Спіро[бензо[е]пірано[3,2-с][1,2]оксатіїн-4,3’-індол]-3-карбонітрил 5,5-діоксиди: синтез і вивчення біологічної активності
The development of medicines with several pharmacological activities, including the analgesic, anti-inflammatory and antimicrobial properties, is one of the challenging tasks of modern medicinal chemistry.Aim. To expand the range of novel spiro-condensed derivatives of 1,2-benzoxathiin-4(3H)-one 2,2...
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| Published in: | Журнал органічної та фармацевтичної хімії |
|---|---|
| Date: | 2026 |
| Volume: | 17 |
| Issue: | 4(68) |
| Pages: | 53-61 |
| ISSN: | 2518-1548 |
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| Main Authors: | , , , , , , |
| Format: | Article |
| Language: | English |
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National University of Pharmacy
2026
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| Online Access: | https://ophcj.nuph.edu.ua/article/view/ophcj.19.182954 |
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| author | Grygoriv, G. V. Lega, D. A. Zupanets, I. A. Shebeko, S. K. Zimin, S. M. Starchikova, I. L. Shemchuk, L. A. |
| author_facet | Grygoriv, G. V. Lega, D. A. Zupanets, I. A. Shebeko, S. K. Zimin, S. M. Starchikova, I. L. Shemchuk, L. A. |
| author_institution_txt_mv | [
{
"author": "G. V. Grygoriv",
"institution": "National University of Pharmacy",
"orcid": ""
},
{
"author": "D. A. Lega",
"institution": "National University of Pharmacy",
"orcid": ""
},
{
"author": "I. A. Zupanets",
"institution": "National University of Pharmacy",
"orcid": ""
},
{
"author": "S. K. Shebeko",
"institution": "National University of Pharmacy",
"orcid": ""
},
{
"author": "S. M. Zimin",
"institution": "National University of Pharmacy",
"orcid": "0000-0002-6245-7167"
},
{
"author": "I. L. Starchikova",
"institution": "National University of Pharmacy",
"orcid": "0009-0001-5917-9557"
},
{
"author": "L. A. Shemchuk",
"institution": "National University of Pharmacy",
"orcid": "0000-0001-8524-4685"
}
] |
| author_orcid_str_mv | 0000-0002-6245-7167 0009-0001-5917-9557 0000-0001-8524-4685 |
| author_sort | Grygoriv, G. V. |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 61 |
| container_issue | 4(68) |
| container_start_page | 53 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 17 |
| datestamp_date | 2026-08-24T18:27:32Z |
| description | The development of medicines with several pharmacological activities, including the analgesic, anti-inflammatory and antimicrobial properties, is one of the challenging tasks of modern medicinal chemistry.Aim. To expand the range of novel spiro-condensed derivatives of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide, and study the biological activity of the substances obtained.Results and discussions. The target compounds were synthesized as a result of the interaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide, malononitrile and isatins. When using ethyl cyanoacetate the interaction appeared to be much more complicated and requires further research. The study of the biological activity has revealed the compounds with the analgesic properties and the antimicrobial effect against gram-positive strains.Experimental part. Two new 2-amino-2’-oxospiro[4H-pyrano[3,2-c][1,2]benzoxathiine-4,3’-indoline]-3-carbonitrile 5,5-dioxides were synthesized by the three-component reaction based on 1,2-benzoxathiin-4(3H)-one 2,2-dioxide. The anti-inflammatory activity was studied on the model of the carrageenan induced paw edema, and the analgesic activity was assessed on the model of the local inflammatory hyperalgesia. The study of the antimicrobial activity of the compounds obtained was performed by the agar well diffusion method.Conclusions. New spiro[benzo[е]pyrano[3,2-c][1,2]oxathiin-4,3’-indolil]-3-carbonitrile 5,5-dioxides have been synthesized. The compounds obtained have revealed high levels of the analgesic properties and the antimicrobial activity. The latter exceeds the activity of the reference drugs, and has appeared to be higher against grampositive bacteria. |
| doi_str_mv | 10.24959/ophcj.19.182954 |
| first_indexed | 2025-07-17T13:00:30Z |
| format | Article |
| fulltext |
Журнал органічної та фармацевтичної хімії. – 2019. – Т. 17, вип. 4 (68)
53
ISSN 2518-1548 (Online) ISSN 2308-8303 (Print)
UDC 615.212:615.276:615.281:542.057 https://doi.org/10.24959/ophcj.19.182954
G. V. Grygoriv, D. A. Lega, I. A. Zupanets, S. K. Shebeko, S. M. Zimin,
I. L. Starchikova, L. A. Shemchuk
National University of Pharmacy
53, Pushkinska str., Kharkiv, 61002, Ukraine
E-mail: galkagrigoriv@gmail.com
Spiro[benzo[е]pyrano[3,2-c][1,2]oxathiin-4,3’-indolil]-
3-carbonitrile 5,5-dioxides: synthesis and the biological
activity study
The development of medicines with several pharmacological activities, including the analgesic, anti-inflam-
matory and antimicrobial properties, is one of the challenging tasks of modern medicinal chemistry.
Aim. To expand the range of novel spiro-condensed derivatives of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide,
and study the biological activity of the substances obtained.
Results and discussions. The target compounds were synthesized as a result of the interaction of 1,2-benzo-
xathiin-4(3H)-one 2,2-dioxide, malononitrile and isatins. When using ethyl cyanoacetate the interaction appeared
to be much more complicated and requires further research. The study of the biological activity has revealed
the compounds with the analgesic properties and the antimicrobial effect against gram-positive strains.
