Synthesis, characterization and evaluation of novel benzothiazole clubbed chromene derivatives for their anti-inflammatory potential

Article abstract of DOI:10.1080/10426507.2018.1514502

A series of chromene derivatives (5a–f) were prepared by multistep synthesis process using 2-[3-phenyl prop-2-ene nitrile] 1,3-benzothiazole and dimedone using piperidine as catalyst in ethanol. The reaction was found to proceed via Knoevenagel condensati

Full text of DOI:10.1080/10426507.2018.1514502

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis, characterization and evaluation of novel
benzothiazole clubbed chromene derivatives for
their anti-inflammatory potential
Divyani Gandhi, Dinesh Kr. Agarwal, Priyanka Kalal, Amit Bhargava, Dinesh
Jangid & Shikha Agarwal
To cite this article: Divyani Gandhi, Dinesh Kr. Agarwal, Priyanka Kalal, Amit Bhargava, Dinesh
Jangid & Shikha Agarwal (2018): Synthesis, characterization and evaluation of novel benzothiazole
clubbed chromene derivatives for their anti-inflammatory potential, Phosphorus, Sulfur, and Silicon
and the Related Elements, DOI: 10.1080/10426507.2018.1514502
To link to this article: https://doi.org/10.1080/10426507.2018.1514502
View supplementary material
Published online: 22 Oct 2018.
Submit your article to this journal
Article views: 16
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=gpss20

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2018.1514502
Synthesis, characterization and evaluation of novel benzothiazole clubbed
chromene derivatives for their anti-inflammatory potential
Divyani Gandhia, Dinesh Kr. Agarwalb, Priyanka Kalala, Amit Bhargavab, Dinesh Jangidc, and Shikha Agarwala
b
aDepartment of Chemistry, Mohanlal Sukhadia University, Udaipur, India; Department of Pharmacy, Bhupal Noble University, Udaipur, India;
cDepartment of Chemistry, University of Rajasthan, Jaipur, India
ABSTRACT
ARTICLE HISTORY
Received 16 February 2018
Accepted 18 August 2018
A series of chromene derivatives (5a–f) were prepared by multistep synthesis process using 2-[3-
phenyl prop-2-ene nitrile] 1,3-benzothiazole and dimedone using piperidine as catalyst in ethanol.
The reaction was found to proceed via Knoevenagel condensation of aldehydes with benzothia-
zole, followed by the elimination to afford the 2-(benzo[d]thiazol-2-yl)-3-(aryl)acrylonitrile, which
then undergoes Michael addition with 5,5-dimethyl-1,3-cyclohexanedione, followed by intramo-
lecular O-cyclization to give the products. The structures of all novel constructed derivatives were
corroborated by elemental analysis and spectral data (FT-IR, 1H-NMR, 13C-NMR and Mass).
Subsequently, the compounds were tested for their in-vivo anti-inflammatory activity. This study
revealed that these synthesized derivatives tend to have significantly anti inflammatory activity
and shall prove as structural templates in the design and development of new anti inflamma-
tory drugs.
KEYWORDS
2-Aminobenzenethiol;
chromene; carrageenan-
induced paw edema;
anti inflammatory
GRAPHICAL ABSTRACT
Introduction
Chromene constitute the basic backbone of various types
of polyphenols and widely found in natural alkaloids, toco-
pherols, flavonoids, and anthocyanins.[13] A number of drug
molecules bearing chromene unit are biologically active nat-
ural products and promising synthetic compounds in the
field of medicinal, agrochemical, cosmetics and pigment
industries and in the treatment of various ailments such as
hypertension, asthma, ischemia and urinary incontinence.
They possess important biological properties such as
antitumor,[14] antivascular,[15] TNF-a inhibitor,[16] antifun-
gal,[17] anticoagulant,[18] estrogenic,[19] antiviral,[20] anti-hel-
Inflammation is a characterized response actuated by nox-
ious stimuli and situations such as infection, injury[1] and
has been associated with many diseases viz. asthma, allergy,
diabetes, cancer.[2–5] Numerous anti-inflammatory drugs
have been approved for the treatment of inflammation
(aspirin, corticosteroids, indomethacin, diclofenac, ibupro-
fen, pranoprofen, celecoxib, roficoxib).[6] Among these, non-
steroidal anti-inflammatory drugs (NSAIDs) are effective
anti-inflammatory agents and analgesics that inhibit the bio-
synthesis or release of prostaglandins from arachidonic acid
by suppressing cyclooxygenases.[7,8] Since these drugs inhibit
the production of prostaglandins and may cause serious side
effectts, such as gastrointestinal irritation, ulceration, hepato-
toxicity, acute renal failure, hypertension, and even heart
failure.[9–12] Therefore, there is urgent requisite to develop
new and safer therapeutic agents and for the purpose, we
have synthesized benzothiazole clubbed chromene deriva-
tives as potential anti-inflammatory agents.
minthic,[21]
anticancer,[22]
anti-inflammatory,[23]
antimalarial[24] and anticonvulsant[25] activities etc.
A literature survey reveals that chromene backbone in
assimilation with benzothiazole significantly increases the
biological activity and broadens their spectrum of activity
Figure 1. The benzothiazole moiety, owing to its diversified
molecular design, possesses remarkable biological properties
like anticancer,[26] antibacterial,[27] anticonvulsant,[28,29] anti-
diabetic,[30] anti-HIV,[31] antimalarial,[32] anthelmintic,[33]
CONTACT Shikha Agarwal
shikha_urj@yahoo.com
Supplemental data for this article can be accessed on the publisher’s website.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
ß 2018 Taylor & Francis Group, LLC

2
D. GANDHI ET AL.
antifungal,[34] anti-inflammatory,[35] antileishmanial[36] and an equimolar mixture of 2-amino benzenethiol and malono-
antitubercular[37] activities. Keeping in light all the nitrile in presence of glacial acetic acid using ethanol as
solvent. Different derivatives of 2-[3-phenyl prop-2-ene
nitrile] 1,3-benzothiazole (4a–f) were prepared by reacting
substituted aldehyde with (3) taking pyridine as catalyst in
absolute alcohol. The compounds obtained (4a–f) were fur-
ther reacted with dimedone in presence of piperidine using
ethanol as suitable solvent which resulted in the formation
of titled compounds (5a–f) in good yields. The mechanism
of reaction proceeds via Knoevenagel condensation of vari-
ous substituted aldehyde with 2-cynomethylbenzothiazole
followed by elimination to obtain 2-[3-phenyl prop-2-ene
nitrile] 1,3-benzothiazole (4) which then undergoes Michael
addition with 5,5-dimethyl-cyclohexane-1,3-dione to give
intermediate followed by an intramolecular ortho cyclization
above findings, we have reported the series of 2-amino-3-
(1,3-benzothiazole-2-yl)-4-phenyl-7,7-dimethyl-4,6,7,8-tetra-
hydro-5H-chromene-5-one derivatives (5a–f).
