α,
IL-1β and MCP-1 production in phorbol 12-myristate 13-ace-
tate (PMA)-stimulated monocytes and discussed their struc-
ture versus activity relationship. The most promising
Biological activity
Inhibition of TNF-α, IL-1β and MCP-1 production by 1,2-
benzothiazine 1,1-dioxide derivatives in PMA-stimulated
THP-1 monocytes. All the final compounds IJ1,2-benzothiazine
1,1-dioxide derivatives 8a–s and 12a–l) were screened for their
Fig. 1 Structures of known 1,2-benzothiazine based NSAIDs.
Fig. 2 Our previous and present modifications on the benzothiazine
scaffold.
Scheme 1 Preparation of 1-alkyl/aryl-substituted triazole linked 1,2-
benzothiazine 1,1-dioxido propenone derivatives (8a–s).
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R = –IJCH2)9–CH3) and a perfluoro alkyl chain (8o, R =
–IJCH2)2–C6F13) showed cytotoxicity at 10 μM, whereas the
compound with an eight-carbon aliphatic chain (8b, R =
–IJCH2)7CH3) possessed a moderate inhibitory effect on IL-1β
and MCP-1 levels without affecting cell viability (Table 1).
The remaining compounds however did not show significant
effects on the viability of cells even at a 20 μM concentration.
This clearly indicates that the anti-inflammatory activities of
these compounds are not due to their cytotoxic effect on
cells.
Among the 1-alkyl/aryl-substituted triazole linked benzo-
thiazine derivatives 8a–s, only the compound having a 2-Cl-5-
NO2 phenyl group on the triazole ring (8l) suppressed the sec-
retion of all the three pro-inflammatory cytokines with more
than 50% inhibition. Among the substituted N-alkyl/aryl-1-
acetamide-triazole linked benzothiazine derivatives 12a–l,
several compounds exhibited more than 50% inhibition of all
the three pro-inflammatory cytokines. Among these, com-
pounds having trifluoromethyl substitutions i.e., 12e IJ4-CF3),
12k IJ3-CF3, 4-Cl) and 12l IJ3-CF3), were found to potently
inhibit cytokine expressions (more than 90%), whereas three
Scheme
2 Preparation of substituted N-alkyl/aryl-1-acetamide-
triazole linked 1,2-benzothiazine 1,1-dioxido propenone derivatives
(12a–l).
anti-inflammatory activity in PMA-stimulated THP-1 mono-
cytes by measuring TNF-α, IL-1β and MCP-1 levels with refer-
ence to piroxicam and celecoxib (Table 1). Among the tested
compounds, compounds having an aliphatic alkyl chain (8a,
Table 1 Secretion inhibition efficacy of the benzothiazine derivatives (8a–s & 12a–l) for TNF-α, IL-1β and MCP-1a
% of inhibition
Cell
viabilityc
(% control)
Entry
Compounds
TNF-αa secretion
IL-1βa secretion
MCP-1a secretion
1
2
3
4
5
6
7
8
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8p
8q
8r
8s
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
Celecoxibb
Piroxicamb
2.9 1.2
24.0 3.4
NA
NA
NA
NA
NA
NA
NA
64.7 5.4
56.9 7.8
50.2 6.5
17.7 2.4
53.9 4.1
36.5 3.7
43.9 3.5
16.3 6.4
37.3 8.6
23.9 4.5
61.8 2.8
47.7 3.8
45.9 4.3
NA
42.6 2.9
25.6 4.7
40.2 4.5
49.3 3.2
42.4 4.5
47.7 5.3
63.8 4.5
91.1 3.2
49.8 5.8
80.4 6.2
46.3 4.6
74.9 7.2
69.5 6.5
93.6 4.8
83.6 5.6
31.1 3.2
21.8 6.2
40.9 6.5
31.9 3.1
45.2 5.3
12.7 2.9
58.9 6.8
31.5 2.6
58.9 5.6
NA
5.4 1.2
NA
67.1 4.5
29.6 3.2
16.2 3.9
NA
92.32 1.20
94.20 3.36
