16
контрольных вопросов и практических навыков по текущей теме занятия, которые должен
знать каждый студент на кафедре физиологии.
Результаты.
В результате самостоятельной работы у студента должны развиться
такие умения, как умение учиться самостоятельно, принимать решения, проводить
исследования, осуществлять и организовывать коммуникацию, формулировать
получаемые результаты, переопределять цели дальнейшей работы, корректировать свое
образовательное направление.
На протяжении всей самостоятельной работы студентов в роли координатора
действий и консультанта должен выступать педагог.
Заключение
. Таким образом, организация самостоятельной подготовки является
многоэтапной, которая включает в себя разнообразные методики преподавания, работа,
направленная на повышение уровня знаний студентов.
Литература/References:
1.
Насонова Н.А. [и др.]. Роль воспитательной работы в медицинском вузе в
формировании нравственного облика врача//Инновационные обучающие технологии в
медицине: сб. матер. Республиканской научно-практической конф. с международным
участием. - 2017. - С. 356-357.
2.
Козловский А.А., Козловская М.М., Мельник С.Н. «Организация внеаудиторной
самостоятельной работы студентов в медицинских вузах» Учебно-методическое пособие
для студентов медицинских вузов, клинических ординаторов, аспирантов, врачей-
интернов. Гомель. ГомГМУ. 2014
3.
Писарев Н.Н. [и др.]. Стиль педагогического общения преподавателя и
студентов//Однораловские морфологические чтения: сб. научн. тр., посвящ. 120-летию со
дня рождения проф. Н.И.Одноралова и 100-летию ВГМУ им. Н.Н.Бурденко. - 2018. - С. 210-
212.
4.
Фетисов С.О., Карандеева А.М., Соболева М.Ю. Проблемы формирования
профессиональных компетенций в процессе самостоятельной работе студентов,
обучающихся
на
иностранном
языке//Медицинское
образование
XXI
века:
компетентностный подход и его реализация в системе непрерывного медицинского и
фармацевтического образования: Сб. матер. Республиканской научно-практич. конф. с
международн. участ. - Витебский гос. мед. ун-т, 2017. - С. 477-479.
5.
Гладилина Г.А. Использование информационно-коммуникационных технологий в
формировании
профессиональных
компетенций
студентов
при
организации
самостоятельной работы. http//jdanova-ren.narod.ru/obob/gladilina.htm
6.
Ходжаева Д.Т., Хайдарова Д.К., Хайдарова Н.К. Рекомендации по снижению
депрессивных и тревожных расстройств в условиях карантина по коронавирусной
инфекции. Услубий – тавсиянома. Бухоро-2020.
УДК: 66.091.2-615.276
THE REACTION OF SUBSTITUTED BENZOYLISOTHIOCYANATES WITH
METHIONINE AND STUDY OF THE ANTI–INFLAMMATORY ACTIVITY OF THE
SYNTHESIZED COMPOUNDS
Abduvakilov J. U.
a
Baltabaev U.A.
b
,
a) Samarkand State Medical Institute, 18, Amir Temur street, Samarkand, Uzbekistan.
b)Tashkent state dental institute. 103, Mahtumkuli street, Tashkent, Uzbekistan.
17
Abstract: The thiourea derivatives were synthesized by the reaction of substituted benzoyl
isothiocyanates and α–amino acid – methionine in a dimethylformamide medium. The anti–
inflammatory activity of the obtained compounds was studied. It has been established that N–
(meta–iodobenzoyl) –NI–methionylthiourea has a much greater latitude of anti–inflammatory
action and is of undoubted practical interest.
Keywords. thiourea; benzoyl isothiocyanate; α-Amino acids; methionine; methionylthiourea
Inflammation; anti-inflammatory activities.
РЕАКЦИЯ ЗАМЕЩЕННЫХ БЕНЗОИЛИЗОТИОЦИАНАТОВ С
МЕТИОНИНОМ И ИЗУЧЕНИЕ ПРОТИВОВОСПАЛИТЕЛЬНОЙ АКТИВНОСТИ
СИНТЕЗИРОВАННЫХ СОЕДИНЕНИЙ.
Ж.У. Абдувакилов, У.А. Балтабаев
Introduction.