Result and discussion
Chemistry
The synthesis of compounds 3, 4(a–f), 5(a–f) have been out-
lined in Schemes 1 and 2. The structures of all the synthe-
sized compounds were confirmed via IR and NMR
Spectroscopy. The formation of titled compounds (5a–f)
(Figure 2) was achieved in three steps. Initially, synthesis of
2-cynomethylbenzothiazole (3) was undertaken by reacting resulting into product (5).[38]
Figure 1. Drug based designing of benzothiazole clubbed chromene.
N
CN
CN
RCHO
N
SH
+
NH2
CN
CN
CH3COOH
C2H5OH
S
R
C2H5OH
S
(4)
O
(3)
(2)
(1)
°
Ethanol / 80 C
O
R
O
N
S
H2N
O
(5)
Scheme 1. Synthesis of 2-amino-3-(1,3-benzothiazole-2-yl)-4-substituted phenyl-7,7-dimethyl-4,6,7,8-tetrahydro-5H-chromene-5-ones.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Knoevenagel
Condensation
CN
N
CN
N
S
Piperidine
S
(3)
R
O
R
O
H
(4)
CN
N
S
O
R
O
O
R
O
O
N
Base
H
N
S
R
O
O
S
C
N
N
H2N
(5)
Intermediate
S
HN
Base
O
R
O
N
S
R
O
N
C
N
S
C
N
O
Scheme 2. Plausible mechanism for synthesised compounds.
CN
O
O
H3C
O
O
N
N
N
S
S
S
H2N
O
H2N
O
H2N
O
(5b)
(5c)
(5a)
OC2H5
S
O
Cl
O
O
N
S
N
S
N
S
H2N
O
H2N
O
H2N
O
(5d)
(5e)
(5f)
Figure 2. Library of synthesized benzothiazole clubbed chromene derivatives.
FT-IR
appearing in the chromene formation confirmed its absorp-
tion peak at d 5.01 ppm indicating the presence of chromene
proton attached to the aldehyde. The geometry of each pro-
FT-IR spectra of (5a–f) showed the appearance of a band at
around 3475 cmꢀ1 indicating the presence of primary amine
group and a weak absorption stretching vibration band ton attached with C¼C double bond of aromatic rings corre-
observed at 2750 cmꢀ1 confirmed the presence of methylene sponded to the d values between 7.24 and 7.56ppm.
13C NMR spectral data helped to confirm the formation
of desired structures (5a–f). The carbon atoms in contact to
the electronegative element oxygen in the carbonyl group
appeared downfield, nearly at d 195.0 ppm and the carbon
in the environment of primary amine and chromene ring
was seen to appear at d 164.0 and 162.5 ppm respectively
than the one near to unsaturated carbon.
group in the final motif. A sharp intensified band at
1670 cmꢀ1 proved the presence of carbonyl group in the
structure (5a–f).
NMR
1H NMR spectrum observed for the compounds under inves-
tigation exhibited several absorption peaks corresponding to
the desired protons. The proton of secondary amine appear-
ing at d 8.40ppm confirmed its presence on nitrogen attached
to aromatic ring by single bond, whereas the peak appearing
Anti-inflammatory screening
particularly at d 0.9 & 1.1 ppm confirmed the protons of All the newly synthesized compounds (5a–f) were subjected
methyl group in the final structure 5(a–f). The protons to in vivo anti-inflammatory screening using the

4
D. GANDHI ET AL.
carrageenan induced paw edema in rats. Diclofenac were mixture was magnetically stirred at room temperature until
used as standard. The results of in vivo anti-inflammatory no further precipitation was produced and mixture was
activity are summarized in (Table S1 and S2, Supplemental allowed to stand overnight. Brown colored crystals were
Materials). Among the synthesized compounds, compound obtained, filtered and recrystallized from ethanol.
5e exhibited 52.77% inhibition of edema after 2 h from time
administration and found to be quite superior in activity.
Compounds 5f, 5d, 5c and 5a showed 47.05%, 40.0%, 38.
General procedure for the synthesis of 2-[3-phenyl prop-2-
ene nitrile] 1, 3-benzothiazole (4a–4f)
88% and 31.25% inhibition of edema after 2 hrs from time
A mixture of 2-cynomethylbenzothiazole (0.01 mol) (3) and
of action respectively. Compound 5b showed 18.18% inhib-
thiophene-2-carbaldehyde/furfural/o-chloro benzaldehyde/p-
ition of edema and was found to be weak in its action. It
cyano benzaldehyde/p-ethoxy benzaldehyde/o-methyl ben-
was also found that activity increased 4 h post carrageenan
zaldehyde (0.01 mol) in a minimum amount of absolute
injection in a similar manner to that of diclofenac with %
alcohol with a catalytic amount of piperidine (0.5 mL) was
age of inhibition of paw edema respectively. The experimen-
magnetically stirred at room temperature until no further
tal data validates with the theoretical data as described in
precipitation occurred, was filtered, washed with ethanol
PASS (Table S3). The data also revealed that the activity of
and recrystallized to yield the products 4.
compounds follow the order 5d > 5e > 5f > 5c > 5b > 5a.
Pharmocologically, the drug (Diclofenac) is categorized as
a NSAID (Nonsteroid anti-inflammatory drug) which acts at
the periphery and not at CNS (Central Nervous System).