Experimental part. Two new 2-amino-2’-oxospiro[4H-pyrano[3,2-c][1,2]benzoxathiine-4,3’-indoline]-3-car-
bonitrile 5,5-dioxides were synthesized by the three-component reaction based on 1,2-benzoxathiin-4(3H)-one
2,2-dioxide. The anti-inflammatory activity was studied on the model of the carrageenan induced paw edema,
and the analgesic activity was assessed on the model of the local inflammatory hyperalgesia. The study of the antimi-
crobial activity of the compounds obtained was performed by the agar well diffusion method.
Conclusions. New spiro[benzo[е]pyrano[3,2-c][1,2]oxathiin-4,3’-indolil]-3-carbonitrile 5,5-dioxides have been
synthesized. The compounds obtained have revealed high levels of the analgesic properties and the antimicro-
bial activity. The latter exceeds the activity of the reference drugs, and has appeared to be higher against gram-
positive bacteria.
Key words: 1,2-benzoxathiin-4(3H)-one 2,2-dioxide; isatins; spiro compounds; analgesic activity; anti-
inflammatory activity; antimicrobial activity
Г. В. Григорів, Д. О. Лега, І. А. Зупанець, С. К. Шебеко, С. М. Зімін, І. Л. Старчікова,
Л. А. Шемчук
Національний фармацевтичний університет, Україна
Спіро[бензо[е]пірано[3,2-с][1,2]оксатіїн-4,3’-індол]-3-карбонітрил 5,5-діоксиди:
синтез і вивчення біологічної активності
Розробка лікарських засобів, що володіють декількома видами фармакологічної активності, включаю-
чи знеболювальну, протизапальну та антимікробну, є одним з важливих завдань сучасної медичної хімії.
Мета. Розширити ряд нових спіроконденсованих похідних 1,2-бензоксатіїн-4(3Н)-он 2,2-діоксиду і до-
слідити біологічну активність одержаних речовин.
Результати та їх обговорення. Цільові сполуки були синтезовані в результаті взаємодії 1,2-бензоксатіїн-
4(3Н)-он 2,2-діоксиду, малонодинітрилу та ізатинів. У випадку використання етилціаноацетату як метиленак-
тивного нітрилу взаємодія виявилася набагато складнішою і потребує подальших досліджень. Вивчення
біологічної активності виявило сполуки з анальгетичними властивостями та антимікробною дією проти
грампозитивних штамів.
Експериментальна частина. Два нових 2-аміно-2’-оксоспіро[4H-пірано[3,2-с][1,2]бензоксатіїн-4,3’-
індолін]-3-карбонітрил 5,5-діоксиди були синтезовані за допомогою трикомпонентної реакції на основі
1,2-бензоксатіїн-4(3Н)-он 2,2-діоксиду. Протизапальну активність вивчали на моделі карагенінового набряку,
анальгетичну активність оцінювали на моделі місцевої запальної гіпералгезії. Були проведені дослідження
антимікробної активності отриманих сполук методом дифузії в агар.
Висновки. Синтезовано нові спіро[бензо[е]пірано[3,2-с][1,2]оксатіїн-4,3’-індол]-3-карбонітрил 5,5-діоксиди.
Отримані сполуки виявили високий рівень анальгетичної та антимікробної активності. Остання перевищує
активність референс-препаратів і виявилася більш ефективною проти грампозитивних бактерій.
Ключові слова: 1,2-бензоксатіїн-4(3H)-он 2,2-діоксид; ізатини; спіроконденсовані сполуки;
анальгетична активність; протизапальна активність; антимікробна активність
Г. В. Григорив, Д. А. Лега, И. А. Зупанец, С. К. Шебеко, С. М. Зимин, И. Л. Старчикова,
Л. А. Шемчук
Национальный фармацевтический университет
Спиро[бензо[е]пирано[3,2-с][1,2]оксатиин-4,3’-индол]-3-карбонитрил 5,5-диоксиды:
синтез и изучение биологической активности
Разработка лекарственных средств с несколькими видами фармакологической активности, включая
анальгетические, противовоспалительные и антимикробные свойства, является одной из важных задач
современной медицинской химии.
Journal of Organic and Pharmaceutical Chemistry. – 2019. – Vol. 17, Iss. 4 (68)
54
ISSN 2308-8303 (Print) ISSN 2518-1548 (Online)
Цель. Расширить ряд новых спироконденсированных производных 1,2-бензоксатиин-4(3Н)-он 2,2-ди-
оксида и изучить биологическую активность полученных веществ.
Результаты и их обсуждение. Целевые соединения были синтезированы в результате взаимодей-
ствия 1,2-бензоксатиин-4(3Н)-он 2,2-диоксида, малонодинитрила и изатинов. В случае использования
этилцианоацетата в качестве метиленактивного нитрила взаимодействие оказалось значительно более
сложным и нуждается в дальнейшем изучении. Исследование биологической активности выявило соеди-
нения с анальгетическими свойствами и антимикробным действием в отношении грамположительных штаммов.
Экспериментальная часть. Два новых 2-амино-2’-оксоспиро[4Н-пирано[3,2-с][1,2]бензоксатиин-4,3’-
индолин]-3-карбонитрил 5,5-диоксида были синтезированы с помощью трехкомпонентной реакции на
основе 1,2-бензоксатиин-4(3Н)-он 2,2-диоксида. Противовоспалительную активность изучали на модели
карагенин-индуцированного отека, а анальгетическую активность оценивали на модели локальной вос-
палительной гипералгезии. Было проведено исследование антимикробной активности полученных соеди-
нений методом диффузии в агар.
