CC BY
7DOI: 10.6060/ivkkt.20226503.6522 УДК: 547.4, 547.7
СИНТЕЗ, АНАЛЬГЕТИЧЕСКАЯ И ПРОТИВОМИКРОБНАЯ АКТИВНОСТЬ N-ГЕТАРИЛАМИДОВ 2-(2-(ДИАРИЛМЕТИЛЕН)ГИДРАЗОНО)-5,5-ДИМЕТИЛ-4-ОКСОГЕКСАНОВОЙ КИСЛОТЫ
А.И. Сюткина, С.В. Чащина, Р.Р. Махмудов, В.В. Новикова, И.Н. Чернов, Н.М. Игидов
Алена Ивановна Сюткина (ORCID 0000-0001-6702-7716)*, Светлана Викторовна Чащина (ORCID 0000-0003-4427-310Х)
Пермская государственная фармацевтическая академия, ул. Екатерининская, 101, Пермь, Российская Федерация, 614990
Пермский государственный национальный исследовательский университет, ул. Букирева, 15, Пермь, Российская Федерация, 614068
E-mail: syutkina.alyona@yandex.ru *, physiology@list.ru Рамиз Рагибович Махмудов (ORCID 0000-0002-2326-3976)
Пермский государственный национальный исследовательский университет, ул. Букирева, 15, Пермь, Российская Федерация, 614068
Федеральный научный центр медико-профилактических технологий управления рисками здоровью населения, ул. Монастырская, 82, Пермь, Российская Федерация, 614045 E-mail: bav@psu.ru
Валентина Васильевна Новикова (ORCID 0000-0003-4475-4421), Назим Мусабекович Игидов (ORCID 0000-0003-0976-9951)
Пермская государственная фармацевтическая академия, ул. Екатерининская, 101, Пермь, Российская Федерация, 614990
E-mail: vvnperm@yandex.ru, igidov_nazim@mail.ru Илья Николаевич Чернов (ORCID 0000-0002-0401-4405)
Пермская государственная фармацевтическая академия, ул. Екатерининская, 101, Пермь, Российская Федерация, 614990
Национальный исследовательский Нижегородский государственный университет им. Н.И. Лобачевского, Научно-исследовательский институт химии, пр. Гагарина, 23, корп. 5, Нижний Новгород, Российская Федерация, 603950 E-mail: ximik59@googlemail.com
Новые N-гетарилзамещенные 2-((диарилметилен)гидразоно)-5,5-диметил-4-ок-согексанамиды были получены в 4 стадии, которые включали конденсацию Кляйзена между пинаколином и диэтилоксалатом в присутствии метилата натрия, конденсацию пивалоилпировиноградной кислоты с диарилметиленгидразонами с образованием 2-диа-рилметиленгидразоно-4-оксо-5,5-диметилгексановой кислоты, внутримолекулярную циклизацию гидразонокислот в гидразонофураноны, дециклизацию последних под действием гетероциклических аминов. Выделение N-гетарил-2-((диарилметилен)гидразоно)-5,5-ди-метил-4-оксогексанамидов осуществлялось фильтрованием полученного осадка с последующей перекристаллизацией из этанола или пропан-2-ола. Структура полученных соединений подтверждена методами 1Н и 13С ЯМР спектроскопии, элементного анализа. Установлено, что полученные замещенные гетариламиды существуют в растворах дей-терированного хлороформа и диметилсульфоксида в гидразоноформе, в отличие от ранее изученных растворов замещённых сложных эфиров аналогичных кислот, где наблюдалось не менее двух таутомерных форм. Изучена анальгетическая и противомикробная активность синтезированных соединений. Анальгетическая активность изучалась по методу термического раздражения «горячая пластина» на белых беспородных мышах обоего пола при внутрибрюшинном введении. Противомикробная активность изучалась методом двукратных серийных разведений в жидкой питательной среде по отношению к двум
штаммам - S. aureus АТСС 6538-Р и E. ^li АТСС 25922. У исследуемых соединений обнаружена выраженная анальгетическая активность, достоверно превышающая таковую препарата сравнения метамизола натрия, а в некоторых случаях соответствующая действию референтного диклофенака натрия. Следовательно, можно заключить, что наличие выраженной анальгетической активности у синтезированных гетариламидов при наличии слабой противомикробной активности или ее полном отсутствии обусловливает перспективность разработки на их основе новой фармакологической активной субстанции с обезболивающими свойствами.