These drugs block the synthesis of ecosanoids by acting at
the site of tissue injury which finally blocks the cyclooxyge-
nase (COX) pathway. Thus, probable mechanism of action
2-(1,3-benzothiazol-2-yl)-3-(2-methylphenyl)prop-2-enenitrile
(4a). Yield: 95%; Yellow; m.p. 146–148 ꢁC; IR (KBr, cmꢀ1):
3083, 3015 (Ar–CH¼C, –CH¼C Stretching), 2925, 2855
(CH3, Stretching), 2210 (CN, Stretching); 1H NMR
(400 MHz, DMSO-d6) d(ppm): 2.13 (s, 3H), 7.20-7.30 (m,
8H, Ar-H), 7.93 (s, 1H, –CH¼C). Anal. calcd for
of carrageenan induced edema is bi-phasic i.e. the first phase
C17H12N2S; C, 73.88; H, 4.38; N, 10.14 Found; C, 73.53; H,
is attributed to release of histamine-HT, kinins in the first
4.62; N, 10.55; MS (EI): m/z 276.07 [Mþ].
hour, while the second phase is the release of prostaglandin
like substance in 3–4 h. Further the chromene derivatives
exhibit structure dependent anti-inflammatory properties
which are evidenced by all the six compounds through
2-(1,3-benzothiazol-2-yl)-2-cyanoethenyl]benzonitrile (4b).
Yield: 92%; pale yellow; m.p. 182–184 ꢁC; IR (KBr, cmꢀ1):
3093, 3027 (Ar–CH¼C, –CH¼C Stretching), 2228 (CN,
mechanism like NSAIDS.
Stretching); 1H NMR (400 MHz, DMSO-d6) d(ppm): 7.47-
7.63 (m, 8H, Ar-H), 8.32 (s, 1H, –CH¼C). Anal. calcd for
Experimental
C17H9N3S; C, 71.06; H, 3.16; N, 14.62 Found; C, 71.43; H,
3.56; N, 14.78; MS (EI): m/z 287.05 [Mþ].
Chemistry
All the chemicals required for synthesis like 2-aminobenzene-
thiol, malononitrile, substituted aldehyde, dimedone were
commercially procured from Merck Ltd., Sigma-Aldrich and
Hi-Media and used without further purification. The melting
points were determined in open capillary tubes and are
reported uncorrected. The IR spectra were recorded on
2-(1,3-benzothiazol-2-yl)-3-(furan-2-yl)prop-2-enenitrile
(4c). Yield: 90%; bright yellow; m.p. 140–142 ꢁC; IR (KBr,
cmꢀ1): 3078, 3015 (Ar-CH¼C, –CH¼C Stretching), 2218
(CN, Stretching), 1275 (C-S, Stretching); 1H NMR
(400 MHz, DMSO-d6) d(ppm): 6.54 (dd, 1H, J ¼ 3.5, 1.8 Hz),
7.30 (dd, 1H, J ¼ 3.5, 0.9 Hz), 7.33-7.42 (m, 4H, Ar-H), 7.90
(1H, dd, J ¼ 1.8, 0.9 Hz), 7.36 (s, 1H, CH¼C). Anal. calcd
for C14H8N2OS; C, 66.65; H, 3.20; N, 11.10 Found; C, 66.32;
H, 3.45; N, 11.53; MS (EI): m/z 252.29 [Mþ].
1
Shimadzu FT-IR Spectrometer. The H NMR spectra (DMSO-
d6) were scanned on a Bruker Avance II (400 MHz) spectrom-
eter using TMS as internal standard and the chemical shifts
are expressed in d, ppm. The mass spectra were recorded on a
Waters Xevo G2-S QTof with UPLC, Sophisticated Analytical
Instruments Facility, Chandigarh, India. The purity of the syn-
thesized compounds was checked by TLC using silica gel-G
plates, n-hexane-ethyl acetate (7:3) as developing solvent sys-
tem and UV light used as a visualizing agent. The
Supplemental Materials contains sample 1H and 13C NMR
spectra for products 5 (Figures S1–S7).
2-(1,3-benzothiazol-2-yl)-3-(thiophen-2-yl)prop-2-enenitrile
(4d). Yield: 96%; dull yellow; m.p. 170–172 ꢁC, IR (KBr,
cmꢀ1): 3085, 3020 (Ar–CH¼C, –CH¼C Stretching), 2222
(CN, Stretching), 1689 (C–O, Stretching). 1H NMR
(400 MHz, DMSO-d6) d(ppm): 7.30 (1H, dd, J ¼ 7.2, 5.2 Hz),
7.34-7.88 (m, 4H, Ar-H), 7.74 (dd, J ¼ 5.2, 1.3 Hz)), 7.99
(1H, dd, J ¼ 7.2, 1.3 Hz), 7.72 (s, 1H, CH¼C). Anal. calcd
for C14H8N2S2; C, 65.97; H, 4.84; N, 6.41 Found; C, 65.92;
H, 4.78; N, 6.55; MS (EI): m/z 268.01 [Mþ].
Synthesis and physical data
Synthesis of 1,3-benzothiazol-2-ylacetonitrile (3)
2-(1,3-benzothiazol-2-yl)-3-(2-chlorophenyl)prop-2-enenitrile
A mixture of 2-aminobenzenethiol (0.01 mol), malononitrile (4e). Yield: 98%; Yellow; m.p. 155–157 ꢁC; IR (KBr, cmꢀ1):
(0.01 mol) and glacial acetic acid (0.01 mol) was dissolved in 3090, 3020 (Ar–CH¼C, –CH¼C Stretching), 2220 (CN,
1
minimum amount of absolute alcohol and the reaction Stretching); H NMR (400 MHz, DMSO-d6) d(ppm): d 7.32-

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
7.53 (m, 8H, Ar-H), 8.08 (s, 1H, –CH¼C); Anal. calcd for (CN), 122.65, 122.92, 124.75, 126.56, 126.95, 126.45, 129.88,
C16H9ClN2S; C, 64.75; H, 3.06; N, 9.44 Found; C, 64.29; H, 132.45, 132.98, 134.55, 145.85, 151.44, [162.76, 163.66 (C-O-
C)], 164.89 (C¼N), 195.93 (C¼O); Anal. calcd for
C25H21N3O2S; C, 70.24; H, 4.95; N, 9.83 Found; C, 70.22; H,
4.92; N, 9.80; MS (EI): m/z 427.74 [Mþ].
3.53; N, 9.57; MS (EI): m/z 296.02 [Mþ], 298.02[M þ 2].