Выводы. Синтезированы новые спиро[бензо[е]пирано[3,2-с][1,2]оксатиин-4,3’-индолил]-3-карбонитрил
5,5-диоксиды. Полученные соединения проявили анальгетические свойства и антимикробную активность,
которая превышает активность препаратов сравнения и оказалась выше в отношении грамположитель-
ных бактерий.
Ключевые слова: 1,2-бензоксатиин-4(3H)-он 2,2-диоксид; изатины; спироконденсированные
соединения; анальгетическая активность; противовоспалительная активность; антимикробная
активность
To date the search of novel medicines with the anti-
inflammatory and analgesic properties still remains
one of the challenging tasks in medicinal chemistry
[1, 2]. The reason is that pain belongs to the most
unpleasant feelings among other symptoms. It can be
an independent problem, for example, in the case
of migraine, or it can accompany injuries and sur-
gical interventions, or can be one of the symptoms
of the musculoskeletal system chronic diseases [3].
However, in all cases, pain becomes a source of suf-
fering and significantly disturbs the natural rhythm
of life. It is important to note that chronic pain, re-
gardless of the cause for its occurrence, is a threat
to the patient’s life since it causes such pathological
conditions as depression, anxiety, sleep and immune
disorders, constant tension of the cardiovascular system.
Therefore, attempts to “endure” pain, as well as the re-
commendation “to learn how to live with pain”, seems
to be vicious and harmful [4].
In current therapeutic practice three groups of
analgesics are used most widely. The first of them,
essentially, consists of only one drug – acetaminophen
(paracetamol, “simple analgesic”). The second type
is represented by a very large group of non-steroidal
anti-inflammatory drugs (NSAIDs): aceclofenac, di-
clofenac, ibuprofen, ketorolac, lornoxicam, meloxicam,
metamizol, naproxen, nimesulide, piroxicam, tenoxi-
cam, phenylbutazone, flurbiprofen, celecoxib, etori-
coxib, etc. The third group is opioid analgesics that
mostly belong to prescription drugs [5]. Unquestio-
nably, this does not exhaust the entire arsenal of pain-
killers. There are specific drugs that are used to treat
certain types of chronic pain. Furthermore, medici-
nes with several pharmacological activities, including
the analgesic one, are being also developed.
In our previous studies spiro-condensed deriva-
tives of 1Н-2,1-benzothiazin 2,2-dioxide A (Fig. 1) were
proven to be a novel and promising class of com-
pounds for treating disorders accompanied by inflam-
mation and pain [6]. The antifungal activity was also
revealed for compounds from this group. In con-
tinuation of these studies we paid our attention to
1,2-benzoxathiin 2,2-dioxide B derivatives as isoster-
ic to the abovementioned compounds A.
As the first logical step a wide range of type B
compounds 4a – n was synthesized based on the three-
component interaction of 1,2-benzoxathiin-4(3Н)-one
2,2-dioxide, malononitrile and substituted isatins [7].
In the current study the range of 2-amino-4H-pyran-
3-carbonitriles 4 was additionally expanded using
bioisosteric
replacement of
N with O
B
O
SO2
O
NH2 CN
N
O
R2
R1
R3
A
N
SO2
O
NH2 CN
NH
O
Me Me
Fig. 1. Isosteric relationships between 1Н2,1benzothiazin 2,2dioxide A and 1,2benzoxathiin 2,2dioxide B core
Журнал органічної та фармацевтичної хімії. – 2019. – Т. 17, вип. 4 (68)
55
ISSN 2518-1548 (Online) ISSN 2308-8303 (Print)
isatins 3o,p (Scheme 1). There was also an attempt
to use isatins 3q – s in the same reaction, but no com-
prehensible results were obtained (because of tarring).
In order to extend the variety of spiro-condensed
derivatives of 1,2-benzoxathiin-4(3Н)-one 2,2-dioxi-
de we replaced malononitrile with ethyl cyanoace-
tate 2b. In the case of its use together with other car-
bonyls the complicated results were mostly obtai-
ned [7 – 9]. This time, carrying out the interaction un-
der the same reaction conditions as for malononit-
rile 2a gave ylidene 5a, and the complex mixtures of
the starting compounds with the ylidenes 5 and the tar-
get products 6 for isatins 3b,c,e (Scheme 2). Previous-
ly, the use of N-ethylisatin allowed us to isolate the tar-
get spiro-derivative 6d in a poor yield 5 % [7]. Applica-
tion of other basic catalysts in this research (triethyl-
amine, DBU, sodium acetate) instead of triethanola-
mine led to a slight increase of 6d yield (15 %), but it
was contaminated with 1,2-benzoxathiin-4(3Н)-one
2,2-dioxide 1. Thereby, the three-component interac-
tion of 1,2-benzoxathiin-4(3Н)-one 2,2-dioxide 1, isa-
tins 3 and ethyl cyanoacetate 2b requires further
detailed study. It is worth mentioning that applica-
tion of the two-stage process, namely the synthesis
N
O
O
R1
EtOH
N(CH2CH2OH)3
∆, 1 h
4a–p
O
SO2
O
CN
CN
+
1 3a–s2a
4q
4r
4s
+
CH2OH –
–
–
CH2-(piperidin-1-yl)
R2
4a
4b
4c
4d
4e
4f
4g
4h
71
45
85
88
58
65
91
95
R1 Yield, %
4i
4 j
4k
4l
4m
4n
84
93
91
51
92
36
HH
HCH2COOEt
Bn H
BrH
HAllyl
H
H
H
NO2H
Br
Br
Br
Br
R3
H
H
H
H
H
H
H
H
H
H
H
Br
H
H
4o
4p
35
33CH2CONHPh H H
HH
Et
Me
Me
Me
Me
Me
Bn
Allyl
CH2CONH2
H H
H H
H H
R2
R3
O
SO2
O
NH2 CN
N
O
R2
R1
R3
№
CH2-(morpholin-4-yl)
H
Scheme 1. The interaction of 1,2benzoxathiin4(3Н)one 2,2dioxide 1, malononitrile 2a and isatins 3
Journal of Organic and Pharmaceutical Chemistry. – 2019. – Vol. 17, Iss. 4 (68)
56
ISSN 2308-8303 (Print) ISSN 2518-1548 (Online)
of ylidene 5a and its further reaction with 1,2-ben-
zoxathiin-4(3Н)-one 2,2dioxide 1, resulted only in
isolation of the initial compounds (Scheme 2).