94.32 1.08
96.62 2.42
94.40 1.92
92.98 2.08
95.32 1.54
94.26 2.60
96.03 1.52
93.80 3.24
94.26 2.06
96.20 2.30
94.40 1.54
93.05 2.16
94.15 1.29
92.60 2.20
96.06 1.15
96.23 1.02
92.5 2.16
95.18 1.19
93.56 2.02
95.08 1.19
94.45 2.23
98.23 1.45
95.62 2.08
97.03 1.25
96.45 2.22
94.28 2.04
96.20 3.03
—
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
NA
52.5 6.3
11.2 6.5
13.7 2.9
48.3 3.4
NA
NA
30.7 5.3
NA
NA
NA
33.3 4.5
73.4 6.5
39.7 2.8
59.8 3.8
94.2 4.5
62.9 5.6
91.1 4.5
31.3 3.2
84.7 6.2
70.7 5.6
93.2 2.8
87.6 4.8
37.4 8.3
25.8 4.5
76.7 6.2
41.4 4.5
56.1 5.5
65.4 3.2
81.1 6.8
64.8 8.2
84.0 4.4
41.3 2.8
87.2 5.3
48.2 4.8
88.4 3.6
85.1 5.3
20.1 3.2
11.4 2.3
—
a
THP-1 monocytes were pre-treated with 10 μM concentration of the above mentioned benzothiazine derivatives (8a–s & 12a–l) for 2 h and
stimulated with 100 nM PMA to induce inflammation for a period of 48 h. At the end of the treatment, conditioned media were collected and
b
TNF-α, IL-1β and MCP-1 levels were measured by ELISA. Celecoxib and piroxicam were used as positive control; NA denotes no inhibition at
c
the observed concentration. THP-1 cell viability with synthesized compounds (20 μM).
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more compounds 12g (3-Cl), 12i IJ4-CH3) and 12j (3-F) showed
60–80% inhibition of all the three pro-inflammatory cyto-
kines. Overall, the screening results indicated that
substituted N-alkyl/aryl-1-acetamide-triazole linked benzo-
thiazine derivatives (12a–l) showed better inhibition of pro-
inflammatory cytokine production than 1-alkyl/aryl-
substituted triazole linked benzothiazine derivatives (8a–s) in
PMA-stimulated monocytes.
Dose-dependent inhibitory effect of promising compounds
on PMA-induced inflammation. Based on the screening
results, the most promising compounds 12e, 12g, 12i, 12j,
12k and 12l were selected for further assessment of their
dose-dependent inhibitory effects on inflammation. For this,
monocytes were pre-treated with the compounds (2.5–20 μM)
for 2 h followed by incubation with PMA (100 nM) for 48 h
and subsequently, TNF-α, IL-1β and MCP-1 levels in condi-
tioned media were analyzed by ELISA. All the promising com-
pounds dose-dependently inhibited PMA-induced TNF-α, IL-
1β and MCP-1 production (Fig. 3A, B and C), thereby
confirming the anti-inflammatory potential of these
compounds.
Effect of promising compounds on PMA-induced COX-2
mRNA expression. Besides TNF-α, IL-1β and MCP-1 as evalu-
ated above, COX-2 has been demonstrated as an inflamma-
tory mediator in various health disorders.21 As compounds
12e, 12g, 12i, 12j, 12k and 12l significantly inhibited the
levels of TNF-α, IL-1β and MCP-1, this triggered our interest
to study the effect of these compounds on COX-2 expression.
In this context, we measured COX-2 mRNA levels with PMA
treatment in the presence or absence of the compounds
using RT-PCR after 48 h.
All these compounds significantly inhibited the transcript
levels of PMA-induced COX-2 (Fig. 3D). These results suggest
that promising compounds with inhibitory effects on pro-
inflammatory cytokine profiles also affect COX-2 signaling at
the transcription level.
