Синтез та противірусна активність щодо вірусу жовтої лихоманки 2-(4,6-ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)гідразин-1-карботіоамідів
Aim. To synthesize 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides and study their antiviral activity against yellow fever virus (YFV). Results and discussion. The target 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamid...
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| Published in: | Журнал органічної та фармацевтичної хімії |
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| Date: | 2021 |
| Volume: | 19 |
| Issue: | 2(74) |
| Pages: | 36-43 |
| ISSN: | 2518-1548 |
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| Format: | Article |
| Language: | English |
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National University of Pharmacy
2021
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| Online Access: | https://ophcj.nuph.edu.ua/article/view/234526 |
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Journal of Organic and Pharmaceutical Chemistry| _version_ | 1874455157145600000 |
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| author | Moskalenko, Oleh V. Barchina, Olena I. Tsyhankov, Serhii A. Lega, Dmitry A. Fedchenkova, Yuliia A. Demchenko, Anatoly M. |
| author_facet | Moskalenko, Oleh V. Barchina, Olena I. Tsyhankov, Serhii A. Lega, Dmitry A. Fedchenkova, Yuliia A. Demchenko, Anatoly M. |
| author_institution_txt_mv | [
{
"author": "Oleh V. Moskalenko",
"institution": "Nizhyn Mykola Gogol State University",
"orcid": ""
},
{
"author": "Olena I. Barchina",
"institution": "Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine",
"orcid": ""
},
{
"author": "Serhii A. Tsyhankov",
"institution": "Nizhyn Mykola Gogol State University",
"orcid": ""
},
{
"author": "Dmitry A. Lega",
"institution": "National University of Pharmacy of the Ministry of Health of Ukraine",
"orcid": ""
},
{
"author": "Yuliia A. Fedchenkova",
"institution": "Nizhyn Mykola Gogol State University",
"orcid": ""
},
{
"author": "Anatoly M. Demchenko",
"institution": null,
"orcid": ""
}
] |
| author_sort | Moskalenko, Oleh V. |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 43 |
| container_issue | 2(74) |
| container_start_page | 36 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 19 |
| datestamp_date | 2026-08-24T15:03:55Z |
| description | Aim. To synthesize 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides and study their antiviral activity against yellow fever virus (YFV).
Results and discussion. The target 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides were obtained in three-step format from cyanuric chloride in good to high yields. The carbothioamides synthesized were estimated to possess the antiviral activity against YFV. The results obtained indicate that most of the compounds studied show the inhibitory activity against YFV in concentrations ≤10 μg/mL. For the most active substances, EC90 was in the range of 0.06 – 2.2 μg/mL. Good effective concentration values were accompanied by low levels of cytotoxicity resulting in excellent selectivity index values. The data obtained also indicate that the presence of an alkyl substituent in ortho-position of the N-aryl fragment is crucial for an effective inhibition of YFV growth.
Experimental part. 2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides were synthesized starting from cyanuric chloride in three steps by its successive interaction with two equivalents of pyrrolidine, hydrazine and a series of alkyl-/arylisothiocyanates. The antiviral and cytotoxic activities of the target carbothioamides were studied in the Southern Research Institute (SRI, Birmingham, Alabama) by the viral cytopathic effect reduction assay and the virus yield reduction assay.
Conclusions. 2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides synthesized have been proven to be a promising class of compounds for treating such a severe viral disease as yellow fever. |
| doi_str_mv | 10.24959/ophcj.21.234526 |
| first_indexed | 2025-07-17T13:01:05Z |
| format | Article |
| fulltext |
Journal of Organic and Pharmaceutical Chemistry. – 2021. – Vol. 19, Iss. 2 (74)
36
ISSN 2308-8303 (Print) ISSN 2518-1548 (Online)
UDC 547.874.13/.057:001.891:615.28:616.92/93 https://doi.org/10.24959/ophcj.21.234526
O. V. Moskalenko1, O. I. Barchina2, S. A. Tsyhankov 1, D. A. Lega3,
Yu. A. Fedchenkova1, A. M. Demchenko1,2
1 Nizhyn Mykola Gogol State University, Ukraine
2 Institute of Pharmacology and Toxicology of the National Academy
of Medical Sciences of Ukraine, Ukraine
14, Antona Tsedika str., Kyiv, 03057, Ukraine. E-mail: demch7758@ukr.net
3 National University of Pharmacy of the Ministry of Health of Ukraine, Ukraine
The synthesis and antiviral activity against yellow fewer
virus of 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl,
aryl)hydrazine-1-carbothioamides
Aim. To synthesize 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides and
study their antiviral activity against yellow fever virus (YFV).
Results and discussion. The target 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-
1-carbothioamides were obtained in three-step format from cyanuric chloride in good to high yields. The car-
bothioamides synthesized were estimated to possess the antiviral activity against YFV. The results obtained in-
dicate that most of the compounds studied show the inhibitory activity against YFV in concentrations ≤10 mg/mL.
For the most active substances, EC90 was in the range of 0.06 – 2.2 mg/mL. Good effective concentration values
were accompanied by low levels of cytotoxicity resulting in excellent selectivity index values. The data obtained
also indicate that the presence of an alkyl substituent in ortho-position of the N-aryl fragment is crucial for an
effective inhibition of YFV growth.
Experimental part. 2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides were
synthesized starting from cyanuric chloride in three steps by its successive interaction with two equivalents of
pyrrolidine, hydrazine and a series of alkyl-/arylisothiocyanates. The antiviral and cytotoxic activities of the target
carbothioamides were studied in the Southern Research Institute (SRI, Birmingham, Alabama) by the viral cyto-
pathic effect reduction assay and the virus yield reduction assay.