According to the isosteric relationships between
benzothiazine and benzoxathiine cores mentioned
the following types of the biological activity was stu-
died: analgesic, anti-inflammatory, antimicrobial.
The results of testing the analgesic and anti-in-
flammatory activities are given in Tab. 1. Compounds
4g, 4i and 4m had an average effect in the applied
model of inflammation and decreased the edema de-
velopment compared to the control group, but their
activity was twice less than for the reference drug
Piroxicam.
The analgesic activity of the compounds studied
appeared to be generally higher, but variable. The abi-
lity to reduce the pain threshold at the level of Piroxi-
cam was found for spiro[(2-amino-3-cyano-4,6-dihydro-
pyrano[3,2-c][2,1]benzoxathiin-5,5-dioxide)-4,3’-
(5-methylindolin-2’-one)] 4g, but with high variability.
It should be noted that, in general, spiro-deriva-
tives of benzoxathiine 4 displayed the lower level of
the analgesic and anti-inflammatory activities com-
pared to benzothiazine ones mentioned above.
The antimicrobial activity was assessed according
to the international standards [10, 11] by the agar
well diffusion method against the standard test-strains
of gram-positive and gram-negative microorganisms
and fungi. As reference drugs the common represen-
tatives of antibacterial (Synthomycin) and antifungal
(Metronidazole) compounds were used. The results
appeared to be higher than for the reference drugs.
The moderate activity found was higher against gram-
positive bacteria than against gram-negative bacte-
ria and fungi in contrast to the isosteric derivatives of
1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide, which anti-
microbial properties were associated predominantly
with the inhibitory effect on gram-negative strains
and fungi. There was no significant distinction for N-
and 5-substituted derivatives at the isatin core. The re-
sults of studying the antimicrobial properties are pre-
sented in Tab. 2.
Spiro[(2-amino-3-cyano-4,6-dihydropyrano
[3,2-c][2,1]benzoxathiin-5,5-dioxide)-4,3’-(N-ethyl-
indoline-2’-one)] 4d seemed to be the most active
antimicrobial agent among the compounds studied.
Thus, the values of the minimum inhibitory concen-
tration (32.25 μg/mL) and the minimum bacteri-
cidal concentration (62.5 μg/mL) were additionally
found for it.
Experimental chemical part
The starting isatin and active methylene nitriles
were obtained from commercial sources and used
without further purification. 1,2-Benzoxathiin-4(3Н)-one
2,2-dioxide 1 and isatins 3b-s were prepared accor-
ding to the procedures described in [7]. Melting points
were determined on a Gallenkamp melting point ap-
paratus, Model MFB-595 in open capillary tubes. 1H NMR-
spectra were recorded on a Varian WXR-400 spectro-
meter using DMSO-d6 as a solvent and TMS as an inter-
nal standard. Elemental analyses were carried out
using a Carlo Erba CHNS-O EA 1108 analyzer.
The general procedure for the synthesis of
2-amino-2’-oxo-1’-R-spiro[benzo[е]pyrano[3,2-c]-
[1,2]oxathiin-4,3’-indolil]-3-carbonitrile 5,5-dioxi-
des 4o,p. To the solution of 1,2-benzoxathiin-4(3H)-
one 2,2-dioxide 1 (0.198 g, 0.001 mole), malononit-
rile 2a (0.066 g, 0.001 mole) and the appropriate isatin
3o,p (0.001 mole) in ethanol (5 – 10 mL) add 20 mole%
of triethanolamine. Reflux the mixture for 1 h. Filter
the precipitates of 4o,p obtained, wash with ethanol
and then dry in air.
2-(2-Amino-3-cyano-5,5-dioxido-2’-oxospiro-
[benzo[e]pyrano[3,2-c][1,2]oxathiin-4,3’-indolin]-
1’-yl)acetamide 4o. A brown crystalline powder.
M. p. 185 – 187 °С (EtOH); Anal. Calcd. for C21H14N4O6S, %:
С 56.00, Н 3.13, N 12.44. Found, %: С 55.87, Н 2.95,
N 12.61. 1Н NMR (400 MHz, DMSO-d6), δ, ppm: 7.90 – 7.98
(1H, m, Ar-H), 7.82 (2H, s, NH2), 7.73 – 7.76 (1H, m, Ar-H),
7.57 – 7.63 (1H, m, Ar-H), 7.49 – 7.56 (1H, m, Ar-H),
7.41 – 7.48 (1H, m, Ar-H), 7.32 – 7.40 (2H, m, CONH2),
6.96 – 7.16 (3H, m, Ar-H), 4.16 – 4.36 (2H, m, CH2).
