Design, synthesis of novel furan appended benzothiazepine derivatives and in vitro biological evaluation as potent VRV-PL-8a and H+/K+ ATPase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2017.05.059

A series of new of furan derivatised [1,4] benzothiazepine analogues were synthesized starting from 1-(furan-2-yl)ethanone. 1-(Furan-2-yl)ethanone was converted into chalcones by its reaction with various aromatic aldehydes, then were reacted with 2-amino

Full text of DOI:10.1016/j.bmcl.2017.05.059

Accepted Manuscript
Design, synthesis of novel furan appended benzothiazepine derivatives and in
vitro biological evaluation as potent VRV-PL-8a and H+/K+ ATPase inhibitors
Devirammanahalli Mahadevaswamy Lokeshwari, Nanjappagowda Dharmappa
Rekha, Bharath Srinivasan, Hamse Kameshwar Vivek, Ajay Kumar Kariyappa
PII:
S0960-894X(17)30547-4
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.05.059
BMCL 25004
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 March 2017
18 April 2017
19 May 2017
Please cite this article as: Lokeshwari, D.M., Rekha, N.D., Srinivasan, B., Vivek, H.K., Kariyappa, A.K., Design,
synthesis of novel furan appended benzothiazepine derivatives and in vitro biological evaluation as potent VRV-
PL-8a and H+/K+ ATPase inhibitors, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/
10.1016/j.bmcl.2017.05.059
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Design, synthesis of novel furan appended benzothiazepine derivatives and
in vitro biological evaluation as potent VRV-PL-8a and H+/K+ ATPase
inhibitors
Devirammanahalli Mahadevaswamy Lokeshwari,a Nanjappagowda Dharmappa Rekha,b
Bharath Srinivasan,c Hamse Kameshwar Vivek,d Ajay Kumar Kariyappaa*
aDepartment of Chemistry, Yuvaraja College, University of Mysore, Mysuru. India.
bDepartment of Biotechnology, JSS College for Arts, Commerce & Science, Mysuru. India.
cCenter for the Study of Systems Biology, School of Biology, Georgia Institute of Technology,
Atlanta, Georgia 30332, USA.
dSri Ram Chem, R & D Centre, Plot No 31, JCK Industrial Park, Belagola Industrial Area,
Mysuru- 570006, India.
Abstract
A series of new of furan derivatised [1, 4] benzothiazepine analogues were synthesized
starting from 1-(furan-2-yl)ethanone. 1-(furan-2-yl)ethanone was converted into chalcones by
its reaction with various aromatic aldehydes, then were reacted with 2-aminobenzenethiol in
acidic conditions to obtain the title compounds in good yields. The synthesized new
compounds were characterized by 1H NMR, 13C NMR, Mass spectral studies and elemental
analyses. All the new compounds were evaluated for their in vitro VRV-PL-8a and H+/K+
ATPase inhibitor properties. Preliminary studies revealed that, some molecules amongst the
designed series showed promising VRV-PL-8a and H+/K+ ATPase inhibitor properties.
Further, rigid body docking studies were performed to understand possible docking sites of
the molecules on the target proteins and the mode of binding. This finding presents a
promising series of lead molecules that can serve as prototypes for the treatment of
inflammatory related disorder that can mitigate the ulcer inducing side effect shown by other
NSAIDs.

Keywords: Antidiabetic, anti-inflammatory, benzothiazepines, chalcones, 1-(furan-2-
yl)ethanone.
The heterocyclic nucleus of thiazepine is present in a number of bioactive molecules,
and is recognized as a key building block for the synthesis of small-molecules with potential
pharmaceutical activities.1 The broad spectrum of clinical applications and commercial
success associated with benzothiazepine derivatives have placed them as important molecules
in the field of medicinal chemistry.2 Various protocols have been developed for the synthesis
of benzothiazepines in literature. To mention two representative examples: the reaction of
acid amides with phosphoryl chloride furnishes 2,3-dihydro-l,4-benzothiazepine3 and the
one-pot reaction between 2-aminobenzo[d]isothiazol-3-one and alkyl propiolates in the
presence of triphenylphosphine produces 1,4-benzothiazepines.4
Further, molecules possessing benzothiazepine skeleton have exhibited high
biological profiles.5 These classes of compounds have been known to show anti-arrhythmic,
angiogenic, central nervous system activities,6 antimicrobial,7 antioxidant,8 anti-
inflammatory, analgesics, antitumor, and anticonvulsant properties.9 1,4-Benzothiazepine
derivatives also show interesting neuroprotective activity in addition to their demonstrated
blockade of the mitochondrial sodium/calcium exchanger.10 The chemical modification of
heterocyclic systems by devising a new protocol for design of new compounds with high
pharmacological profile is always a challenge for the medicinal chemist. We herein report the
synthesis of functionalized 1,4-benzothiazepine derivatives and in vitro screening results for
their VRV-PL-8a and H+/K+ ATPase inhibitor properties.
The strategy adopted for the synthesis of the target compounds, 3(a-h), is depicted in
Fig. 1. The intermediate chalcones, 3(a-h), were synthesized by the Claisen-Schmidt
condensation reaction of 1-(furan-2-yl)ethanone, 1, and aromatic aldehydes, 2(a-h), in the
presence of potassium hydroxide in methyl alcohol. Then, the chalcones, 3(a-h), were