Ключевые слова: 3-имино(гидразоно)-3Н-фуран-2-оны, реакция дециклизации, анальгетическая активность, противомикробная активность, 2,4-диоксобутановые кислоты
SYNTHESIS, ANALGESIC AND ANTIMICROBIAL ACTIVITY OF N-HETARYLAMIDES OF 2-(2-(DIARYLMETHYLENE)HYDRAZONO)-5,5-DIMETHYL-4-OXOHEXANOIC ACID
A.I. Siutkina, S.V. Chashchina, R.R. Makhmudov, V.V. Novikova, I.N. Chernov, N.M. Igidov
Alena I. Siutkina (ORCID 0000-0001-6702-7716)*, Svetlana V. Chashchina (ORCID 0000-0003-4427-310Х)
Perm State Pharmaceutical Academy, Ekaterininskaya st., 101, Perm, 614990, Russia Perm State University, Bukireva st., 15, Perm, 614068, Russia E-mail: syutkina.alyona@yandex.ru *, physiology@list.ru
Ramiz R. Makhmudov (ORCID 0000-0002-2326-3976) Perm State University, Bukireva st., 15, Perm, 614068, Russia
Federal Scientific Center for Medical and Preventive Health Risk Management Technologies, Monastyrskaya st., 82, Perm, 614045, Russia E-mail: bav@psu.ru
Valentina V. Novikova (ORCID 0000-0003-4475-4421), Nazim M. Igidov (ORCID 0000-0003-0976-9951) Perm State Pharmaceutical Academy, Ekaterininskaya st., 101, Perm, 614990, Russia E-mail: vvnperm@yandex.ru, igidov_nazim@mail.ru
Ilya N. Chernov (ORCID 0000-0002-0401-4405)
Perm State Pharmaceutical Academy, Ekaterininskaya st., 101, Perm, 614990, Russia
Lobachevsky State University of Nizhny Novgorod, Research Institute for Chemistry, Gagarin Ave., 23, Nizhny Novgorod, 603950, Russia E-mail: ximik59@googlemail.com
New N-hetaryl substituted 2-((diarylmethylene)hydrazono)-5,5-dimethyl-4-oxohexana-mides were obtained in 4 steps: a) Claisen condensation between pinacolone and diethyl oxalate in the presence of sodium methylate; b) the condensation ofpivaloyl pyruvic acid with diarylmethylene hydrazones to form 2-diarylmethylenehydrazono-4-oxo-5,5-dimethylhexanoic acid; c) intramolecular cyclization of hydrazonoacids in hydrazonofuranones; d) decyclization of the latter under the action of heterocyclic amines. Isolation of N-hetaryl-2-((diarylmethylene)hydrazono)-5,5-dime-thyl-4-oxohexanamides was carried out by filtration of the resulting precipitate with subsequent recrystallization from ethanol or propane-2-ol. The structure of the obtained compounds was confirmed by the methods of 1H and 13C NMR spectroscopy and elemental analysis. It is established that the obtained substituted hetarylamides exist in solutions of deuterated chloroform and DMSO in hydrazonoform. The analgesic and antimicrobial activity of the synthesized compounds was evaluated. Analgesic activity was studied by the "hot plate " thermal irritation method on outbred white mice of both sexes with intraperitoneal injection. Antimicrobial activity of synthesized compounds was established via two-fold serial dilutions method in a liquid growth medium against two strains - S. aureus ATCC 6538-P and E. soli ATCC 25922. The studied compounds showed pronounced analgesic activity significantly exceeding that of the comparison drug metamizole sodium, and in
some cases corresponding to the action of the reference diclofenac sodium. Therefore, pronounced analgesic activity accompanied with weak antimicrobial activity of the synthesized hetarylamides determines the prospects for the development of a new pharmacological active substance with analgesic properties.
Key words: 3-imino(hydrazono)-3H-furan-2-ones, decyclyzation reaction, analgesic activity, antimicrobial activity, 2,4-dioxobutanoic acids
Для цитирования:
Сюткина А.И., Чащина С.В., Махмудов Р.Р., Новикова В.В., Чернов И.Н., Игидов Н.М. Синтез, анальгетическая и противомикробная активность N-гетариламидов 2-(2-(диарилметилен)гидразоно)-5,5-диметил-4-оксогексановой кислоты. Изв. вузов. Химия и хим. технология. 2022. Т. 65. Вып. 3. С. 74-82
For citation:
Siutkina A.I., Chashchina S.V., Makhmudov R.R., Novikova V.V., Chernov I.N., Igidov N.M. Synthesis, analgesic and antimicrobial activity of N-hetarylamides of 2-(2-(diarylmethylene)hydrazono)-5,5-dimethyl-4-oxohexanoic acid. Chem-ChemTech [Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol.]. 2022. V. 65. N 3. P. 74-82
INTRODUCTION
3-Imino(hydrazono)-3#-furan-2-ones are an interesting substrate in medicinal chemistry at least due to a moiety of 2,4-dioxobutanoic acid preserved in the decyclization reactions. 2,4-Dioxobutanoic acid derivatives ensured the presence of various biological action from analgesic [1, 2] and anti-inflammatory [3] to antiviral [4-13] and antifungal [14, 15], which makes it advisable to synthesize and study them.
However, 3-imino(hydrazono)-3#-furan-2-ones can be used not only to create new derivatives of aroyl-and pivaloyl pyruvic acids. The presence of several reaction centers in their structure makes it possible for obtaining of products with various structures [16-21]. The availability and diversity of preparation methods [22-29] is one more advantage of their use.
In this paper, the synthesis of new amides of pivaloyl pyruvic acid, as well as their analgesic and antimicrobial effects, are investigated. Based on these data, it will be possible to assume the expediency of further studying the compounds of this structure as pharmacologically active substances.
EXPERIMENTAL PART
The progress of reactions and the purity of the isolated compounds were monitored by TLC on Silufol plates using diethyl ether - benzene - acetone (10:9:1) as eluent; iodine vapor was used for the spots detection. The 1H and 13C NMR spectra were recorded on a Bruker Avance III HD spectrometer at 400 and 100 MHz, respectively. The elemental analyses were obtained with a Leco CHNS-932 analyzer. The melting (decomposition) points were determined using an SMP40 apparatus.
N-hetaryl-2-((diarylmethylene)hydrazono)-5,5-dimethyl-4-oxohexanamides 4a-i. The general preparation procedure. 20 ml of absolute toluene is
added to the mixture of 1.0 mmol of the initial furanone 3a or 3b and 1.0 mmol of the corresponding heterocyclic amine. The reaction mixture is boiled with stirring for 1020 min, then left at room temperature for 24 h. After removing the solvent, the precipitate is recrystallized.