2-(2-Amino-3-cyano-5,5-dioxido-2’-oxospiro-
[benzo[e]pyrano[3,2-c][1,2]oxathiin-4,3’-indo-
lin]-1’-yl)-N-phenylacetamide (4p). A brown crys-
talline powder. M. p. 238 – 240 °С (EtOH); Anal. Calcd.
for C27H18N4O6S, %: С 61.59, Н 3.45, N 10.64. Found, %:
С 61.35, Н 3.27, N 10.51. 1Н NMR (400 МHz, DMSO-d6),
δ, ppm: 10.14 (1H, s, NH); 7.93 – 7.98 (1H, m,
Ar-H); 7.80 (2H, s, NH2); 7.71 – 7.77 (1H, m, Ar-H);
7.51 – 7.63 (4H, m, Ar-H); 7.44 – 7.49 (1H, m, Ar-H);
7.27 – 7.33 (2H, m, Ar-H); 7.01 – 7.14 (3H, m, Ar-H);
4.46 – 4.65 (2H, m, CH2).
N
O
O
R
O
SO2
O
CN
+
1
3a–e
O
SO2
O
NH2
N
O
EtOH, cat
6d (15%)
Me
O
SO2
O
+
1
N
O
H
NC
CO2Et
5a
2b
EtOH
N(CH2CH2OH)3
∆, 1 h
CO2Et
∆, 4 h
CO2Et
Scheme 2. The interaction of 1,2benzoxathiin4(3Н)one 2,2dioxide 1, ethyl cyanoacetate 2b and isatins 3
Журнал органічної та фармацевтичної хімії. – 2019. – Т. 17, вип. 4 (68)
57
ISSN 2518-1548 (Online) ISSN 2308-8303 (Print)
Experimental biological part
The study of the anti-inflammatory and analgesic
activities was performed in albino adult male and fe-
male rats weighing 150 – 180 g. The animals were ran-
domly divided into seven groups of equal number
(control, 5 experimental and comparison groups).
The use of Piroxicam (Chervona Zirka, Ukraine) as
the reference drug was due to its isosteric relation-
ships with the core of 1,2-benzoxathiine 2,2-dioxide.
The anti-inflammatory activity was studied on the mo-
del of the carrageenan induced paw edema, and the anal-
gesic activity was evaluated on the model of the lo-
cal inflammatory hyperalgesia. Pathology in both ca-
ses was reproduced by the intraplantar injection of
0.1 mL of 1 % solution of γ-carrageenan (Sigma, USA)
Table 1
The results of the study of the anti-inflammatory and analgesic activities of compounds 4
Compound Dose
(mg/kg)
The average percentage
of edema, %*
Anti-inflammatory
activity, %*
Reducing the pain
threshold, %*
Analgesic
activity, %*
O
SO2
O
NH2
N
O
H
CN
4a
2.4 54.27 ± 3.93** 3.3 ± 2.2** 30.6 ± 9.0 46.8 ± 13.3
O
O
N
O
H
CN
Me
SO2
NH2
4g
2.4 35.81 ± 1.65*,** 24.0 ± 3.5** 23.5 ± 5.8* 53.4 ± 11.5
O
O
N
O
H
CN
Br
SO2
NH2
4i
2.8 36.25 ± 4.45** 24.6 ± 8.6** 38.3 ± 5.1** 27.7 ± 7.5**
O
O
N
O
Me
CN
Me
SO2
NH2
4m
2.5 42.02 ± 7.52** 23.5 ± 11.5 26.1 ± 6.5* 48.2 ± 13.0
O
O
N
O
H
CN
Br
SO2
NH2
4n
3.3 51.61 ± 6.7** 8.0 ± 3.1** 29.3 ± 11.7 46.8 ± 21.0
S
N
OH
MeO O
O
N
H
N
Piroxicam
2 23.81 ± 2.73* 49.4 ± 5.8 22.7 ± 3.3* 55.0 ± 6.6
Control – 47.1 ± 3.2 – 50.4 ± 3.1 –
Notes: * – the deviation is valid for the control (р ≤ 0.05); ** – the deviation is valid for Piroxicam (р ≤ 0.05).
Journal of Organic and Pharmaceutical Chemistry. – 2019. – Vol. 17, Iss. 4 (68)
58
ISSN 2308-8303 (Print) ISSN 2518-1548 (Online)
into the right hind limb of rats [12, 13]. The test com-
pounds and the reference drug were introduced oral-
ly as fine aqueous suspensions stabilized with Tween-80
one hour prior to the γ-carrageenan injection. The scre-
ening dose for Piroxicam was 2 mg/kg, the test com-
pounds were introduced in the doses that were equi-
molar to the reference drug. The control group recei-
ved an equivalent amount of Tween-80 water solution.
The initial and final values of the paw edema vo-
lume were measured by the water displacement me-
thod using a digital plethysmometer (IITC Life Science,
USA). The final values of the paw edema volume were
received 3 h after the phlogogen agent injection.