transformed in to target molecules 5(a-h) by their reaction with 2-aminobenzenethiol, 4, and
concentrated hydrochloric acid (4-6 drops) in methyl alcohol under reflux conditions.
Fig. 1. Schematic diagram for the synthesis of benzothiazepines, 5(a-h)
The resultant structures of the synthesized compounds 3(a-h) and 5(a-h) were
1
1
confirmed by H NMR, 13C NMR, Mass spectral studies and CHN analyses. In H NMR
spectrum, compound 3b showed two doublets for one proton each at δ 6.285 ppm and δ
6.793 ppm which were due to olefinic CH=C and C=CH protons, respectively. An array of
signals observed as multiplet for seven protons at δ 7.244-8.201 ppm were due to aromatic
protons. Two methylene (C-3) protons of the newly formed benzothiazepine ring in
compound 5b, exhibit typical ABX spin system, and are diastereotopic appearing as two
doublet of doublets. C3-Ha resonates with both C3-Hb and C2-H appearing as doublet of
doublet at δ 2.923-2.985 (J= 12.4, 24.8 Hz) ppm and C3-Hb resonates with both C3-Ha and

C2-H appearing as doublet of doublet at δ 3.214-3.259 (J=8.0, 18.0Hz) ppm. C2-H coupled
with both C3-Ha and C3-Hb and appeared as doublet of doublet at δ 5.045-5.086 (J= 6.8,
16.4Hz) ppm. An array of signals appearing as multiplets for eleven protons at δ 6.587-8.182
ppm were due to aromatic protons.
In 13C NMR spectrum, compound 3b showed signals at δ 121.41, 144.63 and 170.44
ppm due to olefinic CH=, =CH, and C=O carbons, respectively. Aromatic carbons showed
the signals in the region δ 112.10-153.86 ppm. For compound 5b, the signals due to C-2, C-3
and C-4 carbons of the newly formed thiazepine ring appeared at δ 34.54, 25.76 and 158.32
ppm, respectively. Aromatic carbons showed the signals in the region δ 110.32-153.09 ppm.
Para substitution effect caused the two carbons, each at ortho and meta positions of
chlorophenyl ring, to abosrb at δ 128.76 and 129.54 ppm, respectively. The NMR data of the
synthesised series of compounds 3(a-h) and 5(a-h) are tabulated in Table 1.
Table 1. NMR spectral data of compounds 3(a-h) and 5(a-h).
1H NMR (CDCl3): δ ppm
13C NMR (CDCl3): δ ppm
3a 6.282 (d, 1H, J=6.9Hz), 6.834 (d, 1H, 111.33, 114.85, 121.28, 127.66, 128.34,
J=7.6Hz), 7.241-8.128 (m, 8H).
128.88, 134.20, 144.40, 148.55, 154.20, 170.20
(C=O).
3b 6.285 (d, 1H, J=7.1Hz), 6.793 (d, 1H, 112.10, 115.28, 121.41, 128.26, 128.82,
J=9.0Hz), 7.244-8.201 (m, 7H).
133.10, 133.77, 144.63, 147.88, 153.86, 170.44
(C=O).
3c 6.406 (d, 1H, J=6.6Hz), 6.903 (d, 1H, 112.50, 115.62, 116.80, 121.88, 129.96,
J=7.8Hz), 7.122-8.040 (m, 7H).
131.49, 144.84, 148.46, 151.30, 161.30, 170.77
(C=O).
3d 6.451 (d, 1H, J=6.0Hz), 6.945 (d, 1H, 112.38, 115.74, 121.60, 123.50, 129.56,
J=8.7Hz), 7.230-8.304 (m, 7H).
132.84, 133.90, 145.04, 146.55, 151.33, 170.16
(C=O).
3e 3.840 (s, 3H), 6.286 (d, 1H, J=7.3Hz), 111.98, 114.50, 116.42, 121.44, 127.14,