2-(1,3-benzothiazol-2-yl)-3-(4-ethoxyphenyl)prop-2-enenitrile
(4f). Yield: 88%; Green; m.p. 161–163 ꢁC; IR (KBr, cmꢀ1):
3085, 3022 (Ar–CH¼C, –CH¼C Stretching), 2215 (CN,
Stretching); 1H NMR (400 MHz, DMSO-d6) d(ppm): 1.27
(t,3H, J ¼ 7.0 Hz), 4.26 (q, 2H, J ¼ 7.0 Hz), 7.42-7.52 (m, 8H,
Ar-H), 8.00 (s, 1H, CH¼C). Anal. calcd for C18H14N2OS; C,
70.56; H, 4.61; N, 9.14 Found; C, 70.43; H, 4.32; N, 9.02; MS
(EI): m/z 306.08 [Mþ].
2-Amino-3-benzothiazol-2-yl-4-furan-2-yl-7,7-dimethyl-
4,6,7,8-tetrahydro-chromen-5-one (5c). Yield: 72%;
Black; m.p. 172–174 ꢁC; IR (KBr, cmꢀ1): 3450 (N-H,
Stretching), 3075, 2962, 2872 (Ar–CH¼C, Stretching), 1675
(–C¼O, Stretching), 1H NMR (400 MHz, DMSO-d6)
d(ppm): 0.99 (s, 3H, CH3), 1.12 (s, 3H, CH3), 2.35 (d, 1H,
J ¼ 18.2 Hz), 2.40 (d, 1H, J ¼ 18.2 Hz), 2.58 (d, 1H,
J ¼ 15.6 Hz), 2.63 (d, 1H, J ¼ 15.6 Hz)), 5.05 (s, 1H, chromene-
H), 6.32 (1H, dd, J ¼ 2.9, 1.8 Hz), 6.82 (1H, dd, J ¼ 2.9,
0.8 Hz), 7.12 (1H, dd, J ¼ 1.8, 0.8 Hz), 7.45-8.56 (m, 4H,
Ar–H), 8.96 (s, 2H, NH2); 13C NMR (400 MHz, DMSO-d6) d
(ppm): 28.65 (CH3 at chromene), 29.36 (CH3 at chromene),
31.80, 38.06 (CH, chromene), 39.89 (CH2, chromene), 50.47
(COCH2 chromene), 104.43, 111.50, 112.65, 122.45, 122.68,
124.74, 126.08, 126.39, 126.87, 126.67, 126.93, 129.34, 129.76,
General procedure for the synthesis of 2-amino-3-(1,3-
benzothiazole-2-yl)-4-phenyl-7,7-dimethyl-4,6,7,8-tetra-
hydro-5H-chromene-5-one (5a–5f)
A mixture of 2-[3-phenyl prop-2-ene nitrile] 1, 3-benzothia-
zole (0.01 mol) (4a–4f) and dimedone (0.01 mol), dissolved
in a minimum amount of ethanol was refluxed for 8–10 h
using piperidine (0.5 mL) as a catalyst at 80 ꢁC. The progress
of the reaction was monitored by thin layer chromatog-
raphy. After completion of the reaction, the mixture was
poured into crushed ice with stirring. The obtained solid
was filtered, dried and recrystallized with ethanol.
134.89,
142.13,
145.52,
151.58,
154.16,
[162.65,
163.32(C–O–C)], 164.75 (C¼N), 195.08 (C¼O); Anal. calcd
for C22H20N2O3S; C, 67.33; H, 5.14; N, 7.14 Found; C, 67.30;
H, 5.12; N, 7.11; MS (EI): m/z 392.59 [Mþ].
2-Amino-3-benzothiazol-2-yl-7,7-dimethyl-4-o-tolyl-4,6,7,8-
tetrahydro-chromen-5-one (5a). Yield: 87%; Dark brown;
m.p. 186–188 ꢁC; IR (KBr, cmꢀ1): 3432 (N–H, Stretching),
3080, 2977, 2882 (Ar–CH¼C, Stretching), 1668 (–C¼O,
2-Amino-3-benzothiazol-2-yl-7,7-dimethyl-4-thiophen-2-yl-
4,6,7,8-tetrahydro-chromen-5-one (5d). Yield: 84%; Black;
m.p. 180–182 ꢁC; IR (KBr, cmꢀ1): 3485 (N-H, Stretching),
3087, 2977, 2878 (Ar–CH¼C, Stretching), 1695 (–C¼O,
1
1
Stretching); H NMR (400 MHz, DMSO-d6) d(ppm): 0.75 (s,
Stretching), H NMR (400 MHz, DMSO-d6) d(ppm): 0.85 (s,
3H, CH3), 0.82 (s, 3H, CH3), 2.00 (d, 1H, J ¼ 18.2 Hz), 2.15
(d, 1H, J ¼ 18.2 Hz), 2.23 (s, 3H, CH3), 2.38 (d, 1H,
J ¼ 15.6 Hz), 2.45 (d, 1H, J ¼ 15.6 Hz)), 4.28 (s, 1H, chro-
mene-H), 7.06-7.83 (m, 8H, Ar–H), 8.32 (s, 2H, NH2); 13C
NMR (400 MHz, DMSO-d6) d(ppm): 19.60 (CH3, phenyl
group), 28.12 (CH3 at chromene), 29.52 (CH3 at chromene),
31.98, 37.85 (CH, chromene), 39.82 (CH2, chromene), 50.25
(COCH2 chromene), 112.92, 122.85, 122.91, 122.47, 124.96,
126.46, 126.80, 129.23, 129.65, 131.2, 132.32, 134.77, 139.24,
151.54, [162.23, 163.44 (C-O-C)], 164.94 (C¼N),
195.56(C¼O); Anal. calcd for C25H24N2O2S; C, 72.09; H,
5.81; N, 6.73 Found; C, 72.06; H, 5.80; N, 6.72; MS (EI): m/z
416.88 [Mþ].