Fig. 3 Compounds 12e, 12g, 12i, 12j, 12k and 12l inhibit PMA-induced
TNF-α, IL-1β and MCP-1 release in a dose-dependent manner. THP-1
monocytes were pretreated with indicated concentrations of com-
pounds 12e, 12g, 12i, 12j, 12k and 12l for 2 h, followed by stimulation
with PMA (100 nM) for 48 h and the (A) TNF-α (B) IL-1β and (C) MCP-1
levels in the conditioned medium were analyzed using ELISA. The
results were expressed as the percentage of inhibition compared to
that of the PMA control. (D) Monocytes were pretreated with 10 μM
concentration of the compounds for 2 h, followed by stimulation with
PMA (100 nM) for 48 h and COX-2 mRNA levels were analyzed using
Effect of promising compounds on PMA-induced
monocyte-to-macrophage differentiation. Macrophages are
inflammatory phenotypes of monocytes, known to play a key
role in the development and progression of several vascular
disorders.8 It is well known that PMA stimulation differenti-
ates monocytes into macrophages as reflected by increased
cell adherence and an increase in cell size along with an
increased number of cellular organelles including mitochon-
dria.22 In tune with this, we next examined the effect of
promising acetamide-substituted triazole linked benzo-
thiazine derivatives on the PMA-induced monocyte-to-
macrophage differentiation process by treating monocytes
with compounds 12e, 12g, 12i, 12j, 12k and 12l (5–20 μM) for
2 h followed by stimulation with PMA (100 nM) for 48 h.
From the phase contrast images, it was observed that com-
pounds 12g, 12i and 12l at 15 μM concentration significantly
inhibited PMA-induced cell adherence (Fig. 4A). However,
12e, 12j and 12k failed to inhibit PMA-induced cell adherence
even at 20 μM concentration (data not shown). Also, 12g, 12i
and 12l significantly inhibited the PMA-induced increase in
RT-PCR. Each bar represents the mean
SD of three independent
experiments. Statistical significance relative to the PMA groups is indi-
cated by * (p < 0.05) and ** (p < 0.01).
cell size as reflected by a decrease in the mitochondrial con-
tent (Fig. 4B). In addition, these three compounds signifi-
cantly inhibited the transcript levels of PMA-induced LOX-1
and CD-36 scavenger receptors (markers of monocyte differ-
entiation) by RT-PCR (Fig. 4C). These results were further
supported by lysotracker staining as shown in Fig. 4D. It
is known that macrophages express significantly higher
levels of lysosomal enzymes.22 Treatment of monocytes with
these three compounds greatly inhibited PMA-induced
lysosomal activity (Fig. 4D), thereby indicating that these
compounds inhibit PMA-mediated monocyte-to-macrophage
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Fig.
5
Compounds 12g, 12i and 12l inhibit PMA-induced MMP-9
gelatinase activity and monocyte/macrophage invasion. THP-1 mono-
cytes were pretreated with compounds 12g, 12i and 12l (15 μM) for 2
h, followed by stimulation with PMA (100 nM). (A) Transcript levels of
MMP-1 and MMP-9 were quantified by RT-PCR at 24 h. (B) Same as A,
except that MMP-9 activity was observed in conditioned media using
gelatin loaded gels at 48 h. (C) Monocytes were treated with com-
pounds 12g, 12i and 12l (15 μM) for 2 h, transferred to Matrigel-coated
Boyden chambers followed by stimulation with PMA (100 nM) for 48 h.
Results presented are mean SD of three independent experiments.*
p < 0.01 vs. no treatment; ** p < 0.01 vs. PMA control.
Fig. 4 Compounds 12g, 12i and 12l inhibit PMA-induced monocyte-
to-macrophage differentiation. THP-1 monocytes were pretreated with
compounds 12g, 12i and 12l (15 μM) for 2 h, followed by stimulation
with PMA (100 nM). (A) Phase contrast images indicating the inhibition
of PMA-induced monocyte-to-macrophage differentiation by the
compounds at 48 h. (B) Same as A, except that mitochondrial staining
was performed using mitotracker dye by confocal microscopy. (C)
Same as A, except that the transcript levels of differentiation markers
CD-36 and LOX-1 were measured by RT-PCR at 24 h. (D) Same as A,
except that lysosomal staining was performed to measure lysosomal
activity using lysotracker dye by fluorescence microscopy.