The reaction of primary amines with isothiocyanes usually results in
unsymmetrical 1,3-disubstituted thioureas. However, according to some data [1-3], the
condensation of heterocyclic amines with AITC with longer heating is ambiguous: along with
asymmetrically 1,3-disubstituted thioureas, symmetrically 1,3-disubstituted thioureas are formed.
Symmetrical substituted thioureas, apparently, are products of secondary transformations of the
formed asymmetric thioureas, the cleavage of which leads to the accumulation of two different
amines and two different isothiocyanates in the mixture, then giving two symmetric thioureas:
RNCS + R
1
NH
2
⇄
RNHC (S) NHR
1
⇄
RNH
2
+ R
1
NCS
R
1
NH
2
+ R
1
NCS → R
1
NHC(S)NHR
1
RHN
2
+ RNCS → RNHC(S)NHR
The driving force behind this transformation is the difference in the basicity of the amines
RNH2 and and R1NH2, on the one hand, and the reactivity of amines and aryl isothiocyanates, on
the other. The ratio of the reaction products depends on the stability of the initially formed thiourea
derivative.
Considering that α-amino acids are non-toxic, have very interesting and diverse properties
[4-6] and are, along with proteins, natural constituents of food products, we decided to carry out
the synthesis of thiourea derivatives based on amino acids.
For the synthesis of thiourea derivatives, prolonged heating is often required, and the
product yield is usually low [7-9]. One of the main tasks of our study is the development of new
methods for the preparation of thiourea derivatives based on -amino acids with a high yield of
the target product while reducing the duration of the synthesis time and identifying new biological
properties among them.
In the literature [10], methods for obtaining substituted thioureas based on various amino
acids are given.
Synthesis processes involving substituted aroyl isothiocyanates with α - amino acids have
not been previously studied. This determined the need to develop new reaction methods in order
to obtain thiourea derivatives and to increase the yield of products, to study the patterns of such
reactions, to reveal the biological activity of the synthesized compounds, in order to increase the
arsenal of biologically active substances, to make judgments about the reaction mechanism for the
formation of substituted thioureas.
It is known that among thiourea derivatives there are physiologically active compounds
that have antimicrobial, anti-tuberculosis, antiulcer and anti-inflammatory activity [11-20].
Materials and methods
In order to obtain compounds with anti-inflammatory properties, we synthesized thiourea
derivatives by the reaction of substituted benzoyl isothiocyanates with an α-amino acid -
methionine in dimethylformamide according to the scheme:
18
Experimental part.
N- (para-bromobenzoyl) - NI - methionylthiourea (VI). A solution
consisting of 1.64 g (0.011 mol) of methionine in 20 ml of dimethylformamide is placed into a
four-necked flask with a capacity of 250 ml, equipped with a reflux condenser with a calcium
chloride tube, an auto-stirrer, a thermometer, and a dropping funnel, heated to a temperature of 55-
60 ° C, and added dropwise 2.42 g (0.01 mol) of para-bromobenzoyl isothiocyanate in 20 ml of
dimethylformamide. The reaction mixture is kept for 5 hours at a temperature of 85 ° C.
At the end of the reaction, the mixture is cooled and 150-200 ml of water is added. The
formed precipitate is filtered off, washed with water and 10% hydrochloric acid solution. The
resulting product is dried at a temperature of 40-50 ° C. N– (para – bromobenzoyl) –N1 –
methionylthiourea recrystallized from benzene has a melting point of 214–215 ° C in 2.8 g yield
(60% of theory). The completeness of the purification is controlled by TLC on alumina. The rest
of the compounds (I – V, VII – XII) were obtained in a similar way.
Results and discussion.
The obtained compounds I – XII (Table 1) are white crystals,
soluble in most organic solvents and insoluble in water.
The structure of the synthesized compounds was confirmed by analytical data and IR
spectroscopy.
The IR spectra have similar absorption bands characteristic of C = S, NH – CS, N – CS –
N, CH = CH aryl, C = O, OH, NH and CH bonds. Thus, the IR spectrum of compound II has an
absorption band at 1115 cm – 1, which is inherent in stretching vibrations of the C = S bond, an
absorption band at 1330 cm – 1 indicates the presence of an N – CS – N bond, the band at 1480
cm – 1 corresponds to stretching vibrations of the NH – CS group. The CH = CH groups of phenyl
are characterized by an absorption band at 1610 cm – 1. The absorption regions at 1710 cm – 1
and 1580 cm – 1 are characteristic of the C = O bond. For CH, OH and NH groups, absorption
bands are characteristic in the region of 2930 cm – 1, 2610 cm – 1, 3400 cm – 1, respectively.