2-((Diphenylmethylene)hydrazono)-5,5-di-methyl-4-oxo-N-(pyridin-2-yl)hexanamide (4a).
Yield 0.30 g (71%), yellow crystals, mp 156157 °C (nponaH-2-on). 1H NMR spectrum (400 MHz, CDCl3), 5, ppm: 1.15 s (9H, t-Bu), 4.16 s (2H, CH2), 7.34 m (14Harom), 9.16 s (1H, NH). Found, %: C 73.26; H 6.21; N 13.10. C26H26N4O2. Calculated, %: C 73.22; H 6.14; N 13.14.
2-((Diphenylmethylene)hydrazono)-5,5-dime-thyl-N-(3-methylpyridin-2-yl)-4-oxohexanamide (4b).
Yield 0.31 g (70%), yellow crystals, mp 161162 °C (from propane-2-ol). :H NMR spectrum (400 MHz, CDCh), 5, ppm: 1.11 s (9H, t-Bu), 2.43 s (3H, CH3), 4.08 s (2H, CH2), 7.43 m (13Harom), 8.93 s (1H, NH). Found, %: C 73.69; H 6.55; N 12.80. C27H28N4O2. Calculated, %: C 73.61; H 6.41; N 12.72.
2-((Diphenylmethylene)hydrazono)-5,5-dime-thyl-Ai-(4-methylpyridin-2-yl)-4-oxohexanamide (4c).
Yield 0.32 g (73%), yellow crystals, mp 154155 °C (from propane-2-ol). :H NMR spectrum (400 MHz, DMSO-d6), 5, ppm: 1.15 s (9H, t-Bu), 2.31 s (3H, CH3), 4.15 s (2H, CH2), 7.38 m (13Harom), 9.21 s (1H, NH). Found, %: C 73.73; H 6.62; N 12.80. C27H28N4O2. Calculated, %: C 73.61; H 6.41; N 12.72.
2-((Diphenylmethylene)hydrazono)-5,5-dime-thyl-Ai-(6-methylpyridin-2-yl)-4-oxohexanamide (4d).
Yield 0.33 g (74%), yellow crystals, mp 187188 °C (from propane-2-ol). 1H NMR spectrum (400 MHz, CDCh), 5, ppm: 1.17 s (9H, t-Bu), 1.87 s (3H, CH3), 4.19 s (2H, CH2), 7.41 m (13Harom), 8.88 s (1H, NH). Found, %: C 73.70; H 6.59; N 12.79. C27H28N4O2. Calculated, %: C 73.61; H 6.41; N 12.72. M 440.55.
2-((9#-fluoren-9-ylidene)hydrazono)-5,5-dimethyl-4-oxo-N-(thiazol-2-yl)hexanamide (4e).
Yield 0.41 g (96%), yellow crystals, mp 200202 °C (from ethanol). 1H NMR spectrum (400 MHz, CDCh), 5, ppm: 1.18 s (9H, i-Bu), 4.17 s (2H, CH2), 7.00 m (1Harom), 7.30 m (2Harom), 7.43 m (2Harom), 7.54 m (1 Harom), 7.60 m (2Harom), 7.80 m (1Harom), 7.86 m (1 Harom), 10.60 br s (1H, NH). 13C NMR spectrum (CDCl3), 5, M. g.: 26.47, 35.36, 44.83, 97.92, 113.78, 120.06, 120.23, 123.04, 128.20, 128.55, 129.88, 130.87, 131.70, 132.32, 135.97, 137.56, 141.63, 142.66, 151.92, 156.34, 157.98, 160.85, 208.88. Found, %: C 66.99; H 5.21; N 13.09; S 7.40. C24H22N4O2S. Calculated, %: C 66.96; H 5.15; N 13.01; S 7.45.
2-((9#-fluoren-9-ylidene)hydrazono)-5,5-dimethyl-4-oxo-N-(4-phenylthiazol-2-yl)hexana-mide (4f).
Yield 0.40 g (79%), yellow crystals, mp 201203 °C (from ethanol). NMR spectrum (400 MHz, DMSO-ak), 5, ppm: 1.07 s (9H, i-Bu), 4.11 s (2H, CH2), 7.36 m (3 Harom), 7.44 m (2Harom), 7.51 m (2Harom), 7.73 m (1 Harom), 7.82 m (3Harom), 7.96 m (3Harom), 12.54 br s (1H, NH). 13C NMR spectrum (DMSO-ak), 5, m. g.: 26.48, 27.34, 36.51, 44.70, 94.21, 102.19, 109.42, 121.11, 121.27, 123.13, 126.22, 128.18, 129.01, 130.35, 130.57, 132.32, 132.87, 134.65, 135.73, 141.23, 142.44, 149.87, 152.08, 154.41, 158.00, 162.41, 209.91. Found, %: C 71.25; H 5.28; N 11.00; S 6.25. C30H26N4O2S. Calculated, %: C 71.12; H 5.17; N 11.06; S 6.33.
2-((9#-fluoren-9-ylidene)hydrazono)-5,5-dimethyl-4-oxo-N-(1,3,4-thiadiazol-2-yl)hexana-mide (4g).
Yield 0.34 g (78%), yellow crystals, mp 190192 °C (from ethanol). NMR spectrum (400 MHz, CDCh), 5, ppm: 1.17 s (9H, i-Bu), 4.16 s (2H, CH2), 7.27 m (3Harom), 7.45 m (4Harom), 7.58 m (2Harom), 7.65 m (1 Harom), 7.79 m (2Harom), 8.90 s (1H, CONH). 13C NMR spectrum (CDCh), 5, m. g.: 26.42, 35.40, 44.87, 98.52, 120.02, 120.38, 122.92, 123.16, 128.29, 128.59, 129.78, 129.88, 130.80, 130.95, 131.35, 131.89,
132.53, 135.84, 141.63, 142.83, 147.92, 151.38,
156.54, 160.87, 208.89. Found, %: C 64.11; H 5.01; N 16.32; S 7.36. C23H21N5O2S. Calculated, %: C 64.02; H 4.91; N 16.23; S 7.43.