was not altered (Fig. 5B). To further confirm these results, we
next studied the effect of compounds 12g, 12i and 12l on
PMA-induced monocyte/macrophage invasion using collagen-
coated Boyden invasion chambers. Increased secretion of
MMPs promoted macrophage invasion by degrading the
extracellular matrix components which often accentuates the
migration of macrophages, cytokine signaling and leukocyte
activation during the disease processes. In agreement with
the inhibitory effect of these compounds on MMP-9 activity,
these compounds also greatly inhibited the PMA-induced
invasive capacity of monocytes/macrophages (Fig. 5C). Taken
together, these results suggest that compounds 12g, 12i and
12l regulate PMA-induced alterations during monocyte
differentiation.
differentiation. Taken together, these results confirmed that
compounds 12g, 12i and 12l inhibit PMA-induced monocyte-
to-macrophage differentiation, a key step during the progres-
sion of atherogenesis.
Inhibitory effect of compounds 12g, 12i and 12l on PMA-
induced MMP-9 activity. Increased secretion of matrix meta-
lloproteinases (MMPs) induced by macrophages destabilizes
the plaque and enhances plaque rupture during atherosclero-
sis. Differentiation of human peripheral blood mononuclear
cells (HPBM) to macrophages with M-CSF or differentiation
of THP-1 monocytes by PMA has been shown to increase the
levels of MMP-1, MMP-7, and MMP-9.23 As compounds 12g,
12i and 12l showed an excellent inhibitory effect on the dif-
ferentiation of monocytes, we further examined the beneficial
effects of these compounds by measuring PMA-induced
MMP-1 and MMP-9 transcript levels using RT-PCR. It was
found that these three compounds significantly inhibited the
transcript levels of both MMP-1 and MMP-9 (Fig. 5A). Next,
we measured the MMP-9 activity in conditioned medium
using gelatin loaded gels. In concurrence with the transcript
levels, these compounds significantly inhibited PMA-induced
MMP-9 enzyme activity, as studied by gelatin zymography
(Fig. 5B). However, under these conditions, MMP-2 activity
Conclusion
In summary, triazole linked 1,2-benzothiazine 1,1-dioxido
propenone derivatives were prepared and screened for their
anti-inflammatory activity in vitro. The promising compounds
12e, 12g, 12i, 12j, 12k and 12l dose-dependently inhibited
pro-inflammatory cytokine production and COX-2 expression
during monocyte differentiation. In addition, the structure
versus activity data revealed that the presence of the acet-
amide moiety on the triazole ring further increased the inhi-
bition of pro-inflammatory cytokine production. Finally, we
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conclude that compounds 12g, 12i and 12l modulate pro-
inflammatory cytokine production by inhibiting PMA-
induced monocyte-to-macrophage differentiation and may
have beneficial effects in mitigating inflammation-associated
disorders upon further validation.
13 (a) M. Zia-ur-Rehman, J. A. Choudary, M. R. Elsegood, H. L.
Siddiqui and K. M. Khan, A facile synthesis of novel
biologically active 4-hydroxy-N'-IJbenzylidene)-2H-benzoije]
ij1,2]thiazine-3-carbohydrazide 1,1-dioxides, Eur. J. Med.
Chem., 2009, 44, 1311; (b) M. Ahmad, H. L. Siddiqui, M. Zia-
ur-Rehman and M. Parvez, Anti-oxidant and anti-bacterial
activities of novel N'-arylmethylidene-2-IJ3,4-dimethyl-5,5-
Acknowledgements
dioxidopyrazoloij4,3-c]ij1,2]
benzothiazin-2IJ4H)-yl)
The authors are thankful to the Council of Scientific and
Industrial Research (CSIR), New Delhi, India for providing
financial assistance through XII five year plan projects DITSF
(code: CSC-0204) and “Small Molecules in Lead Exploration
(SMiLE)”. The authors (GMR, PN and SBV) are also thankful
to CSIR, India for financial assistance in the form of a
research fellowship and a contingency grant.
acetohydrazides, Eur. J. Med. Chem., 2010, 45, 698.