For example, in the IR spectrum of N– (meta-bromobenzoyl) - N1 - methionylthiourea (V),
there is an absorption band of stretching vibrations of the C-Br bond in the region of 532 cm-1,
there is an absorption band for the C = S group at 1069 cm-1, there are absorption bands
characteristic of C – N bonds in the region of 1302 cm-1, for N-C (S) -N groups at 1181, 1287,
1302 cm-1 for NH-CS group at 1489 cm-1, for HC = CH groups of the phenyl radical in the region
of 1610 cm – 1, for C = O bonds at 1570 cm – 1, for N – H groups at 3180, 3362 cm – 1.
It is known that thiourea derivatives, along with other types of pharmacological activity,
exhibit an anti-inflammatory effect [12-14].
The study of the anti-inflammatory activity of compounds I – XII was carried out on
white rats of both sexes weighing 140–180 g. Inflammation was caused by 1% formalin solution,
which was injected under the aponeurosis of the ankle joint in an amount of 0.2 ml. The paw
volume of rats was measured oncometrically 3 times before and 3, 6 hours after formalin
administration.
The test compounds were administered orally using a metal probe in the form of a
suspension in cottonseed oil at doses of 50, 100, and 200 mg / kg. The drugs were administered 1
before causing inflammation, that is, 2 hours before the introduction of formalin.
19
Physicochemical characteristics of thiourea derivatives of general formula
Table 1
№
-R
Output %
Melting
temperature
Rƒ
Formula
I
2–Cl
72
148–9
0.75
C
13
H
15
N
2
O
3
S
2
Cl
II
3–Cl
75
153–4
0.62
C
13
H
15
N
2
O
3
S
2
Cl
III
4–Cl
82
161–2
0.83
C
13
H
15
N
2
O
3
S
2
Cl
IV
2–Br
69
133–4
0.69
C
13
H
15
N
2
O
3
S
2
Br
V
3–Br
72
174–5
0.64
C
13
H
15
N
2
O
3
S
2
Br
VI
4–Br
78
214–5
0.73
C
13
H
15
N
2
O
3
S
2
Br
VII
2–I
66
139–40
0.54
C
13
H
15
N
2
O
3
S
2
I
VIII
3–I
70
172–3
0.75
C
13
H
15
N
2
O
3
S
2
I
IX
4–I
74
185–6
0.68
C
13
H
15
N
2
O
3
S
2
I
X
2–NO
2
75
190–1
0.73
C
13
H
15
N
2
O
5
S
2
XI
3– NO
2
78
175–6
0.66
C
13
H
15
N
2
O
5
S
2
XII
4– NO
2
86
171–2
0.61
C
13
H
15
N
2
O
5
S
2
For comparison, well-known anti-inflammatory drugs were taken - butadion (Butadion),
indomethacin (Indometacin) and Voltaren (Voltaren). They have been used in doses that produce
the most pronounced anti-inflammatory effect. (Table 2).
As a result of the studies carried out, it was found that all substances (I – XII) in certain
doses exhibit a distinct anti-inflammatory activity. Among them, the compounds were
comparatively less active, which, within the dose range of 50-200 mg / kg, reduce the intensity of
the inflammatory process by about 17.5-25%. Compounds III, VII – XII have a stronger anti-
inflammatory effect. In doses of 50-200 mg / kg, they suppress formalin edema by 27-45%.
Compound VIII has a rather strong anti-inflammatory effect, so at doses of 50 and 100 mg / kg
after 6 hours it suppresses inflammation by 71.6% and 79.1%, respectively. A further increase in
the dose of the drug did not lead to a noticeable increase in the observed effect. While butadione
at a dose of 100 mg / kg suppresses inflammation by 28.1%, indomethacin at a dose of 10 mg / kg
by 36.4%, voltaren at a dose of 25 mg / kg by 43.2%.