2-((9#-fluoren-9-ylidene)hydrazono)-A'-(5-bromo-1,3,4-thiadiazol-2-yl)-5,5-dimethyl-4-oxohex-anamide (4h).
Yield 0.37 g (73%), yellow crystals, mp 203204 °C (from ethanol). 1H NMR spectrum (400 MHz, CDCh), 5, ppm: 1.18 s (9H, i-Bu), 4.14 s (2H, CH2), 7.29 m (2Harom), 7.43 m (2Harom), 7.58 m (2Harom), 7.74 m
(1 Harom), 7.79 m (1 Harom), 10.94 br s (1H, CONH). 13C NMR spectrum (CDCh), 5, m. g.: 26.40, 35.39, 44.90, 67.08, 98.64, 120.14, 120.42, 123.21, 128.42, 129.65, 130.80, 131.95, 132.61, 135.22, 135.80, 141.64, 142.87, 151.00, 156.57, 160.47, 161.07, 208.87. Found, %: C 54.21; H 4.06; N 13.79; S 6.15. C23H20BrN5O2S. Calculated, %: C 54.12; H 3.95; N 13.72; S 6.28.
2-((9#-fluoren-9-ylidene)hydrazono)-A'-(benzo[d]thiazol-2-yl)-5,5-dimethyl-4-oxohexana-mide (4i).
Yield 0.41 g (86%), yellow crystals, mp 234236 °C (from ethanol). NMR spectrum (400 MHz, DMSO-ak), 5, ppm: 1.08 s (9H, i-Bu), 4.12 s (2H, CH), 7.37 m (2Harom), 7.51 m (3Harom), 7.61 m (1 Harom), 7.79 m (5Harom), 7.93 m (1 Harom), 11.11 br s (1H, CONH). Found, %: C 70.09; H 5.11; N 11.79; S 6.54. C28H24N4O2S. Calculated, %: C 69.98; H 5.03; N 11.66; S 6.67.
The study of biological activity was conducted at the Perm State National Research University and at the Perm State Pharmaceutical Academy. When conducting experiments on animals, the rules of laboratory practice and ethical requirements were observed.
Analgesic activity was determined on outbred white mice of both sexes weighing 18-22 g by the "hot plate" thermal irritation method [30]. The studied compounds were injected intraperitoneally in the form of a suspension in a 2% starch solution at a dose of 50 mg/kg. The animals were placed on a metal plate heated to 53.5 °C 30, 60, 90, 120 min after the injection of the compound. The indicator of the change in pain sensitivity (nociception) was the duration of the animals ' stay on the hot plate until the moment of the defensive pain reflex - licking the hind legs or trying to tear all four paws off the surface of the plate. The time of onset of this reflex from the beginning of placing the animal on the plate was measured in seconds (latency period). The maximum duration of the latent period (the cut off period) is 40 s, since the presence of the animal on the plate for a longer time could lead to burning of the paws and causing physical suffering to the animal. The experiment used animals with an initial time of onset of the defensive reflex of no more than 15 s. Each compound was tested on 6 animals. The results were evaluated by increasing the time of the offensive defensive reflex compared to the initial data. The control group of animals was injected with 2% starch mucus. As comparison drugs, dipyrone (metamizole, Farmkhim-komplekt Ltd.) was used at a dose of 93 mg/kg (ED50), and diclofenac (AlfaAesar) at a dose of 10 mg/kg because of the toxicity of the substance.
The experimental results were processed statistically with the calculation of the Fisher-Student criterion [31]. The effect was considered reliable at p <0.05.
To determine the antimicrobial activity, a twofold serial dilutions method in a liquid growth medium was used against two strains - S. aureus ATCC 6538-P and E. soli ATCC 25922 [30]. To prepare stock solutions, the studied compound in an amount of 0.05 g was dissolved in 5 ml of dimethyl sulfoxide, obtaining a solution concentration of 104 ^g/ml. Then working solutions of the substance was prepared as follows: 4 ml of a liquid growth medium was placed in a sterile test tube; 1 ml of the basic solution was added, obtaining a concentration of 2000 ^g/ml. Next, a number of serial dilutions of compounds with a two-fold decreasing concentration (from 1000 ^g/ml to 0.06 ^g/ml) were prepared. An intact liquid growth medium was used as a negative control, and a medium with an introduced culture without the studied compound was used as a positive control.
The cultures were grown in test tubes on a beveled agarized medium (nutrient agar for bacteria); 24 h cultures were used. To prepare a working suspension of microorganisms, the grown culture was washed off with an isotonic sterile sodium chloride solution and the density of the microbial suspension was set according to the turbidity standard of five units. Next, a working solution with a concentration of 5 106 CFU/ml was prepared from the obtained microbial suspension. The microbial suspension was introduced into each tube in an amount of 0.1 ml. The microbial load was about 2.5 105 CFU/ml. The results were taken into account after 18-24 h of temperature control at 35-37 °C. Minimum inhibitory concentration (MIC) was determined by the absence of visual signs of microbial growth on the growth medium. Substances with a MIC value in
the range of 125-1000 ^g/ml were evaluated as having low bacteriostatic activity, 15.0-62.5 ^g/ml - medium antibacterial activity, 7.8 ^g/ml and less - high antibacterial activity. The antibacterial effect of the compounds was compared with that of dioksidin [2,3-bis(hy-droxymethyl)quinoxaline 1,4-dioxide, 1% solution, Novosibkhimfarm).