6.794 (d, 1H, J=9.5Hz), 7.024-8.004 131.08, 145.10, 146.90, 152.22, 158.20, 169.80
(m, 7H). (C=O).
3f 6.451 (d, 1H, J=6.2Hz), 6.963 (d, 1H, 112.14, 116.63, 121.50, 124.46, 129.60,
J=7.8Hz), 7.280-8.344 (m, 7H).
140.81, 146.06, 146.63, 147.75, 152.80, 169.95
(C=O).
3g 3.866 (s, 3H, J=7.5Hz), 5.807 (s, 1H), 110.10, 112.40, 116.56, 117.77, 120.18,
6.389 (d, 1H, J=10.1Hz), 6.908 (d, 123.30, 127.10, 128.34, 145.32, 147.12,
1H), 7.025-7.972 (m, 6H).
147.96, 148.26, 154.19, 169.80 (C=O).
3h 6.122 (s, 2H, J=7.3Hz), 6.344 (d, 1H, 100.12, 105.24, 109.34, 113.42, 117.44,
J=8.9Hz), 6.866 (d, 1H), 7.186-8.064 121.20, 122.65, 126.88, 143.33, 147.28,
(m, 6H).
148.78, 152.26, 169.16 (C=O).
5a 2.892-2.960 (dd, 1H, J= 12.0, 26.87 (C-3), 36.89 (C-2), 113.80, 122.29,
27.2Hz), 3.240-3.286 (dd, 1H, J= 8.3, 124.09, 124.16, 125.64, 125.94, 127.12,
18.4Hz), 5.060-5.109 (dd, 1H, J= 6.9, 128.97, 130.34, 135.03, 145.70, 147.37,
19.6Hz), 6.620-8.126 (m, 12H).
150.55, 151.85, 152.42, 159.14 (C-4).
5b 2.923-2.985 (dd, 1H, J= 12.4, 25.76 (C-3), 34.54 (C-2), 110.32, 122.29,
24.8Hz), 3.214-3.259 (dd, 1H, J= 8.0, 125.21, 125.66, 126.21, 127.04, 128.76,
18.0Hz), 5.045-5.086 (dd, 1H, J= 6.8, 129.54, 132.76, 139.54, 145.65, 150.85,
16.4Hz), 6.587-8.182 (m, 11H).
151.32, 153.09, 158.32 (C-4).
5c 2.980-3.038 (dd, 1H, J= 12.0, 26.26 (C-3), 36.89 (C-2), 113.32, 120.65,
23.2Hz), 3.288-3.331 (dd, 1H, J= 8.1, 123.21, 126.98, 128.43, 130.94, 131.06,
17.2Hz), 5.080-5.124 (dd, 1H, J= 6.9, 133.86, 135.76, 138.54, 142.41, 148.05,
17.6Hz), 6.68-8.14 (m, 11H).
151.43, 153.21, 158.76 (C-4).
5d 2.881-2.943 (dd, 1H, J= 12.5, 28.32 (C-3), 34.21 (C-2), 110.21, 119.65,
24.8Hz), 3.260-3.308 (dd, 1H, J= 9.1, 120.54, 123.65, 126.32, 130.14, 131.46,
19.2Hz), 5.100-5.146 (dd, 1H, J= 8.1, 132.21, 135.11, 137.32, 141.34, 146.76,
18.4Hz), 6.66-8.18 (m, 11H).
150.21, 152.33, 156.54 (C-4).
5e 2.955-3.010 (dd, 1H, J= 12.9, 27.62 (C-3), 32.65 (C-2), 55.41, 111.43,
22.0Hz), 3.260-3.305 (dd, 1H, J= 8.1, 115.21, 119.33, 120.65, 122.55, 125.17,
18.0Hz), 3.625 (s, 3H), 5.060-5.108 129.21, 132.21, 134.65, 136.21, 140.31,
(dd, 1H, J= 6.4, 19.2Hz), 6.682-8.183 143.43, 149.21, 152.87, 156.88 (C-4).
(m, 11H).
5f 2.864-2.928 (dd, 1H, J= 12.7, 27.76 (C-3), 32.54 (C-2), 111.40, 115.25,