Conclusions. 2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides synthesized
have been proven to be a promising class of compounds for treating such a severe viral disease as yellow fever.
Key words: 1,3,5-triazine; carbothioamides; yellow fever; antiviral activity; cytotoxicity
О. В. Москаленко1, О. І. Барчина2, С. А. Циганков1, Д. О. Лега3,
Ю. А. Федченкова1, А. М. Демченко1,2
1 Ніжинський державний університет імені Миколи Гоголя, Україна
2 Інститут фармакології та токсикології Національної академії медичних наук України,
Україна
3 Національний фармацевтичний університет Міністерства охорони здоров’я України,
Україна
Синтез та противірусна активність щодо вірусу жовтої лихоманки 2-(4,6-ди(піролідин-
1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)гідразин-1-карботіоамідів
Мета. Синтезувати та вивчити противірусну активність щодо вірусу жовтої лихоманки для 2-(4,6-
ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)гідразин-1-карботіоамідів.
Результати та їх обговорення. Цільові 2-(4,6-ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)
гідразин-1-карботіоаміди одержано з ціанурхлориду із середніми та високими виходами, із застосуван-
ням тристадійного підходу. Синтезовані карботіоаміди було досліджено на наявність противірусної актив-
ності щодо вірусу жовтої лихоманки. Одержані результати свідчать, що більшість тестованих сполук ви-
являють інгібувальну активність проти вірусу в концентраціях ≤10 мкг/мл. Для найактивніших субстанцій
EC90 становила 0,06 – 2,2 мкг/мл. Гарні значення ефективних концентрацій супроводжувались низьким рів-
нем цитотоксичності, що зумовило відмінні значення індексу селективності. Одержані дані також є свід-
ченням того, що наявність алкільного замісника в орто-положенні N-арильного фрагмента має вирішаль-
не значення для ефективного пригнічення зростання вірусу.
Експериментальна частина. 2-(4,6-Ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)гідразин-1-
карботіоаміди було синтезовано в три стадії послідовною взаємодією ціанурхлориду з двома еквівален-
тами піролідину, гідразином та рядом алкіл-/арилізотіоціанатів. Противірусну та цитотоксичну активність
цільових карботіоамідів було досліджено в Southern Research Institute (SRI, Birmingham, Alabama) на мо-
делях зменшення вірусного цитопатичного ефекту і зменшення розмноження вірусів.
Висновки. Синтезовані 2-(4,6-ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)гідразин-1-карботіоаміди
є перспективним класом сполук для лікування такого вірусного захворювання, як жовта лихоманка.
Ключові слова: 1,3,5-триазин; карботіоаміди; жовта лихоманка; противірусна активність;
цитотоксичніть
Copyright © 2021, O. V. Moskalenko, O. I. Barchina, S. A. Tsyhankov, D. A. Lega, Yu. A. Fedchenkova, A. M. Demchenko
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0)
Журнал органічної та фармацевтичної хімії. – 2021. – Т. 19, вип. 2 (74)
37
ISSN 2518-1548 (Online) ISSN 2308-8303 (Print)
Yellow fever (yellow jack, yellow plague, bronze
john) is a severe viral disease resulting from human
infection with yellow fever virus (YFV) [1, 2]. It is en-
demic in tropical regions of Africa, as well as in Cent-
ral and South America [3 – 5].
YFV is an RNA virus of the Flaviviridae family (genus
Flavivirus). The virus persists in nature through trans-
mission between non-human primates and mosqui-
toes fed upon them. The latter usually belong to Aedes
species in Africa and Haemagogus species in the Ame-
ricas. Humans may become infected with YFV through
a sylvatic transmission vector when bitten by an in-
fected mosquito (the so-called jungle yellow fever).
However, inter-human transmission of the virus may
also occur with Aedes aegypti as a vector of domes-
tic transmission (the so-called urban yellow fever).
In Africa, a third transmission vector is possible; it is
known as the “intermediate cycle” involving both syl-
vatic and domestic vector species in inter-human trans-
mission. From the epidemiological point of view, the big-
gest concern is given to the urban type of transmission
as it can cause large-scale epidemics due to the high
population density and low or no immunity to the di-
sease [2].
One of the aspects of yellow fever danger lies in
the field of its ability to spread rapidly causing the po-
pulation damage. Due to the developed air and sea
communication between the countries, there is a risk
of importing infected mosquitoes from the endemic
regions and their spread over new territories due to
the ongoing climate change.
The clinical course of yellow fever proceeds through
three phases, which are infection, remission, and intoxi-
cation. The first symptoms appear abruptly 2 – 9 days
after YFV transmission to a living organism through
the bite of an infected mosquito (infection phase).
They include fever (up to 41 °C), headache, myalgia,
malaise, nausea and vomiting. A short phase of re-
mission may follow the infection phase, during which
many patients (about 88 %) recover. Other YFV-infec-
ted patients will progress to the intoxication phase,
which is accompanied by fever, abdominal pain, nausea
and vomiting, oliguria, jaundice, hepatic dysfunction,
renal failure, hemorrhagic manifestations, encepha-
lopathy [1].
According to the World Health Organization reports,
about 200,000 cases of yellow fever are registered
worldwide each year. The mortality rate among pa-
tients entering the phase of intoxication ranges from
20 to 50 % in different outbreaks and case series [1].
Nowadays vaccination is the primary method used
to prevent development of the disease [6]. Vaccines
against YFV usually produce a strong and long-term
immune response in all recipients [7 – 12]. Neverthe-
less, one should not consider vaccination as a totally
successful and safe way of combating yellow fever.