The acute toxicity of the test compounds was determined by calculating the LD50
according to the Litchfield and Wilcoxon method. White mice weighing 18–25 g were injected
with the study drug orally. Each dose was tested in 6 animals. The experimental animals were
observed for 24 hours.
Tests have shown that the LD50 of the compounds is outside 2000mg / kg, while the LD50
of butadione is 430mg / kg, indomethacin –47mg / kg, voltaren 370mg / kg.
Comparison of these data shows that test compound VIII was less toxic than butadione by
4.6 times, indomethacin by 42.6 times, and voltaren by 5.4 times.
Thus, it has been established that of the tested new thiourea derivatives, only compound
VIII, that is, N– (meta-iodobenzoyl) –NI – methionylthiourea, has a significantly greater breadth
of anti-inflammatory action and is of undoubted practical interest.
Table 2.
Anti-inflammatory activity of thiourea derivatives
Compound
Anti-inflammatory activity% Acute toxicity LD50 mg / kg
20
I
21
>2000
II
17,5
>>
III
33,7
>>
IV
19,2
>>
V
25
>>
VI
28
>>
VII
38,5
>>
VIII
79,1
>>
IX
27
>>
X
36,1
>>
XI
39
>>
XII
45
>>
Butadion
28,1
430
Indometacin
36,4
47
Voltaren
43,2
370
Литература/References:
1.
Galstukhova N.B., Shchukina M.N., Berzina I.M. Synthesis of thiourea derivatives V.
Arylthiocarbanilides // Journal of Organ Chemistry. 1967. V.3. S.2134-2139.
2. Novikov E.G., Tugarinova I.N. Selective di (
-oxyethylation) of diamines at the less basic
amino group // Chemistry heterocycle. connect. 1968. T. 4. S. 281-283.
3.A.S. 1391041. N- (Methancarboxy) -N1-p-chlorobenzoylthiourea as an accelerator for
vulcanization of a rubber compound / Makhsumov A.G., Baltabaev U.A., Tukhtamuradov Z.T.,
Asatov Kh., Sadetova Zh.M. - Applied. 12/23/85; No. 3969133; publ. 12/22/87.
4. Pat. 3825560. USA. N-monoacyl derivatives of arginine / Tadaomi S., Masahiro T., Kazuhiko
Y., Ryonosuke Y., Yukiko S. - Appr. 06/28/71; publ. 07/23/74. // RZhKhim. 1975.9 R 492 P.
5. Berezin B.D., Berezin D. B. Course in modern organic chemistry. - M .: Higher school.
1999.768 p.
6. Application 55-620066. Japan. N- (2-substituted pyridyl-4) ureas and thioureas, a method
for their preparation and growth regulators based on them /. Toshi-hiko O., Haruka I., Koichi S.,
Sajiro T. [Sato Susumu]. - Applied. 3.11.78; No. 53-135236; publ. 10.05.80. // RZhKhim. 981.20
0 393 P.
7. Jirman J., Kavalek J., Machacek V. Priprava substituovanych 1-benzoyl-thiomocovin
transacylaci 1-acetyl-thiomocovin // Sb. ved. pr, VSCHT. Pardubice. 1987. V. 50. P.101-110.
8. Saczewski F. 2-Chloro-4.5-dihydroimidazole. Part IV. Reaction with aroyl isothiocyanates
// Pol. J. Chem. 1988. V. 62. no. 7-12. P. 891-893.
9. Cejpek K., Volusek J., Velisek J. Reactions of allylisothiocyanate with alanine, glycine and
several peptides in mobel syctems // J. Agric Food Chem. 2000. Vol. 48. No. 8. P. 3560-3565.
10. Gorak O., Gorak F., Antituberculous properties of some derivatives of p-
ethoxyphenylthiourea // Zhur. Honey. industry. 1963, Issue 2. Pp. 11-12.
11. Pat. 367 (RUz) 1– (p-chlorobenzoyl) –3– (carboxyethyl) –thiourea exhibiting anti-
inflammatory activity // Baltabaev U.A., Makhsumov A.G., Zokirov U.B. // Official Bulletin.
1993. No. 2.
12. Baltabaev U.A., Makhsumov A.G., Zokirov U.B. Babaev I.D., Shukurlaev K.Sh. Anti-
inflammatory activity of new aryl and aroylthioureas // Chem. pharmaceutical journal-Moscow.