26.6Hz), 3.165-3.202 (dd, 1H, J= 8.6, 119.20, 121.60, 122.51, 125.33, 129.56,
15.2Hz), 3.72 (s, 3H), 5.162-5.198 132.06, 134.30, 136.20, 140.50, 143.88,
(dd, 1H, J= 7.2, 14.4Hz), 6.730-8.452 149.10, 152.80, 157.12 (C-4).
(m, 11H).
5g 2.771-2.829 (dd, 1H, J= 12.0, 27.76 (C-3), 32.68 (C-2), 59.46, 111.67,
23.2Hz), 3.240-3.283 (dd, 1H, J= 8.0, 115.34, 119.86, 120.88, 122.66, 125.78,
17.2Hz), 3.61 (s, 3H), 5.091-5.137 129.30, 132.23, 134.87, 136.25, 140.65,
(dd, 1H, J= 7.3, 18.4Hz), 6.745-8.223 143.65, 149.67, 152.89, 156.89 (C-4).
(m, 11H).
5h 2.920-2.976 (dd, 1H, J= 11.7, 27.89 (C-3), 32.87 (C-2), 59.67, 111.87,
22.4Hz), 3.091-3.135 (dd, 1H, J= 8.5, 115.56, 119.72, 120.77, 122.78, 125.38,
17.6Hz), 3.69 (s, 3H), 5.180-5.226 129.37, 132.45, 134.86, 136.45, 140.68,
(dd, 1H, J= 6.0, 18.4Hz), 6.690-8.229 143.76, 149.98, 152.88, 156.88 (C-4).
(m, 11H).
In mass spectra, compounds 3g and 5g showed base peaks at m/z 244.09 and 351.03
respectively, corresponding to their molecular massess. Except, the compounds with chloro
and bromo substitutions, all compounds amongest the series 3(a-h) and 5(a-h) showed the
base peaks corresponding to their molecular masses. Compounds 3b and 5b, having chloro
substitutions, and 3d and 5d, having bromo substitutions, showed base peaks at their
respective molecular masses and M+2 peaks due to isotopes 37Cl, 81Br with relative
abundances of 34%, 34%, 98%, 97.2% respectively. All compounds showed satisfactory
elemental analyses data.
Inflammation is a complex immunological cascade driven by several different factors
and can be initiated by manifold cues including, but not limited to, pathogen invasion, tissue
damage due to oxidative challenge etc. COX-2 is an important player in bringing about
inflammation. Primarily during tissue damage, the first enzyme to get activated is sPLA2,
which drives the substrate for COX-2. Inhibition of sPLA2 will result in substrate depletion
for COX-2, thereby bringing down the inflammation, as there will be no pro-inflammatory

and inflammatory Prostaglandins (PG). In this context, we assessed the inhibitory potential of
the newly synthesized benzothiazepines to inhibit sPLA2, rather than COX-2.11
As a prototype to test our findings, sPLA2 (VRV-PL-8a) from V. russelli venom was
employed instead of the human homologue. The protein was purified to homogeneity by
reported procedure,12 and estimated by Lowry's method.13 In vitro inhibition of sPLA2 (VRV-
PL-8a) by the synthesized benzothiazepine derivatives, 5(a-h) was assayed according to
reported procedure.14 Further, indirect hemolytic activity of the synthesized benzothiazepine
derivatives, 5(a-h), was assayed by reported method.15 The series of benzothiazepine
derivatives 5(a-h) were assessed for sPLA2 inhibition studies and the results are tabulated in
Table 2.
Furthermore, the H+/K+-ATPase (pig stomach mucosal membrane) inhibition activity
of the synthesized benzothiazepine derivatives, 5(a-h) was also determined as described by
W B Im.16 The gastric H+/K+-ATPase, together with Na+/K+-ATPase and Ca2+-ATPase, is a
member of the P-type ATPase. The ion pump is an essential electrogenic pump maintaining
potential difference across the intracellular and extracellular compartments in a cellular
matrix by retaining low sodium and high potassium intracellularly. These proteins engage in
a common catalytic cycle with ion translocation coupled to phosphorylation and
dephosphorylation of a conserved aspartate residue.17 Some of them belong to the Haloacid
dehalogenase family of enzyme with a conserved DXDXV/T motif, with the second aspartate
in the motif critical for the formation of the phosphoenzyme intermediate.18 The assay was
carried out by initiating the ATPase reaction by the addition of the substrate (ATP), carried
out at 37 °C for 15 mins and stopped with 1.0 mL ice cold 20 % TCA. The liberated
inorganic phosphate from ATP was estimated by Fiske Subbarow’s method.19 The assessed
H+/K+ ATPase activity is reported in Table 2.
Table 2. Neutralization of VRV-PL-8a (sPLA2) and H+/K+ ATPase by compounds 5(a-h)#