The initial values of the pain threshold were mea-
sured using an Ugo Basile 37215 analgesimeter [14, 15],
and the final values of the pain threshold were ob-
Table 2
The antimicrobial activity of spiro[benzo[e]pyrano[3,2-c][1,2]oxatiamine-4,3’-indolyl] 5,5-dioxides
Compound
Diameter of the growth inhibition zones (average for three experiments), mm
Gram-positive bacteria Gram-negative bacteria Fungi
S. aureus E. coli B. subtilis P. aeruginosa P. vulgaris C. albicans
Metronidazole 14 14 16 0 0 14
Synthomycin 14 17 17 17 17 0
O
SO2
O
NH2
N
O
H
CN
4a
22 19 22 17 16 18
O
O
CN
N
O
CH2COOEt
SO2
NH2
4b
21 19 22 16 16 17
O
O
CN
N
O
Allyl
SO2
NH2
4c
21 19 23 16 17 18
O
O
CN
N
O
Et
SO2
NH2
4d
22 20 23 17 17 18
O
O
CN
N
O
Bn
SO2
NH2
4e
22 19 22 16 17 18
O
O
N
O
H
CN
Br
SO2
NH2
4i
21 20 22 15 16 18
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tained on the inflamed paw 2 h after administration
of the test substances.
The anti-inflammatory activity (%) was expres-
sed as percentage of edema inhibition in the animals
treated with the test compound and Piroxicam com-
pared to the control rats. The anti-inflammatory ac-
tivity was calculated by the formula:
100 %,.AIA =
ΔVc
ΔVc – ΔVe
where: AIA – is the anti-inflammatory activity, %;
∆Vc – is the average percentage of edema in the cont-
rol group, %; ∆Ve – is the average percentage of edema
in the experimental group (comparison group), %.
The analgesic activity was evaluated by the change
of the pain threshold checked on the inflamed paw
in the rats received the test compound and the refe
rence drug compared to the animals from the con-
trol group. The analgesic activity was calculated by
the formula:
100 %,.AA =
ΔPTc
ΔPTc – ΔPTe
where: АА – is the analgesic activity, %; ∆PTc – is the ave-
rage percentage of the pain threshold decrease in
the control group, %; ∆PTe – is the average percentage
of the pain threshold decrease in the experimental
group (comparison group), %.
The results of biological tests were also proces-
sed by the method of variation statistics using Stu-
dent’s t-criterion and Mann – Whitney U Test, and such
programs as STATISTIСА 7.0, Stat-Plus 2009 and MS
Exсel 2007 [16 – 18]. The current study was carried
out in full compliance with the Directive 86/609/EU
of the European Parliament and of the Council of
24 November 1986 on protection of animals used
for scientific purposes [19, 20].
Experimental microbiological part
According to the WHO recommendations [10],
the following test-strains were used: Staphylo-
coccus aureus АТСС 25923, Escherichia coli АТСС
25922, Pseudomonas aeruginosa АТСС 27853, Bacil-
lus subtilis АТСС 6633, Proteus vulgaris ATCC 4636,
Candida albicans АТСС 653/885. The inoculum sus-
pension was prepared using a Densi-La-Meter ap-
paratus (made by PLIVA-Lachema, Czech Republic;
the wavelength of 540 nm).
The suspension was prepared according to the ma-
nual for the device and the information sheet No 163-2006
“Standardization for preparation of microbial sus-
pensions” (Kyiv) about innovations in the healthcare
system. The inoculum density was 107 cells in 1 mL
of the medium, and it was determined by compar-
ing to McFarland standard [21]. The 18 to 24-hour
old cultures of the microorganisms were employed
for the test. For the antimicrobial evaluation the
Mueller – Hinton agar was used, for Candida albicans
strain the Sabouraud agar was taken. The compounds
were introduced into agar by the “well” method [10].
The antibacterial activity was evaluated by measur-
ing zones of inhibition of the corresponding microor-
ganism and was compared to those for the reference
antimicrobial drugs.
The bacteriostatic and bactericidal activity of new
compounds was determined in accordance with the re-
quirements of the State Pharmacopoeia of Ukraine
(ed. 1) by the double serial dilution method in the li-
quid growth medium. Testing was made in the volu-
me of 1 mL of each dilution of substances with the fi-
nal concentration of the microorganism under study
about 5 × 105 CFU/mL. After incubation for a day or
48 – 72 hours for Candida spp. the cuvettes were seen
in bright light to determine the presence of the micro-
organism growth. The minimum inhibitory concentra-
tion (MIC) was set at the lowest concentration of
the test substance, which suppressed the apparent
growth of the culture. To determine the minimum bac-
tericidal concentration (MBC), dosage seeds were fed
on a solid nutrient medium (Muller – Hillton agar) of
the culture fluid from all the tubes, in which no growth
of the microorganism was observed. The lowest con-
centration, which caused the death of at least 90% of
bacteria, was taken as the MBC. The additional cont-
rol was performed for the culture in the medium without
the substances studied, in the solvent; the purity of
the suspension with the microorganism (by seeding
on the non-selective media) and the sterility of the me-
dium were controlled.
Conclusions
1. The use of malononitrile in the three-compo-
nent interaction with 1,2-benzoxathiin-4(3H)-one
2,2-dioxide and isatins has led to the formation of
the target amino-2’-oxospiro[4H-pyrano[3,2-c][1,2]
benzoxathiine-4,3’-indoline]-3-carbonitrile 5,5-di-
oxides. The replacement of malononitrile with ethyl
cyanoacetate in the reaction has resulted in mix-
tures of the target and starting compounds.
2. The analgesic activity of the spiro-derivatives
synthesized has appeared to be generally higher than
the anti-inflammatory one.
3. The current study implies that 1,2-benzox-
athiin 2,2-dioxide pyran-annulated derivatives are
lower active than those constructed on the basis of
1Н-2,1-benzothiazin-4(3H)-one 2,2-dioxide.