Thus, it can cause severe adverse events, including
yellow fever vaccine-associated viscerotropic disease
and acute neurotropic disease [13, 14] resulting in
the immune system failure [15, 16].
There are no effective antiviral drugs for yellow
fever by now. Meanwhile, several antiviral compounds
are under investigation for use with this purpose,
including sofosbuvir (Fig.) [17]. The study revealed
that sofosbuvir may be used as an option to cure yellow
fever until other more effective medicines are found
and approved for human use.
During the high-throughput screening research
aimed at finding novel antiviral substances, a benzo-
diazepine acetic acid derivative (BDAA, Fig.) with the pro-
mising antiviral properties was identified [18]. It comp-
rises the 7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzo-
diazepin-2-one core, which is typical for many benzo-
diazepine drugs, and inhibits YFV potently.
Among other possible cures for yellow fever, one
should note Favipiravir (sold under the brand name
Avigan®) which is a pyrazinecarboxamide deriva-
tive (Fig.). The mechanism of its action is thought to
be selective inhibition of viral RNA-dependent RNA
polymerase [19].
N
HN
O
O
HO
F
Me O
O
P
NHO
O
Ph
Me
O
O
Me
Me
Sofosbuvir
N
NF
OH
O
NH2
Favipiravir
N
N
O
Cl
CO2H
H
Me
Me
BDAA
Fig. The compounds with the confirmed antiviral activity against YFV
Journal of Organic and Pharmaceutical Chemistry. – 2021. – Vol. 19, Iss. 2 (74)
38
ISSN 2308-8303 (Print) ISSN 2518-1548 (Online)
Despite the availability of synthetic substances
directly affected YFV, the symptomatic treatment is
usually applied to people suffering from yellow fever.
The treatment may consist of fluid replacement, hemo-
dialysis (in case of kidney failure), blood transfusion
(when indicated), vasopressors, antipyretics, antibio-
tics (if secondary infections appear) [20, 21].
Taking into account the information stated above
modern medicine is in urgent need of effective, specific
and safe antiviral drugs against yellow fever. Such
a state of affairs encouraged us to carry out a research in
this field. This paper describes the results of the syn-
thesis and evaluation of the anti-YFV activity of some
1,3,5-triazine derivatives. The reason of our attention
to the 1,3,5-triazine core is the previously published re-
sults revealing valuable pharmacological properties
of its derivatives. Thus, 1,3,5-triazines have been found
in a number of bioactive molecules, such as herbici-
des and pharmaceutical products [22]. Compounds
comprising this heterocyclic system exhibit the car-
diotonic [23], antitumor [24] and anticancer activi-
ties [25]. Moreover, antiviral agents of 1,3,5-triazine
class have been proven to be effective against the hu-
man immunodeficiency viruses (HIV) [26, 27] and
herpes simplex virus 1 (HSV-1) [28].
In the current research we set the task to synthe-
size a series of 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-
2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides 5, 7
(Scheme) and evaluate their usefulness in treating
yellow fever. The starting compound in the synthetic
strategy towards the target derivatives was cyanuric
chloride (1). Its interaction with a double amount of
pyrrolidine in the acetone solution in the presence of
potassium carbonate led to 2-chloro-4,6-di(pyrrolidin-
1-yl)-1,3,5-triazine (2) [29]. The latter easily gave
2-hydrazinyl-4,6-di(pyrrolidin-1-yl)-1,3,5-triazine (3)
when refluxed with hydrazine hydrate in propanol-2
[30]. Hydrazine derivative 3 was further used in
the reaction with alkyl- 4a – c and arylisothiocyana-
tes 6a – k producing the corresponding carbothioami-
des 5, 7 [31].
The next step was to study the antiviral activity of
compounds 5a – c and 7a – k against YFV. These stu-
dies were performed in the Southern Research Insti-
tute (SRI, Birmingham, Alabama). Testing was done
by the viral cytopathic effect (CPE) reduction assay
and the virus yield reduction assay (Virus Yield). CPE
was determined by the microscopic observation of
cell culture monolayers (Visual), as well as the up-
take of neutral red dye (Neutral Red). The results ob-
tained are given in the Table below as EC50, EC90, IC50
and IS values (see notes under the Table).
The antiviral assay determining CPE is used for
the initial screening of potential antiviral compounds.
The antiviral activity of the compounds is evaluated
based on their ability to prevent the virus from causing
viral CPE in a cell culture. Compounds demonstrating
the activity in the CPE assay are further evaluated by
the virus yield reduction assay. This test evaluates
the ability of the compounds to inhibit virus produc-
tion in a cell culture.
The results obtained indicate that most of the com-
pounds studied showed the inhibitory activity against
YFV (EC50≤10 mg/mL) though it was less pronounced
as compared to the reference drug Infergen® (Inter-
feron Alphacon) (Table).