14 S. Sabatini, F. Gosetto, S. Serritella, G. Manfroni, O.
Tabarrini, N. Iraci, J. P. Brincat, E. Carosati, M. Villarini,
G. W. Kaatz and V. Cecchetti, Pyrazoloij4,3-c]ij1,2] benzo
thiazines 5,5-dioxide: a promising new class of Staphylococ-
cus aureus NorA efflux pump inhibitors, J. Med. Chem.,
2012, 55, 3568.
15 N. Ahmad, M. Zia-ur-Rehman, H. L. Siddiqui, M. F. Ullah
and M. Parvez, Microwave assisted synthesis and structure-
activity relationship of 4-hydroxy-N'-ij1-phenylethylidene]-
2H/2-methyl-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides
as anti-microbial agents, Eur. J. Med. Chem., 2011, 46, 2368.
16 (a) M. L. Barreca, G. Manfroni, P. Leyssen, J. Winquist, N.
Kaushik-Basu, J. Paeshuyse, R. Krishnan, N. Iraci, S.
Sabatini, O. Tabarrini, A. Basu, U. H. Danielson, J. Neyts and
Notes and references
1 C. J. Quintáns, Immunity and inflammation: the cosmic
view, Immunol. Cell Biol., 1994, 72, 262.
2 G. R. Romeo, J. Lee and S. E. Shoelson, Metabolic syndrome,
insulin resistance, and roles of inflammation-mechanisms
and therapeutic targets, Arterioscler., Thromb., Vasc. Biol.,
2012, 32, 1771.
V.
Cecchetti,
Structure
based
discovery
of
3 A. Kalogeropoulos, V. Georgiopoulou, B. Psaty, N. Rodondi,
A. Smith, D. G. Harrison, Y. Liu, U. Hoffmann, D. C. Bauer,
A. B. Newman, S. B. Kritchevsky, T. B. Harris and J. Butler,
Inflammatory markers and incident heart failure risk in
older adults: the Health ABC (Health, Aging, and Body
Composition) study, J. Am. Coll. Cardiol., 2010, 55, 2129.
4 C. A. Dinarello, A clinical perspective of IL-1β as the gate-
keeper of inflammation, Eur. J. Immunol., 2011, 41, 1203.
5 M. Postal and S. Appenzeller, The role of Tumor Necrosis
Factor-alpha (TNF-α) in the pathogenesis of systemic lupus
erythematosus, Cytokine+, 2011, 56, 537.
6 S. L. Deshmane, S. Kremlev, S. Amini and B. E. Sawaya,
Monocyte chemoattractant protein-1 (MCP-1): an overview,
J. Interferon Cytokine Res., 2009, 29, 313.
7 M. F. Linton and S. Fazio, Macrophages, inflammation and
atherosclerosis, Int. J. Obes. Relat. Metab. Disord., 2003, 3,
35.
pyrazolobenzothiazine derivatives as inhibitors of hepatitis
C virus replication, J. Med. Chem., 2013, 56, 2270; (b) G.
Manfroni, D. Manvar, M. L. Barreca, N. Kaushik-Basu, P.
Leyssen, J. Paeshuyse, R. Cannalire, N. Iraci, A. Basu, M.
Chudaev, C. Zamperini, E. Dreassi, S. Sabatini, O. Tabarrini,
J. Neyts and V. Cecchetti, New Pyrazolo benzothiazine
Derivatives as Hepatitis C Virus NS5B Polymerase Palm Site I
Inhibitors, J. Med. Chem., 2014, 57, 3247.