RESULTS AND DISCUSSION
Synthesis of starting hydrazonofuranones 3a,b is shown on the scheme 1. Firstly, Claisen condensation between pinacolone and diethyl oxalate led to 5,5-dimethyl-2,4-dioxohexanoic acid (pivaloyl pyruvic acid) 1 [32], which interacting with the hydrazones of diarylmethylene ketones gave hydrazonic acids 2a,b [33]. Hydrazonofuranones 3a, b were obtained as a result of intramolecular cyclization of acids 2a,b in a propionic anhydride medium [34, 35].
N-hetaryl-2-((diarylmethylene)hydrazono)-5,5-dimethyl-4-oxohexanamides 4a-i were obtained due to the interaction between hydrazonofuranones 3a,b with heterocyclic amines (scheme 2).
Amides 4a-i are yellow crystalline compounds obtained with yields of up to 96%, insoluble in ether, hexane, water, hardly soluble in toluene, ethanol and propane-2-ole, easily soluble in dichloromethane, DMSO, chloroform, acetone.
In the :H NMR spectra of compounds 4a-i recorded in CDCl3 (4c,f,i in DMSO-flk), a tautomer form of hydrazone is observed, as evidenced by the presence of the methylene group protons signal resonated at S 4.08-4.17 ppm. In the 13C NMR spectra of compounds 4a-i, there are characteristic signals of carbonyl carbon C4 located at S 208.87-209.91 ppm and the signal of methylene carbon C3 appeared at S94.21-98.64 ppm.
О
о
i-Bu
OH
i-Bu^Me ?"BU
О l.MeONa °"H'° A
2. HCl
+ -
™ к к Q*NI *
о
-EtOH
ЕЮ
OEt
i-Bu
О
H2N
r
N
О
О о
он
в
i-Bu
R R'
О
R
(EtC0)20 //^R'
—-——N—N
-2EtCOOH //
OH
О N
N
R-^R'
В
JTX
i-Bu Q O 3a,b
2a,b
2,3: R, R' = Ph (a), R+R' = Qrf} (b).
Scheme 1 Схема 1
R
N-N
,_(/
R-NH2
i-Bu^o^O 3a,b
Toluene, 110 °C, 15 min ¿_Bu
VR'
° A
R"
О 4a-i
(b).
3: R, R' = Ph (a), R+R' = 4: R, R' = Ph, R" = pyridine-2-yl (a), 3-methylpyridine-2-yl (b), 4-methylpyridine-2-yl (c), 6-methylpyridine-2-yl (d); R+R' = , thiazol-2-yl (e), 4-phenylthiazol-2-yl (f), thiadiazol-2-yl (g), 5-bromothiadiazol-2-yl (h), benzothiazol-2-yl (i).
Scheme 2 Схема 2
Analgesic activity of compounds 4 studied by the "hot plate" method
Table 1
Compound no. R" c, mg/kg Defensive response time at the maximum effect, s
R, R' = Ph
4b 3 -methylpyridine -2 -yl 50 22.40 ± 3.36*
4c 4 -methylpyridine -2 -yl 50 12.18 ± 0.45
R + R' = OP
4e Thiazol-2-yl 50 24.20 ± 1.93*
4f 4-Phenylthiazol-2-yl 50 26.00 ± 1.00*
4g 1,3,4-Thiadiazol-2-yl 50 26.80 ± 2.24*
4h 5-Bromo-1,3,4-thiadiazole-2-yl 50 25.60 ± 1.17*
4i Benzothiazole-2-yl 50 20.60 ± 2.56*
Dipyrone - 93 (ED50) 16.60 ± 1.00*
Diclofenac - 10 26.20 ± 0.96*
Control - - 11.38 ± 0.93
Note: *Reliability with respect to control p <0.05 Примечание: *Надежность по отношению к контролю p<0,(
Analgesic and antimicrobial activities were evaluated for compounds 4. It was found that the studied compounds have a pronounced analgesic activity, with the exception of compound 4c (Table 1). The most active compounds were amides 4e-h, which contain fragments of substituted thiazole or thiadiazole in the amide moiety.
According to the antimicrobial activity tests data, the MIC values of the examined amides are in the range of 500-1000 ^g/ml or more, which indicates low bacteriostatic activity or its absence (Table 2).
CONCLUSIONS
New N-hetaryl substituted 2-((diaryl-methylene)hydrazono)-5,5-dimethyl-4-oxohexana-mides were obtained from commercially available pi-nacolone and diethyl oxalate in 4 steps with yields of up to 96%. The pronounced analgesic activity of the synthesized substances with low or absent bacteriostatic activity was established, which makes further in-depth research promising in order to develop a new pharmacologically active substance.
Table 2
Antimicrobial activity of compounds 4 Таблица 2. Противомикробная активность _соединений 4_
MIC, ^g/ml
Compound no. S. aureus ATCC E. coli ATCC
6538P 25922
4а 1000 1000
4b >1000 >1000
4c >1000 >1000
4d 500 1000
4e 1000 1000
4g 1000 1000
4i 1000 1000
Dioksidin, 1% solution 62.5 31.0
FUNDING
The research was supported by ihe Perm Research and Education Centre for Rational Use of Subsoil, 2021.
The authors declare the absence a conflict of inieresi warraniing disclosure in ihis ariicle.