N
N
N
Cl
ClCl
1
N
H
2 equiv
K2CO3
N
N
N
Cl
NN
2
NH2NH2 N
N
N
HN
NN
3
Alk
NCS
4a-c
Ar
NCS
6a-kN
N
N
HN
NN
3
NH2
N
N
N
HN
NN
H
N
H
N
S
Ar
7a-k
N
N
N
HN
NN
H
N
H
N
S
Alk
5a-c
NH2
5a: 5b: 5c:Alk = Me; Alk = Et; Alk = Bn
7a: Ar = 2-Me-C6H4; Ar = 4-Me-C7b: 6H4; Ar = 2-MeO-C7c: 6H4; Ar = 4-EtO-C7d: 6H4; Ar = 3-Cl-C7e: 6H4;
7f: Ar = 4-Cl-C6H4; Ar = 2,3-diMe-C7g: 6H4; Ar = 2,4-diMe-C7h: 6H4; Ar = 2,5-diMe-C7i: 6H4;
7j: Ar = 2,6-diMe-C6H4; Ar = 3,4-diMe-C7k: 6H4
Scheme. The synthesis of 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides 5a-c and 7a-k
Журнал органічної та фармацевтичної хімії. – 2021. – Т. 19, вип. 2 (74)
39
ISSN 2518-1548 (Online) ISSN 2308-8303 (Print)
Considering the structure of the compounds un-
der research one should note that N-alkyl substituted
derivatives 5 demonstrated high values of EC50, hence,
were out of interest. Meanwhile, compounds 7 bearing
an N-aryl residue turned out to be much more potent
against YFV. Their EC50 were in the range of 1 – 10 mg/mL
in accordance with the CPE assay, except for 3-chloro-
phenyl derivative 7e which was nearly inactive. The more
precise virus yield reduction assay provided even less
EC90 concentration values – 0.06 – 2.2 mg/mL. It is worth
mentioning that good effective concentration values
were accompanied by low levels of cytotoxicity resul-
ting in the excellent selectivity index, which was up
to 362. It is interesting that the substitution pattern
of the N-aryl fragment significantly affected the anti-
viral potency of compounds 7. Thus, the most active
molecules had a substituent in the ortho-position of
the aryl residue. The introduction of the second sub-
stituent to the aryl residue altered the antiviral ac-
tivity though it still remained to be high. However,
Table
The antiviral activity of 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl,
aryl)hydrazine-1-carbothioamide 5 and 7 against YFV
Cmp R Assay Trial* EC50 EC90 IC50 SI
5a NHCH3 Neutral Red 1 >100 – >100 0
5b NHC2H5 Neutral Red 1 31 – 58 1.9
5c CH2Ph Neutral Red 1 >36 – 36 0
7a 2-Me-C6H4 Visual 2 1.1 – 23 22
7a 2-Me-C6H4 Neutral Red 1 3.2 – 32 10
7a 2-Me-C6H4 Neutral Red 2 1.1 – 25 23
7a 2-Me-C6H4 Virus Yield 3 – 2.2 – 11
7b 4-Me-C6H4 Neutral Red 1 11 – 17 1.5
7c 2-MeO-C6H4 Visual 2 5.1 – 270 53
7c 2-MeO-C6H4 Neutral Red 1 10 – >100 >10
7c 2-MeO-C6H4 Neutral Red 2 2.8 – 170 61
7c 2-MeO-C6H4 Virus Yield 3 – 0.47 – 362
7d 4-EtO-C6H4 Neutral Red 1 10 – 29 2.9
7e 3-Cl-C6H4 Neutral Red 1 >100 – >100 0
7f 4-Cl-C6H4 Neutral Red 1 10 – 28 2.8
7g 2,3-diMe-C6H3 Visual 2 2.3 – 18 7.8
7g 2,3-diMe-C6H3 Neutral Red 1 0.85 – 7.9 9.3
7g 2,3-diMe-C6H3 Neutral Red 2 1.2 – 18 15
7g 2,3-diMe-C6H3 Virus Yield 3 – 0.09 – 200
7h 2,4-diMe-C6H3 Visual 2 1.6 – 18 11
7h 2,4-diMe-C6H3 Neutral Red 1 3.2 – 32 10
7h 2,4-diMe-C6H3 Neutral Red 2 1.4 – 18 13
7h 2,4-diMe-C6H3 Virus Yield 3 – 1.8 – 10
7i 2,5-diMe-C6H3 Visual 2 0.81 – 32 40
7i 2,5-diMe-C6H3 Neutral Red 1 1.1 – 10 9.1
7i 2,5-diMe-C6H3 Neutral Red 2 0.4 18 45
7i 2,5-diMeC6H3 Virus Yield 3 – 0.06 – 300
7j 2,6-diMe-C6H3 Neutral Red 1 18 – 89 4.9
7j 2,6-diMe-C6H3 Visual 1 9 – 16 1.8
7k 3,4-diMe-C6H3 Neutral Red 1 10 – 18 1.8
Infergen (Interferon Alphacon) Neutral Red, Visual – 0.01 – – –
Notes: EC50 – the half maximal effective concentration causing 50 % virus inactivation (μg/mL); EC90 – the effective concentration causing 90 %
virus inactivation (μg/mL); IC50 – 50 % cytotoxicity value (μg/mL); SI – the selectivity index, it is the ratio that measures the window between
cytotoxicity and the antiviral activity by dividing the given IC50 value into the EC50 or EC90 value.
* – Depending on the time the cell cultures are being infected the following cell concentrations were prepared:
100 000 cells/mL – 72 h incubation (3); 200 000 cells/mL – 48 h incubation (2); 400 000 cells/mL – 24 h incubation (1).
Journal of Organic and Pharmaceutical Chemistry. – 2021. – Vol. 19, Iss. 2 (74)
40
ISSN 2308-8303 (Print) ISSN 2518-1548 (Online)
another ortho-position must be free as 2,6-dimethyl-
phenyl derivative 7j lost in its antiviral efficacy as com-
pared to other N-dimethylphenyl ones.
Thus, 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-
N-(alkyl, aryl)hydrazine-1-carbothioamides 5 and 7
provide a high antiviral activity against YFV. The data
obtained confirm the feasibility of further studies of
the title compounds as potential antiviral agents.