Test compound
sPLA2
H+/K+ ATPase
IC50 (µM) SEM
8.014 0.076
5.277 0.051
5.099 0.051
2.112 0.021
1.989 0.020
3.732 0.037
4.390 0.042
5.143 0.050
IC50 (µM) SEM
12.014 0.110
19.287 0.162
25.192 0.205
24.142 0.190
11.014 0.101
56.882 0.507
43.410 0.394
25.128 0.221
5a
5b
5c
5d
5e*
5f
5g
5h
#
*5e denotes the potent ligand; the experiments were performed in quadruplicates (n=4) and
the results are reported as mean of the values SEM.
The tested benzothiazepine derivatives, 5(a-h) inhibited sPLA2 in dose depended
manner with an IC50 value ranging from 11.01 to 56.88 µM which are computed and
analyzed using sigmoidal 4PL curve fit. Among the tested compounds, 5e showed significant
inhibition against VRV-PL-8a with IC50 value of 11.01µM (Fig. 2), when compared to other
structurally related molecules. In-situ indirect hemolytic activity of VRV-PL-8a in presence
of compounds 5e was evaluated using egg yolk and packed erythrocytes as substrate. VRV-
PL-8a alone exhibited 96 2.0% hemolysis of erythrocyte (positive control) when compared
with pure water (100% lysis). VRV-PL-8a incubated with 5e (0-100µM) respectively for 60
min at 37°C, inhibited hemolysis in a dose dependent manner with an IC50 of 21.23 2.1 µM
as estimated by non-linear fit (Fig. 3).

Fig. 2. Neutralization of indirect haemolytic activity of VRV-PL-8a by compound 5e. Values
represent means SEM (n = 4).
Fig. 3. Dose-response curves-showing the effect of 5e on VRV-PL-8a. IC50 was calculated
using sigmoidal four parameter logistic fit (4PL) plot. Values represent means SEM (n = 4).

To understand the mechanism of action of inhibition, we studied the effect of
substrate and calcium concentrations on VRV-PL-8a enzyme inhibition by 5e. We examined
its inhibition as a function of calcium and substrate concentrations. 5e at its IC50
concentration (11.01µM) and with varying calcium concentration 0-12mM, showed no
change in sPLA2 activity neither did it change the extent of inhibition of 5e, Fig. S1(a).
This indicates to possible non-competition of compound 5e with the calcium binding site or
the active site on the VRV-PL- 8a enzyme. Thus, it can be surmised that inhibition of
sPLA2
5e is independent of calcium concentration and is not brought about by chelating
by
calcium ions required for the enzyme activity. Effect of 5e (11.01µM) on varying DMPC
substrate concentration (0-400µM) was evaluated. sPLA2 activity increased with increased
substrate concentration Fig. S1(b); suggesting that 5e does not compete with substrate
binding site on VRV-PL-8a. In presence of 5e, only 51% enzyme activities was observed at
maximum substrate concentration of 400 µM. GII PLA2 has a conserved active site within a
hydrophobic channel lined by invariant hydrophobic residues. The active site residues His48,
Asp49, Tyr52 and Asp99 are directly connected to the channel.20 His48 is known to play a
major role in catalysis by facilitating the formation of hydrogen bond between Asp99 and
Asp49 via water molecule that is part of the catalytic network. It is known that, any structural
perturbations in His48, at the N-terminal α-helix of sPLA2, plays an important role in both
membrane binding of the enzyme and substrate binding to the catalytic site that reduces the
binding affinity of the enzyme-substrate complex.21
In order to determine the possible binding modes for compound 5e, molecular
docking studies were performed for ligands 5(a-h). The structure of the protein from Daboia
russelii (PDB ID: 1SXK) was employed for docking studies. Analysis of the interaction mode
for the lower energy docking pose among the ensemble indicated that compound 5a
interacted with Phe5, His48 and Tyr52 by π-π stacking (Fig. 4). Whereas, in case of 5e,

Lys69, Trp31 and His48 interacted with the small molecule by π-π stacking (Fig. 5).
Importantly, binding of ligand 5e near the α-helical random coil clearly suggests that it had
interaction with His48, which resides near the random coil.22
Fig. 4. In silico analysis of VRV-PL-8a with 5a, Molecular docking studies showed an
interacting map of 5a with VRV-PL-8a showing molecular interaction.