Исследование выполнено при поддержке Пермского научно-образовательного центра рационального недропользования, 2021.
ЛИТЕРАТУРА
1. Шипиловских С.А., Махмудов Р.Р., Лупач Д.Ю., Павлов П.Т., Бабушкина Е.В., Рубцов А.Е. Синтез и аналь-гетическая активность замещенных 4-(гет)арил-4-оксо-2-тиениламинобут-2-еновых кислот. ХФЖ. 2013. Т. 47. Вып. 7. С. 26-30. DOI: 10.1007/s11094-013-0960-z.
2. Denisova E.L, Shipilovskikh S.A., Makhmudov R.R., Rubtsov A.E. Search of analgesic activity of N-substituted 2-((3-R-4,5,6,7-tetrahydrobenzo [b]thiophen-2-yl)amino )-4-oxo-4-phenylbut-2-enamides. AIP Conf. Proc. 2020. V. 2280. N 1. P. 040013. DOI: 10.1063/5.0018515.
3. Кизимова И.А., Игидов Н.М., Дмитриев М.В., Чащина
C.В., Махмудов Р.Р., Сюткина А.И. Синтез, особенности строения и биологическая активность 4-Я-4-оксо-2-[2-(фениламино)бензоил]гидразинилиден-Ы-гетарилбутана-мидов. ЖОХ. 2019. Т. 89. Вып. 12. С. 1820-1828. DOI: 10.1134/s0044460x19120035.
4. Kowalinski E., Zubieta C., Wolkerstorfer A., Szolar O.H., Ruigrok R.W., Cusack S. Structural analysis of specific metal chelating inhibitor binding to the endonuclease domain of influenza pH1N1 (2009) polymerase. PLoS Pathogens. 2012. V. 8. N 8. P. e1002831. DOI: 10.1371/jour-nal.ppat.1002831.
5. Baughman B.M., Jake Slavish P., DuBois R.M., Boyd V.A., White S.W., Webb T.R. Identification of influenza endonuclease inhibitors using a novel fluorescence polarization assay. ACS Chem. Biol. 2012. V. 7. N 3. P. 526-534. DOI: 10.1021/cb200439z.
6. Michelini Z., Galluzzo C.M., Negri D.R., Leone P., Amici R., Bona R., Summa V., Di Santo R., Costi R., Pommier Y., Marchand C., Palmisano L., Vella S., Cara A. Evaluation of HIV-1 integrase inhibitors on human primary macrophages using a luciferase-based single-cycle phenotypic assay. J. Virol. Methods. 2010. V. 168. N 1-2. P. 272-276. DOI: 10.1016/j.jviromet.2010.06.004.
7. de Melo E.B., Ferreira M.M. Four-dimensional structure-activity relationship model to predict HIV-1 integrase strand transfer inhibition using LQTA-QSAR methodology. J. Chem. Inf. Model. 2012. V. 52. N 7. P. 1722-1732. DOI: 10.1021/ci300039a.
8. Hu L., Zhang S., He X., Luo Z., Wang X., Liu W., Qin X. Design and synthesis of novel beta-diketo derivatives as HIV-1 integrase inhibitors. Bioorg. Med. Chem. 2012. V. 20. N 1. P. 177-182. DOI: 10.1016/j.bmc.2011.11.014.
9. Dias A., Bouvier D., Crepin T., McCarthy A.A., Hart
D.J., Baudin F., Cusack S., Ruigrok R.W. The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature. 2009. V. 458. N 7240. P. 914-918. DOI: 10.1038/nature07745.
10. Sharma H., Sanchez T.W., Neamati N., Detorio M., Schinazi R.F., Cheng X., Buolamwini J.K. Synthesis, docking, and biological studies of phenanthrene beta-diketo acids as novel HIV-1 integrase inhibitors. Bioorg. Med. Chem. Lett. 2013. V. 23. N 22. P. 6146-6151. DOI: 10.1016/j.bmcl.2013.09.009.
11. Uchil V., Seo B., Nair V. A novel strategy to assemble the beta-diketo acid pharmacophore of HIV integrase inhibitors on purine nucleobase scaffolds. J. Org. Chem. 2007. V. 72. N 22. P. 8577-8579. DOI: 10.1021/jo701336r.
Авторы заявляют об отсутствии конфликта интересов, требующего раскрытия в данной статье.
REFERENCES
1. Shipilovskikh S.A., Makhmudov R.R., Lupach D.Y., Pavlov P.T., Babushkina E.V., Rubtsov A.E. Synthesis and Analgesic Activity of Substituted 4-(Het)aryl-4-oxo-2-thienyla-minobut-2-enoic Acids. Pharm. Chem. J. 2013. V. 47. N 7. P. 366-370. DOI: 10.1007/s11094-013-0960-z.
2. Denisova E.L, Shipilovskikh S.A., Makhmudov R.R., Rubtsov A.E. Search of analgesic activity of N-substituted 2-((3-R-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-4-oxo-4-phenylbut-2-enamides. AIP Conf. Proc. 2020. V. 2280. N 1. P. 040013. DOI: 10.1063/5.0018515.
3. Kizimova I.A., Igidov N.M., Dmitriev M.V., Chashchina S.V., Makhmudov R.R., Siutkina A.I. Synthesis, Structure, and Biological Activity of 4-R-4-Oxo-2-[2-(phenyla-mino)benzoyl]hydrazinylidene-N-hetarylbutanamides. Russ. J. Gen. Chem. 2019. V. 89. N 12. P. 2345-2352. DOI: 10.1134/S107036321912003X.