Experimental part
Chemistry part
1Н NMR spectra of compounds 5 and 7 were re-
corded on a Bruker VXR-400 spectrometer (Germany)
operating at a frequency of 400 MHz in DMSO-d6 using
tetramethylsilane (TMS) as an internal standard. Chemi-
cal shifts were reported in ppm using the δ scale.
The melting points were measured on a small-sized
heating table with an Electrothermal ІА 9200 obser-
vation device. The elemental analysis was performed
on an EuroEA 3000 elemental analyzer.
The general procedure for the synthesis of 2-(4,6-
di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)
hydrazine-1-carbothioamides 5a – c, 7a – k
The mixture of 2-hydrazinyl-4,6-di(pyrrolidin-1-yl)-
1,3,5-triazine (3) (0.249 g, 0.01 mol) and the cor-
responding alkyl- 4a – c or arylisothiocyanate 6a – k
(0.01 mol) was refluxed in 50 mL of ethanol for 2 h
and then cooled. After cooling the solid products for-
med were filtered off, washed with ethanol, dried in
air and recrystallized from propanol-2 or ethanol to
afford the pure target carbothioamides 5a – c and 7a – k.
2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-
methylhydrazine-1-carbothioamide (5a)
Yield – 2.16 g (67 %). M. p. 227 – 228 °С (from
ethanol). Anal. Calcd. for C13H22N8S, %: N 34.75; S 9.94.
Found, %: N 34.53; S 9.89. 1H NMR (400 MHz, DMSO-d6),
δ, ppm: 1.82 – 1.85 (8Н, m, 2 × CH2СН2); 2.85 (3Н, d,
J = 4.3 Hz, NHСН3); 3.38 – 3.43 (8Н, m, 2 × CH2NСН2);
7.77 (1Н, q, J = 4.3 Hz, NНCH3); 8.39 (1Н, s, NН); 8.84
(1Н, s, NН).
2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-
ethylhydrazine-1-carbothioamide (5b)
Yield – 2.15 g (64 %). M. p. 191 – 192 °С (from
ethanol). Anal. Calcd. for C14H24N8S, %: N 33.30; S 9.53.
Found, %: N 33.13; S 9.47. 1H NMR (400 MHz, DMSO-d6),
δ, ppm: 1.03 (3H, t, J = 7.2 Hz, NHCH2СН3); 1.82 – 1.85
(8Н, m, 2×CH2СН2); 3.38 – 3.46 (10Н, m, NHCH2СН3 +
2 × CH2NСН2); 7.77 (1Н, t, J = 5.6 Hz, NНCH2CH3);
8.36 (1Н, s, NН); 8.79 (1Н, s, NН).
N-Benzyl-2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-
2-yl)hydrazine-1-carbothioamide (5c)
Yield – 3.03 g (76 %). M. p. 226 – 226 °С (from
propanol-2). Anal. Calcd. for C19H26N8S, %: N 28.12; S 8.04.
Found, %: N 28.31; S 8.13. 1H NMR (400 MHz, DMSO-d6),
δ, ppm: 1.82 – 1.87 (8Н, m, 2 × CH2СН2); 3.39 – 3.45
(8Н, m, 2 × CH2NСН2); 4.71 (2Н, d, J = 5.6 Hz, NHСН2),
7.18 – 7.29 (5H, m, C6H5); 7.36 (1Н, t, J = 5.6 Hz, NНCH2);
8.50 (1Н, s, NН); 9.07 (1Н, s, NН).
2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-
(o-tolyl)hydrazine-1-carbothioamide (7a)
Yield – 2.79 g (70 %). M. p. 173-174 °С (from etha-
nol). Anal. Calcd. for C19H26N8S, %: N 28.12; S 8.04.
Found, %: N 28.24; S 8.15. 1H NMR (400 MHz, DMSO-d6),
δ, ppm: 1.80 – 1.85 (8Н, m, 2 × CH2СН2); 2.15 (3H, s,
CH3); 3.40 – 3.45 (8Н, m, 2 × CH2NСН2); 7.10 – 7.24
(4H, m, C6H4); 7.36 (1Н, s, NН); 8.48 (1Н, s, NН); 9.17
(1Н, s, NН).
2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-
(p-tolyl)hydrazine-1-carbothioamide (7b)
Yield – 3.07 g (77 %). M. p. 167-168 °С (from
propanol-2). Anal. Calcd. for C19H26N8S, %: N 28.12;
S 8.04. Found, %: N 27.91; S 7.96. 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 1.83 – 1.86 (8Н, m, 2 × CH2СН2);
2.27 (3H, s, CH3); 3.41 – 3.45 (8Н, m, 2 × CH2NСН2);
7.09 and 7.40 (4H, d, J = 8.1 Hz, C6H4); 8.53 (1Н, s,
NН); 9.27 (1Н, s, NН); 9.40 (1Н, s, NН).
2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-
(2-methoxyphenyl)hydrazine-1-carbothioamide (7c)
Yield – 2.98 g (72 %). M. p. 188 – 189 °С (from
propanol-2). Anal. Calcd. for C19H26N8OS, %: N 27.03;
S 7.73. Found, %: N 27.33; S 7.87. 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 1.82 – 1.86 (8Н, m, 2 × CH2СН2);
3.41 – 3.45 (8Н, m, 2×CH2NСН2); 3.75 (3H, s, OCH3);
6.90 – 8.37 (4H, m, C6H4); 8.76 (1Н, s, NН); 8.95 (1Н,
s, NН); 9.50 (1Н, s, NН).