3H, CH3), 0.93 (s, 3H, CH3), 2.20 (d, 1H, J ¼ 18.2 Hz), 2.32
(d, 1H, J ¼ 18.2 Hz), 2.38 (d, 1H, J ¼ 15.6 Hz), 2.46 (d, 1H,
J ¼ 15.6 Hz)), 4.96 (s, 1H, chromene-H). 7.00 (1H, dd,
J ¼ 8.4, 5.0 Hz), 7.21 (1H, dd, J ¼ 8.4, 1.3 Hz), 7.34 (1H, dd,
J ¼ 5.0, 1.3 Hz), 7.43-8.55 (m, 4H, Ar-H), 8.72 (s, 2H, NH2);
13C NMR (400 MHz, DMSO-d6) d (ppm): 28.56 (CH3 at
chromene), 29.06 (CH3 at chromene), 31.83, 40.22 (CH,
chromene), 41.02 (CH2, chromene), 50.42 (COCH2 chro-
mene), 112.98, 122.78, 122.34, 123.98, 124.54, 125.54, 125.95,
126.33, 126.65, 127.76, 127.90, 128.43, 129.53, 133.76,
134.87, 143.79, 145.76, 151.39, [162.02, 163.99 (C–O–C)],
164.55 (C¼N), 195.83 (C¼O); Anal. calcd for
C22H20N2O2S2; C, 64.68; H, 4.93; N, 6.86 Found; C, 64.65;
H, 4.90; N, 6.88; MS (EI): m/z 408.82 [Mþ].
4-(2-Amino-3-benzothiazol-2-yl-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromen-4-yl)-benzonitrile (5b). Yield: 90%;
Coffee brown; m.p. 210–212 ꢁC; IR (KBr, cmꢀ1): 3475
(N–H, Stretching), 3098, 2985, 2892 (Ar–CH¼C,
Stretching), 1690 (–C¼O, Stretching), 2200 (CN,
2-Amino-3-benzothiazol-2-yl-4-(2-chloro-phenyl)-7,7-
dimethyl-4,6,7,8-tetrahydro-chromen-5-one
(5e).
Yield: 82%; Red-brown; m.p. 203–205 ꢁC; IR (KBr, cmꢀ1):
3456 (N–H, Stretching), 3073, 2970, 2724 (Ar–CH¼C,
1
1
Stretching), H NMR (400 MHz, DMSO-d6) d(ppm): 1.10 (s,
Stretching), 1638 (–C¼O, Stretching); H NMR (400 MHz,
3H, CH3), 1.21 (s, 3H, CH3), 2.20 (d, 1H, J ¼ 18.2 Hz), 2.29
(d, 1H, J ¼ 18.2 Hz), 2.52 (d, 1H, J ¼ 15.6 Hz), 2.56 (d, 1H,
J ¼ 15.6 Hz)), 4.89 (s, 1H, chromene-H), 7.30-8.22 (m, 8H,
Ar–H), 8.54 (s, 2H, NH2); 13C NMR (400 MHz, DMSO-d6)
d (ppm): 28.76 (CH3 at chromene), 29.65 (CH3 at chro-
DMSO-d6) d(ppm): 0.98 (s, 3H, CH3), 1.00 (s, 3H, CH3),
2.17 (d, 1H, J ¼ 18.2 Hz), 2.26 (d, 1H, J ¼ 18.2 Hz), 2.53 (d,
1H, J ¼ 15.6 Hz), 2.58 (d, 1H, J ¼ 15.6 Hz)), 4.92 (s, 1H,
chromene-H), 7.08-8.13 (m, 8H, Ar–H), 8.40 (s, 2H, NH2);
13C NMR (400 MHz, DMSO-d6) d(ppm): 28.42 (CH3 at
mene), 32.09, 37.99 (CH, chromene), 39.77 (CH2, chro- chromene), 29.84 (CH3 at chromene), 31.61, 37.35 (CH,
mene), 50.58 (COCH2 chromene), 112.22, 112.78, 118.83 chromene), 39.55 (CH2, chromene), 50.17 (COCH2

6
D. GANDHI ET AL.
chromene), 115.73, 120.29, 120.79, 122.85, 123.44, 125.59, PASS online program (PASS Online-Way2drug) and the
126.16, 127.81, 129.70, 131.61, 132.80, 134.12, 142.52, possible mechanisms of action as well as biological activities
154.11, [161.82, 165.16 (C–O–C)], 168.23 (C¼N), 195.25
can be predicted.
(C¼O); Anal. calcd for C24H21ClN2O2S; C, 65.97; H, 4.84;
N, 6.41 Found; C, 65.95; H, 4.81; N, 6.39; MS (EI): m/z
Anti-inflammatory activity (carrageenan induced paw
436.98 [Mþ], 438.98 [M þ 2].
edema method)
Anti-inflammatory activity was determined by paw edema
2-Amino-3-benzothiazol-2-yl-4-(4-ethoxy-phenyl)-7,7-
method in rats.[41] Experiments were performed on Wistar
dimethyl-4,6,7,8-tetrahydro-chromen-5-one
(5f).
Yield: 78%; Brick red; m.p. 195–197 ꢁC, IR (KBr, cmꢀ1):
3466 (N-H, Stretching), 3092, 2983, 2888 (Ar–CH¼C,
albino rats-with a body weight between 175 and 225 g at
Bhopal Nobles’ college of Pharmacy, Udaipur (Rajasthan). All
the animal experiments were subjected to Institutional
Animal Ethical Committee (870/ac/05/CPCSEA) and were
conducted according to the guidelines of Experimental
Animal Care issued by the Committee for Purpose of Control
and Supervision of Experiments on Animals (CPCSEA). The
animals were housed in polypropylene cages and maintained
on standard chow diet and water ad libitum and on 12h/12h
light-dark cycle at temperature: 25 2 ꢁC, humidity: 45- 55%
and ventilation: 10-12 exchanges/h.
The animals were starved overnight. To insure uniform
hydration, the rats received 5 mL of water by stomach tube
(controls) or the test drug dissolved or suspended in the
same volume. Thirty minutes later, the rats were challenged
by a subcutaneous injection of 0.1 mL of 1% solution of car-
rageenan into the plantar side of the right hind paw. The
paw was marked with ink at the level of the lateral malleolus
and immersed in mercury up to this mark. The paw volume
was measured by using plethysmograph immediately after
injection, and procedure was repeated at 1, 2, 3, 4 h after
carrageenan injection. Rats were divided into nine groups
containing six rats each.