4. The compounds synthesized have appeared to
be unpromising antimicrobial agents.
Conflict of interests: authors have no conflict of
interests to declare.
Journal of Organic and Pharmaceutical Chemistry. – 2019. – Vol. 17, Iss. 4 (68)
60
ISSN 2308-8303 (Print) ISSN 2518-1548 (Online)
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Надійшла до редакції 07. 10. 2019 р.
|
| id | oai:ojs.journals.uran.ua:article-182954 |
| institution | Journal of Organic and Pharmaceutical Chemistry |
| issn | 2518-1548 |
| keywords_txt_mv | |
| language | English |
| last_indexed | 2026-08-25T01:01:20Z |
| publishDate | 2026 |
| publisher | National University of Pharmacy |
| record_format | ojs |
| resource_txt_mv | ophcjnupheduua/81/a688a29caa75def5c01aec669429e381.pdf |
| spelling | oai:ojs.journals.uran.ua:article-1829542026-08-24T18:27:32Z Spiro[benzo[е]pyrano[3,2-c][1,2]oxathiin-4,3’-indolil]-3-carbonitrile 5,5-dioxides: synthesis and the biological activity study Спиро[бензо[е]пирано[3,2-с][1,2]оксатиин-4,3’-индол]-3-карбонитрил 5,5-диоксиды: синтез и изучение биологической активности Спіро[бензо[е]пірано[3,2-с][1,2]оксатіїн-4,3’-індол]-3-карбонітрил 5,5-діоксиди: синтез і вивчення біологічної активності Grygoriv, G. V. Lega, D. A. Zupanets, I. A. Shebeko, S. K. Zimin, S. M. Starchikova, I. L. Shemchuk, L. A. 1 2-benzoxathiin-4(3H)-one 2 2-dioxide isatins spiro compounds analgesic activity anti-inflammatory activity antimicrobial activity UDC 615.212 615.276 615.281 542.057 1 2-бензоксатиин-4(3H)-он 2 2-диоксид изатины спироконденсированные соединения анальгетическая активность противовоспалительная активность антимикробная активность УДК 615.212 615.276 615.281 542.057 1 2-бензоксатіїн-4(3H)-он 2 2-діоксид ізатини спіроконденсовані сполуки анальгетична активність протизапальна активність антимікробна активність УДК 615.212 615.276 615.281 542.057 The development of medicines with several pharmacological activities, including the analgesic, anti-inflammatory and antimicrobial properties, is one of the challenging tasks of modern medicinal chemistry.Aim. To expand the range of novel spiro-condensed derivatives of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide, and study the biological activity of the substances obtained.Results and discussions. The target compounds were synthesized as a result of the interaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide, malononitrile and isatins. When using ethyl cyanoacetate the interaction appeared to be much more complicated and requires further research. The study of the biological activity has revealed the compounds with the analgesic properties and the antimicrobial effect against gram-positive strains.Experimental part. Two new 2-amino-2’-oxospiro[4H-pyrano[3,2-c][1,2]benzoxathiine-4,3’-indoline]-3-carbonitrile 5,5-dioxides were synthesized by the three-component reaction based on 1,2-benzoxathiin-4(3H)-one 2,2-dioxide. The anti-inflammatory activity was studied on the model of the carrageenan induced paw edema, and the analgesic activity was assessed on the model of the local inflammatory hyperalgesia. The study of the antimicrobial activity of the compounds obtained was performed by the agar well diffusion method.Conclusions. New spiro[benzo[е]pyrano[3,2-c][1,2]oxathiin-4,3’-indolil]-3-carbonitrile 5,5-dioxides have been synthesized. The compounds obtained have revealed high levels of the analgesic properties and the antimicrobial activity. The latter exceeds the activity of the reference drugs, and has appeared to be higher against grampositive bacteria. Разработка лекарственных средств с несколькими видами фармакологической активности, включая анальгетические, противовоспалительные и антимикробные свойства, является одной из важных задач современной медицинской химии.Цель. Расширить ряд новых спироконденсированных производных 1,2-бензоксатиин-4(3Н)-он 2,2-диоксида и изучить биологическую активность полученных веществ.Результаты и их обсуждение. Целевые соединения были синтезированы в результате взаимодействия 1,2-бензоксатиин-4(3Н)-он 2,2-диоксида, малонодинитрила и изатинов. В случае использования этилцианоацетата в качестве метиленактивного нитрила взаимодействие оказалось значительно более сложным и нуждается в дальнейшем изучении. Исследование биологической активности выявило соединения с анальгетическими свойствами и антимикробным действием в отношении грамположительных штаммов.Экспериментальная часть. Два новых 2-амино-2’-оксоспиро[4Н-пирано[3,2-с][1,2]бензоксатиин-4,3’-индолин]-3-карбонитрил 5,5-диоксида были синтезированы с помощью трехкомпонентной реакции на основе 1,2-бензоксатиин-4(3Н)-он 2,2-диоксида. Противовоспалительную активность изучали на модели карагенин-индуцированного отека, а анальгетическую активность оценивали на модели локальной воспалительной гипералгезии. Было проведено исследование антимикробной активности полученных соединений методом диффузии в агар.