2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-
(4-ethoxyphenyl)hydrazine-1-carbothioamide (7d)
Yield – 3.47 g (81 %). M. p. 161 – 162 °С (from
propanol-2). Anal. Calcd. for C20H28N8OS, %: N 26.15;
S 7.48. Found, %: N 26.07; S 7.55. 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 1.31 (3H, t, J = 7.2 Hz, OCH2CH3);
1.82 – 1.86 (8Н, m, 2 × CH2СН2); 3.42 – 3.46 (8Н, m,
2 × CH2NСН2); 4.00 (2H, q, J = 7.2 Hz, OCH2CH3); 6.84
and 7.31 (4H, d, J = 8.4 Hz, C6H4); 8.52 (1Н, s, NН);
9.21 (1Н, s, NН); 9.36 (1Н, s, NН).
N-(3-chlorophenyl)-2-(4,6-di(pyrrolidin-1-yl)-
1,3,5-triazin-2-yl)hydrazine-1-carbothioamide (7e)
Yield – 3.69 g (88 %). M. p. 221 – 222 °С (from etha-
nol). Anal. Calcd. for C18H23ClN8S, %: N 26.75; S 7.65.
Found, %: N 26.54; S 7.59. 1H NMR (400 MHz, DMSO-d6),
δ, ppm: 1.83 – 1.86 (8Н, m, 2 × CH2СН2); 3.42 – 3.46
(8Н, m, 2×CH2NСН2); 7.14 – 7.72 (4H, m, C6H4); 8.60
(1Н, s, NН); 9.52 (1Н, s, NН); 9.65 (1Н, s, NН).
N-(4-chlorophenyl)-2-(4,6-di(pyrrolidin-1-yl)-
1,3,5-triazin-2-yl)hydrazine-1-carbothioamide (7f)
Yield – 3.81 g (91 %). M. p. 206 – 207 °С (from
ethanol). Anal. Calcd. for C18H23ClN8S, %: N 26.75;
S 7.65. Found, %: N 26.9; S 7.70. 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 1.83 – 1.87 (8Н, m, 2 × CH2СН2);
3.39 – 3.43 (8Н, m, 2 × CH2NСН2); 7.33 and 7.55 (4H,
d, J = 8.8 Hz, C6H4); 8.54 (1Н, s, NН); 9.41 (1Н, s, NН);
9.59 (1Н, s, NН).
Журнал органічної та фармацевтичної хімії. – 2021. – Т. 19, вип. 2 (74)
41
ISSN 2518-1548 (Online) ISSN 2308-8303 (Print)
2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-
(2,3-dimethylphenyl)hydrazine-1-carbothioamide (7g)
Yield – 2.85 g (69 %). M. p. 178 – 179 °С (from etha-
nol). Anal. Calcd. for C20H28N8S, %: N 27.16; S 7.77.
Found, %: N 27.23; S 7.83. 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 1.83 – 1.87 (8Н, m, 2 × CH2СН2);
2.04 (3H, s, CH3); 2.23 (3H, s, CH3); 3.42 – 3.47 (8Н,
m, 2 × CH2NСН2); 6.93 – 7.05 (3H, m, C6H3); 8.56 (1Н,
s, NН); 9.23 (2Н, br. s, 2NН).
2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-
(2,4-dimethylphenyl)hydrazine-1-carbothioamide (7h)
Yield – 2.72 g (66 %). M. p. 165 – 166 °С (from pro-
panol-2). Anal. Calcd. for C20H28N8S, %: N 27.16; S 7.77.
Found, %: N 27.01; S 7.89. 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 1.82 – 1.85 (8Н, m, 2 × CH2СН2);
2.13 (3H, s, CH3); 2.29 (3H, s, CH3); 3.42 – 3.47 (8Н,
m, 2 × CH2NСН2); 6.83 – 7.13 (3H, m, C6H3); 8.34 (1Н,
s, NН), 8.97 (2Н, br. s, 2NН).
2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-
(2,5-dimethylphenyl)hydrazine-1-carbothioamide (7i)
Yield – 3.30 g (80 %). M. p. 175 – 176 °С (from pro-
panol-2). Anal. Calcd. for C20H28N8S, %: N 27.16; S 7.77.
Found, %: N 27.11; S 7.85. 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 1.83 – 1.87 (8Н, m, 2 × CH2СН2);
2.10 (3H, s, CH3); 2.24 (3H, s, CH3); 3.42 – 3.47 (8Н,
m, 2 × CH2NСН2); 6.93 – 7.06 (3H, m, C6H3); 8.57 (1Н,
s, NН); 9.17 (1Н, s, NН); 9.24 (1Н, s, NН).
2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-
(2,6-dimethylphenyl)hydrazine-1-carbothioamide (7j)
Yield – 2.74 g (66 %). M. p. 161 – 162 °С (from pro-
panol-2). Anal. Calcd. for C20H28N8S, %: N 27.16; S 7.77.
Found, %: N 27.27; S 7.91. 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 1.82 – 1.87 (8Н, m, 2 × CH2СН2); 2.14
(6H, s, 2 × CH3); 3.42 – 3.47 (8Н, m, 2 × CH2NСН2);
6.98 – 7.06 (3H, m, C6H3); 8.58 (1Н, s, NН); 9.10 (1Н,
s, NН); 9.21 (1Н, s, NН).
2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-
(3,4-dimethylphenyl)hydrazine-1-carbothioamide (7k)
Yield – 2.72 g (73 %). M. p. 174 – 175 °С (from pro-
panol-2). Anal. Calcd. for C20H28N8S, %: N 27.16; S 7.83.