Fig. 5. In silico analysis of VRV-PL-8a with 5e, Molecular docking studies showed an
interacting map of 5e with VRV-PL-8a showing molecular interaction.
Likewise, to rationalize the inhibition seen for Na+/K+ ATPase and o gain insights
into the possible binding modes, rigid-body docking studies of the compounds was carried
out with the receptor structure. Crystal structure of Na+/K+-ATPase from Squalus acanthias
(Spiny Dogfish) (PDB ID: 2ZXE) was used for molecular docking studies as a prototype
instead of the structure of the protein from human for ease of target structure preparation.
Molecular docking studies showed an interacting map of Na+/K+-ATPase (Fig. 6 and Fig. 7)
with compound 5a and 5e respectively. Based on XP glide score, 5e showed a promising
scoring function, when compared to other structurally related compounds (Table 3).
Additionally, the low E model value indicated that the binding affinity between protein and
ligand is energetically favorable.23

Fig. 6. In silico analysis of Na+/K+-ATPase pump with 5a, Molecular docking studies showed
an interacting map of 5a with Na+/K+-ATPase showing molecular interaction.

Fig. 7. In silico analysis of Na+/K+-ATPase pump with 5e, Molecular docking studies showed
an interacting map of 5e with Na+/K+-ATPase showing molecular interaction.
Pharmacodynamics parameters play an important role in determining the success of a
lead candidate for further therapeutic development. ADME descriptors were computed for the
various synthesized compounds. ADME descriptors simulation suggests that 5e is better drug
molecule which falls within the range of 95% of drugs (Table S1).
Table 3: Molecular docking scores of all synthesized compounds against VRV-PL-8a and
Na+/K+ ATPase as obtained through Glide docking.
1SXK
2ZXE
RMSD
OPLS-
2005
RMSD
OPLS-
2005
Ligand
Docking Glide Glide
Docking Glide Glide
score
gscore emodel
score
gscore emodel
0.002
-5.08
-4.96
-4.59
-4.89
-5.10
-5.09 -51.82 0.003
-4.97 -46.18 0.012
-4.60 -46.51 0.002
-4.91 -51.14 0.036
-5.11 -49.15 0.032
-5.42
-5.42
-5.46
-5.67
-6.02
-5.43 -39.34
-5.44 -40.01
-5.48 -43.18
-5.69 -42.94
-6.04 -46.82
5a
5b
5c
5d
5e
0.036
0.003
0.038
0.012

0.002
0.001
0.003
-3.99
-4.11
-4.84
-4.00 -43.49 0.002
-4.12 -48.21 0.007
-4.85 -46.30 0.003
-5.53
-5.51
-5.43
-5.54 -38.75
-5.53 -42.10
-5.45 -39.33
5f
5g
5h
Recent studies show that over 50% of patients consuming known NSAIDs like
Fenoprofen, Diclofenac, Ibuprofen, etc., undergo major damage to their small intestine.24,25
This necessitates that better small-molecules with lesser side-effects and better
pharmacological properties are discovered. This study is an attempt, among many others, that
attempts to discover novel small molecules that have both NSAID and gastric ATPase
inhibition properties.
In summary, in order to develop anti-inflammatory and antiulcer agents, we have
synthesized series of bioactive benzothiazepines and evaluated them for anti-inflammatory
and ATPase inhibitory activities. Compounds inhibiting sPLA2 have been implicated as
potential therapeutic agents in the treatment of inflammatory disorders. Hence, we targeted
the primary enzyme (sPLA2), which drives the inflammatory cascade. Use of NSAIDs
causes’ gastric ulcer, hence anti-inflammatory and ulcer activities are closely related in order
to bring down inflammation. Compound 5e showed both better anti-inflammatory as well as
ATPase inhibitory activities. Thus, 5e could be promising drug in treating inflammatory
related disorder that can mitigate the ulcer inducing side effect shown by other NSAIDs.
Acknowledgements
The authors are grateful to the IOE Instrumentation Facility, Vijnana Bhavana, University of
Mysore, for recording spectra of the synthesized compounds.
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