1
Stretching), 1687 (–C¼O, Stretching), H NMR (400 MHz,
DMSO-d6) d(ppm): 0.82 (s, 3H, CH3), 0.99 (s, 3H, CH3),
1.24 (t, 3H, CH3, J ¼ 7.0 Hz), 2.10 (d, 1H, J ¼ 18.2 Hz), 2.16
(d, 1H, J ¼ 18.2 Hz), 2.46 (d, 1H, J ¼ 15.6 Hz), 2.51 (d, 1H,
J ¼ 15.6 Hz)), 4.02 (q, 2H, CH2, J ¼ 7.0 Hz), 4.66 (s, 1H,
chromene-H), 7.12-8.22 (m, 8 H, Ar-H), 8.56 (s, 2H, NH2);
13C NMR (400 MHz, DMSO-d6) d (ppm): 14.73 (CH2CH3),
28.44 (CH3 at chromene), 29.72 (CH3 at chromene), 31.67,
38.56 (CH, chromene), 39.09 (CH2, chromene), 50.65
(COCH2 chromene), 63.54 (CH2CH3), 112.77, 116.27, 116.80,
122.32, 122.76, 124.44, 126.07, 128.12, 128.68, 129.36, 134.40,
145.98, 151.92, 161.56, [162.88, 163.39 (C–O–C)], 164.67
(C¼N), 195.88 (C¼O); Anal. calcd for C26H26N2O3S; C,
69.93; H, 5.87; N, 6.27 Found; C, 69.95; H, 5.80; N, 6.17; MS
(EI): m/z 446.66 [Mþ].
Biological evaluation
Theoretical prediction of anti-inflammatory activity
The PASS computer program allows to estimate the prob-
able profile of biological activity of a drug-like organic com-
pound (whose molecular mass ranges from 50 to 1250 Da)
based on its structural formula. The categorical description
of biological activity as "active" or "inactive" is used in the
PASS program. The biological activity types for which the
probability to be revealed (Pa) and probability not to be
revealed (Pi) are calculated. Pa and Pi values are independ-
ent, and their values vary from 0.000 to 1.000. It is reason-
able that only those types of activities may be revealed by
the compound, where Pa > Pi and so they are put into the
biological activity spectrum. If Pa >0.7, the compound is
likely to reveal its activity in the experiment, but in this
case, the chance of being the analog of the known pharma-
ceutical agent is high. If Pa <0.5, the compound is unlikely
to reveal this activity in the experiment, but if the presence
of this activity is confirmed in the experiment, the com-
pound might be a new chemical entity.[39,40]
In Group I, rats were given only vehicle, in Group II, rats
were given carrageenan (0.1 mL of 1% mg/kg, bw) whereas in
Group III, animal were given carrageenan (0.1 mL of 1% mg/
kg, bw) single dose plus drug diclofenac (12.5 mg/kg bw) and
Group IV-Group IX rats were given carrageenan (0.1 mL of
1% mg/kg, bw) plus synthesized compounds 5a–5f (200 mg/
kg/day, bw) orally. The mean paw volume at different time
intervals was calculated and compared with control and the
percentage inhibition was calculated.
The percent reduction value calculated according to the
following formula given below:-
Anti–inflammatory activity % reduction of edema
¼ ½1 ꢀ Vt=Vcꢂ ꢃ 100
Where, Vt and Vc are the mean relative changes in the
volume of paw edema in the test and control respectively.
PASS compares the structure of a new compound with
structures of well-known biologically active substance and
therefore, it is possible to estimate if a new compound may
have a particular effect. It operates with many thousands of
substances from the training set and provides a more object-
ive estimation. Since only the structural formula of the
chemical compound is necessary to obtain PASS predictions,
this approach can be used at the earliest stage of the investi-
Conclusion
In the present research work we have synthesized benzothia-
zole clubbed chromene derivatives and most of the com-
pounds were found to possess outstanding anti-inflammatory
properties. The practical data however matches with the the-
oretical (PASS) data and this clearly indicates that the synthe-
gation. Structures of the title compounds were drawn sized molecules are potent anti-inflammatory molecules. On
through ACD labs Chem sketch software, submitted to the the basis of above results, alterations are made to optimize the

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
7
[14] Anderson, D. R.; Hegde, S.; Reinhard, E.; Gomez, L.; Vernier,
W. F.; Lee, L.; Liu, S.; Sambandam, A.; Snider, P. A.; Masih, L.
Aminocyanopyridine Inhibitors of Mitogen Activated Protein
Kinase-Activated Protein Kinase 2 (MK-2). Bioorg. Med. Chem.
Lett 2005, 15, 1587–1590. https://doi.org/10.1016/j.bmcl.2005.
01.067
[15] Gourdeau, H.; Leblond, L.; Hamelin, B.; Desputeau, C.; Dong,
K.; Kianicka, I.; Custeau, D.; Boudreau, C.; Geerts, L.; Cai, S.-
X.; et al. Antivascular and Antitumor Evaluation of 2-amino-4-
lead structure by introducing varied groups on the reactant
itself, and this modification in future will help to develop
much better anti-inflammatory heterocyclic scaffolds.
Acknowledgements
The authors are thankful to Department of Chemistry, Mohanlal
Sukhadia University, Udaipur, Rajasthan and Pharmacy College, B. N.
University for anti-inflammatory activity. The UGC Project, New Delhi
is duly acknowledged.
(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes,
a
novel series of anticancer agents. Mol. Cancer Ther. 2004, 3,
1375–1384.,
[16] Cheng, J. F.; Ishikawa, A.; Ono, Y.; Arrhenius, T.; Nadzan, A.
Novel Chromene Derivatives as TNF-a Inhibitors. Bioorg. Med.
Chem. Lett 2003, 13, 3647–3650. https://doi.org/10.1016/j.bmcl.
2003.08.025
Disclosure statement
No potential conflict of interest was reported by the authors.
[17] Thareja, S.; Verma, A.; Kalra, A.; Gosain, S.; Rewatkar, P. V.;
Kokil, G. R. Novel Chromeneimidazole Derivatives as
Antifungal Compounds: synthesis and in Vitro Evaluation.
Acta. Pol. Pharm 2010, 67, 423–427. PMID 20635539
[18] Riveiro, M. E.; De Kimpe, N.; Moglioni, A.; Vazquez, R.;
Monczor, F.; Shayo, C.; Davio, C. Coumarins: old Compounds
with Novel Promising Therapeutic Perspectives. Cmc. 2010, 17,
1325–1338. DOI: 10.2174/092986710790936284
ORCID
Shikha Agarwal
http://orcid.org/0000-0003-2946-0409
References
[19] Jain, N.; Xu, J.; Kanojia, R. M.; Du, F.; Jian-Zhong, G.; Pacia,
E.; Lai, M.-T.; Musto, A.; Allan, G.; Reuman, M.; et al.