4. Kowalinski E., Zubieta C., Wolkerstorfer A., Szolar O.H., Ruigrok R.W., Cusack S. Structural analysis of specific metal chelating inhibitor binding to the endonuclease domain of influenza pH1N1 (2009) polymerase. PLoS Pathogens. 2012. V. 8. N 8. P. e1002831. DOI: 10.1371/jour-nal.ppat.1002831.
5. Baughman B.M., Jake Slavish P., DuBois R.M., Boyd V.A., White S.W., Webb T.R. Identification of influenza endonuclease inhibitors using a novel fluorescence polarization assay. ACS Chem. Biol. 2012. V. 7. N 3. P. 526-534. DOI: 10.1021/cb200439z.
6. Michelini Z., Galluzzo C.M., Negri D.R., Leone P., Amici R., Bona R., Summa V., Di Santo R., Costi R., Pommier Y., Marchand C., Palmisano L., Vella S., Cara A. Evaluation of HIV-1 integrase inhibitors on human primary macrophages using a luciferase-based single-cycle phenotypic assay. J. Virol. Methods. 2010. V. 168. N 1-2. P. 272-276. DOI: 10.1016/j.jviromet.2010.06.004.
7. de Melo E.B., Ferreira M.M. Four-dimensional structure-activity relationship model to predict HIV-1 integrase strand transfer inhibition using LQTA-QSAR methodology. J. Chem. Inf. Model. 2012. V. 52. N 7. P. 1722-1732. DOI: 10.1021/ci300039a.
8. Hu L., Zhang S., He X., Luo Z., Wang X., Liu W., Qin X. Design and synthesis of novel beta-diketo derivatives as HIV-1 integrase inhibitors. Bioorg. Med. Chem. 2012. V. 20. N 1. P. 177-182. DOI: 10.1016/j.bmc.2011.11.014.
9. Dias A., Bouvier D., Crepin T., McCarthy A.A., Hart D.J., Baudin F., Cusack S., Ruigrok R.W. The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature. 2009. V. 458. N 7240. P. 914-918. DOI: 10.103 8/nature07745.
10. Sharma H., Sanchez T.W., Neamati N., Detorio M., Schinazi R.F., Cheng X., Buolamwini J.K. Synthesis, docking, and biological studies of phenanthrene beta-diketo acids as novel HIV-1 integrase inhibitors. Bioorg. Med. Chem. Lett. 2013. V. 23. N 22. P. 6146-6151. DOI: 10.1016/j.bmcl.2013.09.009.
11. Uchil V., Seo B., Nair V. A novel strategy to assemble the beta-diketo acid pharmacophore of HIV integrase inhibitors on purine nucleobase scaffolds. J. Org. Chem. 2007. V. 72. N 22. P. 8577-8579. DOI: 10.1021/jo701336r.
12. Jiang X. -H., Long Y.-Q. A simple and highly efficient preparation of structurally diverse aryl P-diketoacids as hiv-1 integrase inhibitors. CJC. 2010. V. 22. N 9. P. 978-983. DOI: 10.1002/cjoc .20040220920.
13. Deore R.R., Chen G.S., Chen C.S., Chang P.T., Chuang M.H., Chern T.R., Wang H.C., Chern J.W. 2-Hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid with inbuilt beta-N-hydroxy-gamma-keto-acid pharmacophore as HCV NS5B polymerase inhibitors. Curr. Med. Chem. 2012. V. 19. N 4. P. 613-624. DOI: 10.2174/092986712798918833.
14. Shipilovskikh S.A., Makhmudov R.R., Balandina S.Y., Rubtsov A.E. Search of antimicrobial activity in a series of substituted 4-aryl-4-oxo-2-tienilaminobut-2-enoic acids. AIP Conf. Proc. 2020. V. 2280. N 1. P. 030018. DOI: 10.1063/5.0018494.
15. Новикова В.В., Пулина Н.А., Собин Ф.В., Липатни-ков К.В. Противогрибковая активность новых производных 4-(гет)арил-2,4-диоксобутановых кислот. Обзоры по клин. фармакол. и лекарств. терапии. 2020. Т. 18. Вып. 3. С. 225-228. DOI: 10.17816/RCF183225-228.
16. Шипиловских С.А., Рубцов А.Е. Рециклизация of 3-(тиофен-2-ил)имино-3Н-фуран-2-онов под дествием производных цианоуксусной кислоты. ЖОХ. 2020. Т. 90. Вып. 5. С. 708-714. DOI: 10.31857/S0044460X2005008X.
17. Сюткина А.И., Игидов Н.М., Кизимова И.А. Синтез и свойства алкил 2-[2-(диарилметилен)гидразинил]-5,5-ди-метил-4-оксогекс-2-еноатов. ЖОрХ. 2020. Т. 56. Вып. 4. C. 613-618. DOI: 10.31857/S0514749220040138.
18. Кизимова И.А., Игидов Н.М., Киселев М.А., Иванов Д.В., Сюткина А.И. Синтез, особенности строения и биологическая активность 4-Я-4-оксо-2-[2-(фениламино)бензоил]гид-разигилиден-М-гетарилбутанамидов. ЖОХ. 2020. Т. 90. Вып. 5. С. 715-722. DOI: 10.31857/S0044460X20050091.
19. Shipilovskikh S.A., Rubtsov A.E. One-Pot Synthesis of Thieno[3,2-e]pyrrolo[1,2-a]pyrimidine Derivative Scaffold: A Valuable Source of PARP-1 Inhibitors. J. Org. Chem. 2019. V. 84. N. 24. P. 15788-15796. DOI: 10.1021/acs.joc.9b00711.