17 (a) S. H. Kim, R. Ramu, S. W. Kwon, S. H. Lee, C. H. Kim,
S. K. Kang, S. D. Rhee, M. A. Bae, S. H. Ahn, D. C. Ha, H. G.
Cheon, K. Y. Kim and J. H. Ahn, Discovery of cyclic
sulfonamide derivatives as 11 beta-hydroxysteroid dehydro-
genase 1 inhibitors, Bioorg. Med. Chem. Lett., 2010, 20, 1065;
(b) S. H. Kim, S. W. Kwon, S. Y. Chu, J. H. Lee, B. Narsaiah,
C. H. Kim, S. K. Kang, N. S. Kang, S. D. Rhee, M. A. Bae,
S. H. Ahn, D. C. Ha, K. Y. Kim and J. H. Ahn, Identification
of cyclic sulfonamide derivatives with an acetamide group as
8 A. C. Li and C. K. Glass, The macrophage foam cell as a
target for therapeutic intervention, Nat. Med., 2002, 8, 1235.
9 C. Gialeli, A. D. Theocharis and N. K. Karamanos, Roles of
matrix metalloproteinases in cancer progression and their
pharmacological targeting, FEBS J., 2011, 278, 16.
10 C. B. Jones, D. C. Sane and D. M. Herrington, Matrix
metalloproteinases: a review of their structure and role in
acute coronary syndrome, Cardiovasc. Res., 2003, 59, 812.
11 K. J. Moore and I. Tabas, Macrophages in the pathogenesis
of atherosclerosis, Cell, 2011, 145, 341.
12 S. B. Vasamsetti, S. Karnewar, A. K. Kanugula, A. T. Raj, J. M.
Kumar and S. Kotamraju, Metformin inhibits monocyte-to-
macrophage differentiation via AMPK mediated inhibition of
STAT3 activation: Potential role in atherosclerosis, Diabetes,
2015, 64, 2028.
11β-hydroxysteroid dehydrogenase
Pharm. Bull., 2011, 59, 46.
1
inhibitors, Chem.
18 E. S. Lazer, C. K. Miao, C. L. Cywin, R. Sorcek, H. C. Wong,
Z. Meng, I. Potocki, M. Hoermann, R. J. Snow, M. A.
Tschantz, T. A. Kelly, D. W. McNeil, S. J. Coutts, L.
Churchill, A. G. Graham, E. David, P. M. Grob, W. Engel, H.
Meier and G. Trummlitz, Effect of structural modification of
enol-carboxamide-type nonsteroidal antiinflammatory drugs
on COX-2/COX-1 selectivity, J. Med. Chem., 1997, 40, 980.
19 J. Wang, D. Limburg, J. Carter, G. Mbalaviele, J. Gierse and
M. Vazquez, Selective inducible microsomal prostaglandin
E2 synthase-1 (mPGES-1) inhibitors derived from an oxicam
template, Bioorg. Med. Chem. Lett., 2010, 20, 1604.
20 M. R. Gannarapu, S. B. Vasamsetti, N. Punna, N. K. Royya,
S. R. Pamulaparthy, J. B. Nanubolu, S. Kotamraju and N.
Med. Chem. Commun.
This journal is © The Royal Society of Chemistry 2015

View Article Online
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Concise Article
Banda, Synthesis of novel 1,2-benzothiazine 1,1-dioxide-3-
ethanone oxime N-aryl acetamide ether derivatives as potent
anti-inflammatory agents and inhibitors of monocyte-to-
macrophage transformation, Eur. J. Med. Chem., 2014, 75,
143.
and D. H. Dockrell, The identification of markers of
macrophage differentiation in PMA-stimulated THP-1 cells
and monocyte-derived macrophages, PLoS One, 2010, 5,
e8668.
23 G. Corea, E. Fattorusso, V. Lanzotti, P. Di Meglio, P. Maffia,
G. Grassia, A. Ialenti and A. Ianaro, Discovery and biological
evaluation of the novel naturally occurring diterpene
pepluanone as antiinflammatory agent, J. Med. Chem.,
2005, 48, 7055.
21 R. N. Dubois, S. B. Abramson, L. Crofford, R. A. Gupta, L. S.
Simon, L. B. Van De Putte and P. E. Lipsky, Cyclooxygenase
in biology and disease, FASEB J., 1998, 12, 1063.
22 M. Daigneault, J. A. Preston, H. M. Marriott, M. K. Whyte
This journal is © The Royal Society of Chemistry 2015
Med. Chem. Commun.