Identification and Structure ꢀ Activity Relationships of
Chromene-Derived Selective Estrogen Receptor Modulators for
Treatment of Postmenopausal Symptoms. J. Med. Chem. 2009,
52, 7544–7569. DOI j 10.1021/jm900146e
[1] Kidd, B. L.; Urban, L. A. Mechanisms of Inflammatory Pain.
Br. J. Anaesth 2001, 87, 3–11. https://doi.org/10.1093/bja/87.1.3
[2] Rosenfeld, M. E. Inflammation and Atherosclerosis: direct ver-
sus Indirect Mechanisms. Curr. Opin. Pharmacol 2013, 13,
154–160. DOI: 10.1016/j.coph.2013.01.003
[3] Donath, M. Y. Targeting Inflammation in the Treatment of
Type 2 Diabetes: time to Start. Nat. Rev. Drug Discov. 2014, 13,
465–476. DOI: 10.1038/nrd4275
[20] Mori, J.; Iwashima, M.; Takeuchi, M.; Saito, H. A. Synthetic
Study on Antiviral and Antioxidative Chromene Derivative.
Chem. Pharm. Bull. 2006, 54, 391–396. https://doi.org/10.1248/
cpb.54.391
[4] Walsh, D. A.; McWilliams, D. F. Mechanisms, Impact and
Management of Pain in Rheumatoid Arthritis. Nat. Rev. [21] Tripathi, R. P.; Tripathi, R.; Bhaduri, A. P.; Singh, S. N.;
Chatterjee, R. K.; Murthy, P. K. Antifilarial Activity of Some
2H-1-Benzopyran-2-Ones (Coumarins). Acta. Tropica 2000, 76,
101–106. https://doi.org/10.1016/S0001-706X(00)00070-X
[22] Ough, M.; Lewis, A.; Bey, E. A.; Gao, J.; Ritchie, J. M.;
Bornmann, W.; Boothman, D. A.; Oberley, L. W.; Cullen, J. J.
Efficacy of Beta-Lapachone in Pancreatic Cancer Treatment:
exploiting the Novel, Therapeutic Target NQO1. Cancer. Biol.
Ther 2005, 4, 102–102. DOI: 10.4161/cbt.4.1.1382
Rheumatol. 2014, 10, 581–592. DOI: 10.1038/nrrheum.2014.64
[5] Akdis, C. A. Therapies for Allergic Inflammation: refining
Strategies to Induce Tolerance. Nat. Med. 2012, 18, 736–749.
DOI: 10.1038/nm.2754
ꢀ
[6] Rodrigues, E. B.; Farah, M. E.; Bottos, J. M.; Bom Aggio, F.
Nonsteroidal anti-Inflammatory Drugs in the Treatment of
Retinal Diseases. Dev. Ophthalmol. 2016, 55, 212–220. DOI:
10.1159/000431197
[23] Moon, D. O.; Choi, Y. H.; Kim, N. D.; Park, Y. M.; Kim, G. Y. Anti-
Inflammatory Effects of Beta-Lapachone in Lipopolysaccharide-
Stimulated BV2 Microglia. Int. Immunopharmacol 2007, 7, 506–514.
DOI: 10.1016/j.intimp.2006.12.006
[24] Elisa, P. S.; Ana, E. B.; Ravelo, A. G.; Yapu, D. J.; Turba, A. G.
Antiplasmodial Activity of Naphthoquinones Related to
Lapachol and b-Lapachone. Chem. Biodivers 2005, 2, 264–274.
DOI: 10.1002/cbdv.200590009
[7] Meek, I. L.; van de Laar, M. A. F. J.; Vonkeman, H. E. Non-
Steroidal anti-Inflammatory Drugs: An Overview of
Cardiovascular Risks. Pharmaceuticals 2010, 3, 2146–2162.
DOI: 10.3390/ph3072146
[8] Simmons, D. L.; Westover, D. W. K. Nonsteroidal anti-
Inflammatory Drugs, Acetaminophen, Cyclooxygenase 2, and
Fever. Clin. Infect. Dis 2000, 31, S211–S218. DOI:10.3390/
ph3072146
[9] Musumba, C.; Pritchard, D. M.; Pirmohamed, M. Review
Article: cellular and Molecular Mechanisms of NSAID-Induced
Peptic Ulcers. Aliment. Pharmacol. Ther 2009, 30, 517–531.
https://doi.org/10.1111/j.1365-2036.2009.04086.x
[10] Cannon, C. P.; Cannon, P. J. Physiology. COX-2 Inhibitors and
Cardiovascular Risk. Science 2012, 336, 1386–1387. doi:
10.1126/science.1224398
[25] Bhat, M. A.; Siddiqui, N.; Khan, S. A. Synthesis of Novel 3-(4-
Acetyl- 5H/Methyl-5-Substituted Phenyl-4,5-Dihydro-1,3,4-
Oxadiazol-2-Yl)-2H-Chromen-2-Ones
as
Potential
Anticonvulsant Agents. Acta. Pol. Pharm 2008, 65, 235–239.
PMID:18666431
[26] Huang, S. T.; Hsei, I. J.; Chen, C. Synthesis and Anticancer
Evaluation of Bis(-Benzimidazoles), Bis(Benzoxazoles), and
Benzothiazoles. Bioorg. Med. Chem 2006, 14, 6106–6119.
https://doi.org/10.1016/j.bmc.2006.05.007
[27] Patel, N. B.; Shaikh, F. M. Synthesis and Antimicrobial Activity
of New 4-Thiazolidinone Derivatives Containing 2-Amino-6-
[11] Bao, H.; Ge, Y.; Zhuang, S.; Dworkin, L. D.; Liu, Z.; Gong, R.
Inhibition of Glycogen Synthase Kinase 3b Prevents NSAID-
Induced Acute Kidney Injury. Kidney Int 2012, 81, 662–673.
DOI: 10.1038/ki.2011.443
Methoxybenzothiazole. Saudi Pharm.
J 2010, 18, 129–136.
[12] Aithal, G. P. Hepatotoxicity Related to Antirheumatic Drugs.