2002. T.36. No. 2. P.24-26.
13. Baltabaev U.A., Dzhuraev A.D., Makhsumov A.G. New derivatives of thiourea and their
biological activity // Zhur. Chemistry and chemical technology. –2007. # 1. Pp. 23–26.
14. Baltabaev U.A., Abdullaeva U.M., Kadyrova M.N., Ergasheva N.Sh. Reactions of
derivatives of benzoyl isothiocyanates with α-amino acids // V International youth competition of
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scientific works "YOUTH IN SCIENCE: NEW ARGUMENTS" Russia, Lipetsk, November 10,
2016 pp. 82-85.
15. Mavlyanov I.R. Non-steroidal anti-inflammatory drugs: mechanism of action, the search
for new effective and safe drugs.
Medical journal of Uzbekistan. -2002.№1. S.94-97.
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. Nasonov E.L Stomach damage associated with the use of non-steroidal anti-inflammatory
drugs//Clin.Med. 2000. T.78. №3. S. 4-10.
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Devineni, S.R., Golla, M., Chamarthi, N.R., Meriga, B., Saddala, M.S., Asupathri, U.R. 2-
Amino-2,3-dihydro-1H-2λ5-[1,3,2]diazaphospholo[4,5-b]pyridin-2-one-based urea and thiourea
derivatives:
Synthesis,
molecular
docking
study
and
evaluationof
anti-
inflammatoryandantimicrobialactivities //(2016) Medicinal Chemistry Research, 25 (4), pp. 751-
768.https://www.scopus.com/inward/record.urieid=2-s2.0- 84959549710&doi=10.1
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19.
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УДК: 616.211/.216-072.1-053.2
ЮҚОРИ ЛАБ ВА ТАНГЛАЙИ ТУҒМА КЕМТИКЛИ БОЛАЛАРДА
БУРУН БЎШЛИҒИ ВА БУРУН ЁНДОШ БЎШЛИҚЛАРИ ПАТОЛОГИЯСИНИ
ЭНДОСКОПИК ТАШХИСЛАШ
Маҳкамова Н.Е.
1
, Набиева Ж.М.
2
, Якубджанов Д.Д.
1
1
Тошкент давлат стоматология институти, Оториноларингология кафедраси,
2
ТТА
кўп тармоқли клиника маслаҳат поликникасининг
ЛОР касалликлар ва сурдалогия бўлими шифокори
Мазкур ишда
юқори лаб ва танглайи туғма кемтикли болаларда бурун ва бурун
ёндош бўшлиқларини туғма нуқсонни жарроҳлик йўли билан даволаш босқичларида
эндоскопик текшируви ўтказилган ва ҳар бир босқичдаги ҳолати батафсил ўрганилган. Бу
ўз ўрнида бурун ва бурун ёндош бўшлиқларидаги патологик жараёнларни эрта босқичларда
аниқлаш ва реабилитация муваффақиятни оширади.
Калит сўзлар:
бурун ва бурун ёндош бўшлиқлари, эндоскопия, юқори лаб ва
танглайи туғма кемтиги, болалар
В данной работе было проведено подробное эндоскопическое исследование полости носа и
придаточных пазух носа у детей с врожденной расщелиной верхней губы и неба на этапах
хирургического лечения врожденных пороков для определения влияния, данного аномалия
на развития патологии в этих органах. Это, в свою очередь, увеличивает успешность
раннего выявления и реабилитации патологических процессов в полости носа и
придаточных пазух носа.
Ключевые слова:
носовая полость, придаточнқй пазухи носа, эндоскопия,
врожденная расщелина верхней губы и неба, дети.
Туғма юқори лаб ва танглай кемтикли (ТЛТК) болалар сонининг ўсиб бораётганини
ҳисобга олиб, турли ихтисосликдаги шифокорларнинг ушбу контингентни даволаш ва
реабилитация қилишга қизиқиши йилдан-йилга ортиб бормоқда. Ҳозирги вақтда бундай
аномалияли болаларни олиб бориш алгоритмлари асосан юз-жағ жарроҳлари учун ишлаб
чиқилган ва ЛОР аъзоларининг патологиясига эса эътибор кам. ТЛТКли болаларнинг