Found, %: N 26.98; S 7.65. 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 1.83 – 1.86 (8Н, m, 2 × CH2СН2); 2.18
(6H, s, 2 × CH3); 3.41 – 3.46 (8Н, m, 2 × CH2NСН2);
7.03 – 7.22 (3H, m, C6H3); 8.52 (1Н, s, NН); 9.23 (1Н,
s, NН); 9.30 (1Н, s, NН).
Pharmacological part
The viral cytopathic effect (CPE) reduction assay
and the virus yield reduction assay were performed
according to the known procedures [32, 33].
Briefly, the viral cytopathic effect (CPE) reduction
assay consists in the following. Vero cells were seeded
into 96-well clear plates, and all of the plates were
incubated for about 18 h prior to use for assays. Com-
pounds were first applied to the cell monolayers, fol-
lowed within minutes by addition of virus suspen-
sions. Uninfected wells with the compounds tested
were used for assessing cytotoxicity (IC50), infected
wells – for assessing the antiviral activity, drug-free
infected wells – as virus controls, uninfected drug-
free wells – as cell controls, background wells con-
tained only water. After incubation the microplates
were read visually to estimate the percentage of cell
destruction caused by the virus infection or by cyto-
toxicity. When the maximum CPE was observed, each
plate was treated with a neutral red dye followed by
incubation of the plates at 37 °C. The neutral red solu-
tion used was prepared by dilution of its 0.68 % solu-
tion with the physiological saline solution in the ratio
of 1:20. The resulting solution (0.1 mL) was added
to each cell monolayer. The plates were incubated for
2 h in order to allow the dye to be adsorbed. After incu-
bation the plates were aspirated dry, and the mono-
layers were washed twice with a brine/phosphate buf-
fer mixture followed by addition of 0.25 mL of 1:1
Sörensen’s citrate buffer (pH 4.2) in ethanol to
each well to desorb the dye. To complete desorption
of the dye from the cells the plates were placed in a
dark place for 30 min at room temperature and af-
ter read using the colorimetry method at 540 nm.
Absorbance units were converted to percentages of
uninfected control cells. Fifty percent virus inhibitory
(EC50) or 50 % cytotoxicity (IC50) values were deter-
mined by linear regression using an Excel spreadsheet.
The virus yield reduction assay is a two-step assay
where the virus is first produced in Vero cells cultu-
res containing the antiviral substance in varying di-
lutions, followed later by titration of the samples for
the virus titer by the endpoint dilution in 96-well
plates. Dilutions of the test compound were assayed,
and the effective antiviral concentration was deter-
mined by the regression analysis.
Vero cells were infected with the virus at 0.3 pfu/cell
and then incubated for 24 h. After incubation the in-
fected cells were exposed to solutions of the test com-
pounds for 72 h. After virus adsorption the culture
fluid was diluted to the required concentration by semi-
logarithmic dilutions of test compounds prepared in
the assay medium. Depending on the situation, the super-
natants were pooled either 24 h or 72 h after infec-
tion, and the extracellular viral infectivity titers were
determined in duplicate by analysis of plaques in Vero
cell monolayers. The endpoint for the 24-hour assay
is the effective concentration (EC50), which reduces
the virus yield by 50 % compared to control cultures.
The effective concentration (EC90) was determined
from the data obtained.
Conclusions
2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-
(alkyl, aryl)hydrazine-1-carbothioamides synthesized
have been proven to be a promising class of compounds
for treating such a severe viral disease as yellow fever.
Acknowledgements
We would like to offer our special thanks to Ms
Yulia Renkas for assistance in collaboration with
Southern Research Institute (Birmingham, Alabama).
Conflict of interests: the authors have no conflict
of interests to declare.
Journal of Organic and Pharmaceutical Chemistry. – 2021. – Vol. 19, Iss. 2 (74)
42
ISSN 2308-8303 (Print) ISSN 2518-1548 (Online)
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ISSN 2518-1548 (Online) ISSN 2308-8303 (Print)
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Received: 03. 05. 2021
Revised: 23. 05. 2021
Accepted: 30. 05. 2021
The work was carried out according to the research plan of the Nizhyn Mykola Gogol State University on the topic
“Synthesis of novel sulfur- and nitrogen-containing heterocyclic compounds and investigation of their practically useful properties”
(the state registration No. 0115U005451).