Nat. Rev. Rheumatol. 2011, 7, 139–150. DOI: 10.1038/
nrrheum.2010.214
[13] Pratap, R.; Ram, V. J. Natural and Synthetic Chromenes, Fused
Chromenes, and Versatility of Dihydrobenzo[h]Chromenes in
Organic Synthesis. Chem. Rev. 2014, 114, 10476–10526. DOI:
10.1021/cr500075s
https://doi.org/10.1016/j.jsps.2010.05.002
[28] Siddiqui, N.; Rana, A.; Khan, S. A.; Haque, S. E.; Alam, M. S.;
Ahsan, W.; Ahmed, S. Synthesis of 8-Substituted-4-(2/4-
Substituted Phenyl)-2H-[1,3,5]Triazino[2,1-b][1,3]Benzothiazole-
2-Thiones and Their Anticonvulsant, anti-Nociceptive, and
Toxicity Evaluation in Mice. J. Enz. Inhib. Med. Chem 2009, 24,
1344–1350. DOI: 10.3109/14756360902888176

8
D. GANDHI ET AL.
[29] Yogeeswari, P.; Sriram, D.; Mehta, S.; Nigam, D.; Kumar, [35] Oketani, K.; Nagakura, N.; Harada, K.; Inoue, T. In Vitro
M. M.; Murugesan, S.; Stables, J. P. Anticonvulsant and
Neurotoxicity Evaluation of Some 6-Substituted Benzothiazolyl-
2-Thiosemicarbazones. IL Farmaco. 2005, 60, 1–5. DOI:
10.1016/j.farmac.2004.09.001
Effects of E3040, a Dual Inhibitor of 5-Lipoxygenase and
Thromboxane A2 Synthetase, on Eicosanoid Production. Eur. J.
Pharmacol 2001, 422, 209–216. https://doi.org/10.1016/S0014-
2999(01)01022-6
[30] Van Zandt, M. C.; Jones, M. L.; Gunn, D. E.; Geraci, L. S.; [36] Florence, D.; Antonio, A.; Carole, D. G.; Maxime, R.; Erik,
Jones, J. H.; Sawicki, D. R.; Sredy, J.; Jacot, J. L.; DiCioccio,
A. T.; Petrova, T.; et al. Discovery of 3-[(4,5,7-
D. C.; Pierre, T.; Jean-Pierre, G. Synthesis and Antileishmanial
Activity of (1,3-Benzothiazol-2-Yl) Amino-9-(10H)-Acridinone
Derivatives. Eur. J. Med. Chem 2004, 39, 685–690. DOI:
10.1016/j.ejmech.2004.04.006
Trifluorobenzothiazol-2-Yl)Methyl]Indole-N-Acetic
Acid
(Lidorestat) and Congeners as Highly Potent and Selective
Inhibitors of Aldose Reductase for Treatment of Chronic [37] Koci, J.; Klimesova, V.; Waisser, K.; Kaustova, J.; Dahse, H. M.;
Diabetic Complications. J. Med. Chem. 2005, 48, 3141–3152.,.
DOI:10.1021/jm0492094
[31] Nagarajan, S. R.; De Crescenzo, G. A.; Getman, D. P.; Lu, H.-
F.; Sikorski, J. A.; Walker, J. L.; McDonald, J. J.; Houseman,
Mollmann, U. Heterocyclic Benzazole Derivatives with
Antimycobacterial in Vitro Activity. Bioorg. Med. Chem.
Lett 2002, 12, 3275–3278. https://doi.org/10.1016/S0960-
894X(02)00697-2
K. A.; Kocan, G. P.; Kishore, N.; et al. Discovery of Novel [38] Wen, L. R.; Xie, H. Y.; Li, M. A Basic Ionic Liquid Catalyzed
Benzothiazolesulfonamides as Potent Inhibitors of HIV-1
Protease. Bioorg. Med. Chem 2003, 11, 4769–4777. https://doi.
org/10.1016/j.bmc.2003.07.001
Reaction of Benzothiazole, Aldehydes, and 5,5-Dimethyl-1,3-
Cyclohexanedione: Efficient Synthesis of
Tetrahydrobenzo[b]Pyrans. J. Heterocyclic Chem. 2009, 46,
954–959. https://doi.org/10.1002/jhet.183
[32] Takasu, K.; Inoue, H.; Kim, H.; Suzuki, M.; Shishido, T.;
Wataya, Y.; Ihara, M. Rhodacyanine Dyes as Antimalarials. 1. [39] Stepanchikova, A. V.; Lagunin, A. A.; Filimonov, D. A.; Poroikov,
Preliminary Evaluation of Their Activity and Toxicity. J. Med.
Chem. 2002, 45, 995–998. DOI: 10.1021/jm0155704
[33] Munirajasekhar, D.; Himaja, M.; Mali, S. V. A Facile and
V. V. Prediction of Biological Activity Spectra for Substances:
evaluation on the Diverse Sets of Drug-like Structures. Cmc. 2003,
10, 225–233. DOI: 10.2174/0929867033368510
Efficient Synthesis of 2-(5-(4-Substitutedphenyl)-4,5-Dihydro-3- [40] Anzali, S.; Barnickel, G.; Cezanne, B.; Krug, M.; Filimonov, D.;
Phenylpyrazol-1-Yl)-6-Substituted Benzo Thiazoles and Their
Biological Studies. J. Heterocyclic Chem. 2014, 51, 459–465.
DOI: 10.1002/jhet.1618
Poroikov, V. Discriminating between Drugs and Nondrugs by
Prediction of Activity Spectra for Substances (PASS). J. Med.
Chem. 2001, 44, 2432–2437. DOI: 10.1021/jm0010670
[34] Patel, R. V.; Park, S. W. Catalytic N-Formylation for Synthesis of 6- [41] Winter, C. A.; Risley, E. A.; Nuss, G. W. Carageenan-Induced
Substituted-2-Benzothiazolylimino-5-Piperazinyl-4-Thiazolidinone
Antimicrobial Agents. Res. Chem. Intermed. 2015, 41, 5599–5609.
https://doi.org/10.1007/s11164-014-1684-8
Edema in Hind Paw of the Rat as an Assay for
Antiinflammatory Drugs. Proc. Soc. Exp. Biol. Med 1962, 111,
544–547. https://doi.org/10.3181/00379727-111-27849