Выводы. Синтезированы новые спиро[бензо[е]пирано[3,2-с][1,2]оксатиин-4,3’-индолил]-3-карбонитрил 5,5-диоксиды. Полученные соединения проявили анальгетические свойства и антимикробную активность, которая превышает активность препаратов сравнения и оказалась выше в отношении грамположительных бактерий. Розробка лікарських засобів, що володіють декількома видами фармакологічної активності, включаючи знеболювальну, протизапальну та антимікробну, є одним з важливих завдань сучасної медичної хімії.Мета. Розширити ряд нових спіроконденсованих похідних 1,2-бензоксатіїн-4(3Н)-он 2,2-діоксиду і дослідити біологічну активність одержаних речовин.Результати та їх обговорення. Цільові сполуки були синтезовані в результаті взаємодії 1,2-бензоксатіїн-4(3Н)-он 2,2-діоксиду, малонодинітрилу та ізатинів. У випадку використання етилціаноацетату як метиленактивного нітрилу взаємодія виявилася набагато складнішою і потребує подальших досліджень. Вивчення біологічної активності виявило сполуки з анальгетичними властивостями та антимікробною дією проти грампозитивних штамів.Експериментальна частина. Два нових 2-аміно-2’-оксоспіро[4H-пірано[3,2-с][1,2]бензоксатіїн-4,3’-індолін]-3-карбонітрил 5,5-діоксиди були синтезовані за допомогою трикомпонентної реакції на основі 1,2-бензоксатіїн-4(3Н)-он 2,2-діоксиду. Протизапальну активність вивчали на моделі карагенінового набряку, анальгетичну активність оцінювали на моделі місцевої запальної гіпералгезії. Були проведені дослідження антимікробної активності отриманих сполук методом дифузії в агар.Висновки. Синтезовано нові спіро[бензо[е]пірано[3,2-с][1,2]оксатіїн-4,3’-індол]-3-карбонітрил 5,5-діоксиди. Отримані сполуки виявили високий рівень анальгетичної та антимікробної активності. Остання перевищує активність референс-препаратів і виявилася більш ефективною проти грампозитивних бактерій. National University of Pharmacy 2026-08-24 Article Article application/pdf https://ophcj.nuph.edu.ua/article/view/ophcj.19.182954 10.24959/ophcj.19.182954 Journal of Organic and Pharmaceutical Chemistry; Vol. 17 No. 4(68) (2019); 53-61 Журнал органической и фармацевтической химии; Том 17 № 4(68) (2019); 53-61 Журнал органічної та фармацевтичної хімії; Том 17 № 4(68) (2019); 53-61 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/ophcj.19.182954/185179 Copyright (c) 2019 National University of Pharmacy https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | 1 2-бензоксатіїн-4(3H)-он 2 2-діоксид ізатини спіроконденсовані сполуки анальгетична активність протизапальна активність антимікробна активність УДК 615.212 615.276 615.281 542.057 Grygoriv, G. V. Lega, D. A. Zupanets, I. A. Shebeko, S. K. Zimin, S. M. Starchikova, I. L. Shemchuk, L. A. Спіро[бензо[е]пірано[3,2-с][1,2]оксатіїн-4,3’-індол]-3-карбонітрил 5,5-діоксиди: синтез і вивчення біологічної активності |
| title | Спіро[бензо[е]пірано[3,2-с][1,2]оксатіїн-4,3’-індол]-3-карбонітрил 5,5-діоксиди: синтез і вивчення біологічної активності |
| title_alt | Spiro[benzo[е]pyrano[3,2-c][1,2]oxathiin-4,3’-indolil]-3-carbonitrile 5,5-dioxides: synthesis and the biological activity study Спиро[бензо[е]пирано[3,2-с][1,2]оксатиин-4,3’-индол]-3-карбонитрил 5,5-диоксиды: синтез и изучение биологической активности |
| title_full | Спіро[бензо[е]пірано[3,2-с][1,2]оксатіїн-4,3’-індол]-3-карбонітрил 5,5-діоксиди: синтез і вивчення біологічної активності |
| title_fullStr | Спіро[бензо[е]пірано[3,2-с][1,2]оксатіїн-4,3’-індол]-3-карбонітрил 5,5-діоксиди: синтез і вивчення біологічної активності |
| title_full_unstemmed | Спіро[бензо[е]пірано[3,2-с][1,2]оксатіїн-4,3’-індол]-3-карбонітрил 5,5-діоксиди: синтез і вивчення біологічної активності |
| title_short | Спіро[бензо[е]пірано[3,2-с][1,2]оксатіїн-4,3’-індол]-3-карбонітрил 5,5-діоксиди: синтез і вивчення біологічної активності |
| title_sort | спіро[бензо[е]пірано[3,2-с][1,2]оксатіїн-4,3’-індол]-3-карбонітрил 5,5-діоксиди: синтез і вивчення біологічної активності |
| topic | 1 2-бензоксатіїн-4(3H)-он 2 2-діоксид ізатини спіроконденсовані сполуки анальгетична активність протизапальна активність антимікробна активність УДК 615.212 615.276 615.281 542.057 |
| topic_facet | 1 2-benzoxathiin-4(3H)-one 2 2-dioxide isatins spiro compounds analgesic activity anti-inflammatory activity antimicrobial activity UDC 615.212 615.276 615.281 542.057 1 2-бензоксатиин-4(3H)-он 2 2-диоксид изатины спироконденсированные соединения анальгетическая активность противовоспалительная активность антимикробная активность УДК 615.212 615.276 615.281 542.057 1 2-бензоксатіїн-4(3H)-он 2 2-діоксид ізатини спіроконденсовані сполуки анальгетична активність протизапальна активність антимікробна активність УДК 615.212 615.276 615.281 542.057 |
| url | https://ophcj.nuph.edu.ua/article/view/ophcj.19.182954 |
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