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| id | oai:ojs.journals.uran.ua:article-234526 |
| institution | Journal of Organic and Pharmaceutical Chemistry |
| issn | 2518-1548 |
| keywords_txt_mv | |
| language | English |
| last_indexed | 2026-08-25T01:02:20Z |
| publishDate | 2021 |
| publisher | National University of Pharmacy |
| record_format | ojs |
| resource_txt_mv | ophcjnupheduua/38/b09d9e976ee0380f4cd091c80d374438.pdf |
| spelling | oai:ojs.journals.uran.ua:article-2345262026-08-24T15:03:55Z The synthesis and antiviral activity against yellow fewer virus of 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides Синтез та противірусна активність щодо вірусу жовтої лихоманки 2-(4,6-ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)гідразин-1-карботіоамідів Moskalenko, Oleh V. Barchina, Olena I. Tsyhankov, Serhii A. Lega, Dmitry A. Fedchenkova, Yuliia A. Demchenko, Anatoly M. 1,3,5-triazine; carbothioamides; yellow fever; antiviral activity; cytotoxicity 1,3,5-триазин; карботіоаміди; жовта лихоманка; противірусна активність; цитотоксичніть Aim. To synthesize 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides and study their antiviral activity against yellow fever virus (YFV). Results and discussion. The target 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides were obtained in three-step format from cyanuric chloride in good to high yields. The carbothioamides synthesized were estimated to possess the antiviral activity against YFV. The results obtained indicate that most of the compounds studied show the inhibitory activity against YFV in concentrations ≤10 μg/mL. For the most active substances, EC90 was in the range of 0.06 – 2.2 μg/mL. Good effective concentration values were accompanied by low levels of cytotoxicity resulting in excellent selectivity index values. The data obtained also indicate that the presence of an alkyl substituent in ortho-position of the N-aryl fragment is crucial for an effective inhibition of YFV growth. Experimental part. 2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides were synthesized starting from cyanuric chloride in three steps by its successive interaction with two equivalents of pyrrolidine, hydrazine and a series of alkyl-/arylisothiocyanates. The antiviral and cytotoxic activities of the target carbothioamides were studied in the Southern Research Institute (SRI, Birmingham, Alabama) by the viral cytopathic effect reduction assay and the virus yield reduction assay. Conclusions. 2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides synthesized have been proven to be a promising class of compounds for treating such a severe viral disease as yellow fever. Мета. Синтезувати та вивчити противірусну активність щодо вірусу жовтої лихоманки для 2-(4,6-ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)гідразин-1-карботіоамідів. Результати та їх обговорення. Цільові 2-(4,6-ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)гідразин-1-карботіоаміди одержано з ціанурхлориду із середніми та високими виходами, із застосуванням тристадійного підходу. Синтезовані карботіоаміди було досліджено на наявність противірусної активності щодо вірусу жовтої лихоманки. Одержані результати свідчать, що більшість тестованих сполук виявляють інгібувальну активність проти вірусу в концентраціях ≤10 мкг/мл. Для найактивніших субстанцій EC90 становила 0,06 – 2,2 мкг/мл. Гарні значення ефективних концентрацій супроводжувались низьким рівнем цитотоксичності, що зумовило відмінні значення індексу селективності. Одержані дані також є свідченням того, що наявність алкільного замісника в орто-положенні N-арильного фрагмента має вирішальне значення для ефективного пригнічення зростання вірусу. Експериментальна частина. 2-(4,6-Ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)гідразин-1-карботіоаміди було синтезовано в три стадії послідовною взаємодією ціанурхлориду з двома еквівалентами піролідину, гідразином та рядом алкіл-/арилізотіоціанатів. Противірусну та цитотоксичну активність цільових карботіоамідів було досліджено в Southern Research Institute (SRI, Birmingham, Alabama) на моделях зменшення вірусного цитопатичного ефекту і зменшення розмноження вірусів. Висновки. Синтезовані 2-(4,6-ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)гідразин-1-карботіоаміди є перспективним класом сполук для лікування такого вірусного захворювання, як жовта лихоманка. National University of Pharmacy 2021-06-23 Article Article application/pdf https://ophcj.nuph.edu.ua/article/view/234526 10.24959/ophcj.21.234526 Journal of Organic and Pharmaceutical Chemistry; Vol. 19 No. 2(74) (2021); 36-43 Журнал органической и фармацевтической химии; Том 19 № 2(74) (2021); 36-43 Журнал органічної та фармацевтичної хімії; Том 19 № 2(74) (2021); 36-43 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/234526/233838 Copyright (c) 2021 Oleh V. Moskalenko, Olena I. Barchina, Serhii A. Tsyhankov, Dmitry A. Lega, Yuliia A. Fedchenkova, Anatoly M. Demchenko http://creativecommons.org/licenses/by/4.0 |
| spellingShingle | 1,3,5-триазин карботіоаміди жовта лихоманка противірусна активність цитотоксичніть Moskalenko, Oleh V. Barchina, Olena I. Tsyhankov, Serhii A. Lega, Dmitry A. Fedchenkova, Yuliia A. Demchenko, Anatoly M. Синтез та противірусна активність щодо вірусу жовтої лихоманки 2-(4,6-ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)гідразин-1-карботіоамідів |
| title | Синтез та противірусна активність щодо вірусу жовтої лихоманки 2-(4,6-ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)гідразин-1-карботіоамідів |
| title_alt | The synthesis and antiviral activity against yellow fewer virus of 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides |
| title_full | Синтез та противірусна активність щодо вірусу жовтої лихоманки 2-(4,6-ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)гідразин-1-карботіоамідів |
| title_fullStr | Синтез та противірусна активність щодо вірусу жовтої лихоманки 2-(4,6-ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)гідразин-1-карботіоамідів |
| title_full_unstemmed | Синтез та противірусна активність щодо вірусу жовтої лихоманки 2-(4,6-ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)гідразин-1-карботіоамідів |
| title_short | Синтез та противірусна активність щодо вірусу жовтої лихоманки 2-(4,6-ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-N-(алкіл, арил)гідразин-1-карботіоамідів |
| title_sort | синтез та противірусна активність щодо вірусу жовтої лихоманки 2-(4,6-ди(піролідин-1-іл)-1,3,5-триазин-2-іл)-n-(алкіл, арил)гідразин-1-карботіоамідів |
| topic | 1,3,5-триазин карботіоаміди жовта лихоманка противірусна активність цитотоксичніть |
| topic_facet | 1,3,5-triazine carbothioamides yellow fever antiviral activity cytotoxicity 1,3,5-триазин карботіоаміди жовта лихоманка противірусна активність цитотоксичніть |
| url | https://ophcj.nuph.edu.ua/article/view/234526 |
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