20. Зыкова C.C., Кизимова И.А., Сюткина А.И., Токсарова Ю.С., Игидов Н.М., Ибишов Д.Ф, Бойчук С.В., Дунаев П.Д., Галембикова А.Р., Корочкина Р.Р. Синтез и цитостатическая активность (Е)-этил-2-амино-5-(3,3-диметил-4-оксобутилиден)-4-оксо-1-(2-фенил-аминобензамидо)-4,5-дигидро-1Н-пиррол-3-карбокси-лата. ХФЖ. 2019. Т. 53. Вып. 10. C. 15-18. DOI: 10.30906/0023-1134-2019-53-10-15-18.
21. Кизимова И.А., Игидов Н.М., Киселев М.А., Дмитриев М.В., Чащина С.В., Сюткина А.И. Синтез новых производных 2-аминопирролов реакцией 3-ацилгидразонов 2,3-фурандионов с СН-нуклеофилами. ЖОХ. 2020. Т. 90. Вып. 2. С. 192-198. DOI: 10.31857/S0044460X20020031.
22. Taiseer Abdul-Kader S., Rafah Razooq Hameed A.-S., Noor Essam A.-R. The antioxidant and antimicrobial activity for some new synthesized Schiff bases derived from Ascorbic acid. IJRPS. 2019. V. 10. N 2. P. 1510-1515. DOI: 10.26452/ijrps.v10i2.730.
23. Арзямова Е.М., Ибрагимова Д.Н., Федотова О.В., Пчелинцева Н.В. 5-(Я)бензилиден-2,2-диметил-1,3-диоксан-4,6-дионов синтезе ароматических оксимов, тиосемикарбазонов и гидразонов. Изв. вузов. Химия и хим. технология. 2021. Т. 64. Вып. 6. С. 20-24. DOI: 10.6060/ivkkt.20216406.6353.
24. Mokhonova I.D., Maksimov E.A., Ledenyona I.V., Yego-rova A.Y., Shikhaliev K.S. Reactions of 3H-furan-2-ones and 2H-chromen-2-ones with pyrazole-3(5)-diazonium salts. Heterocyc.Commun. 2018. V. 24. N 4. P. 183-185. DOI: 10.1515/hc-2017-0192.
12. Jiang X.-H., Long Y.-Q. A simple and highly efficient preparation of structurally diverse aryl ß-diketoacids as hiv-1 integrase inhibitors. CJC. 2010. V. 22. N 9. P. 978-983. DOI: 10.1002/cjoc .20040220920.
13. Deore R.R., Chen G.S., Chen C.S., Chang P.T., Chuang M.H., Chern T.R., Wang H.C., Chern J.W. 2-Hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid with inbuilt beta-N-hydroxy-gamma-keto-acid pharmacophore as HCV NS5B polymerase inhibitors. Curr. Med. Chem. 2012. V. 19. N 4. P. 613-624. DOI: 10.2174/092986712798918833.
14. Shipilovskikh S.A., Makhmudov R.R., Balandina S.Y., Rubtsov A.E. Search of antimicrobial activity in a series of substituted 4-aryl-4-oxo-2-tienilaminobut-2-enoic acids. AIP Conf. Proc. 2020. V. 2280. N 1. P. 030018. DOI: 10.1063/5.0018494.
15. Novikova V.V., Pulina N.A., Sobin F.V., Lipatnikov K.V. Antifungal activity of new derivatives of 4-(het)aryl-2,4-di-oxobutanoic acids. Obzory Klin. Farmakol. Lekarstv. Tera-pii. 2020. V. 18. N 3. P. 225-228 (in Russian). DOI: 10.17816/RCF183225-228.
16. Shipilovskikh S.A., Rubtsov A.E. Recyclization of 3-(Thi-ophen-2-yl)imino-3H-furan-2-ones under the Action of Cy-anoacetic Acid Derivatives. Russ. J. Gen. Chem. 2020. V. 90. N 5. P. 809-814. DOI: 10.1134/S1070363220050084.
17. Siutkina A.I., Igidov N.M., Kizimova I.A. Synthesis and Properties of Alkyl 2-[2-(Diarylmethylidene)hydrazinyl]-5,5-dimethyl-4-oxohex-2-enoates. Russ. J. Org. Chem. 2020. V. 56. N 4. P. 649-653. DOI: 10.1134/S1070428020040132.
18. Kizimova I.A., Igidov N.M., Kiselev M.A., Syutkina A.I., Ivanov D.V. Reactions of N'-[2-Oxo-5-R-furan-3(2H)-yli-dene]acylhydrazides with Primary and Secondary Alcohols. Russ. J. Gen. Chem. 2020. V. 90. N 5. P. 815-821. DOI: 10.1134/S1070363220050096.
19. Shipilovskikh S.A., Rubtsov A.E. One-Pot Synthesis of Thieno[3,2-e]pyrrolo[1,2-a]pyrimidine Derivative Scaffold: A Valuable Source of PARP-1 Inhibitors. J. Org. Chem. 2019. V. 84. N. 24. P. 15788-15796. DOI: 10.1021/acs.joc.9b00711.
20. Zykova S.S., Kizimova I.A., Syutkina A.I., Toksarova Yu.S., Igidov N.M., Ibishov D.F., Boichuk S.V., Dunaev P.D., Galembikova A.R. Synthesis and Cytostatic Activity of (E)-Ethyl-2-Amino-5-(3,3-Dimethyl-4-Oxobutyliden)-4-Oxo-1-(2-Phenylaminobenzamido)-4,5-Dihydro-1H-pyrrol-3-Car-boxylate. Pharm. Chem. J. 2020. V. 53. N 10. P. 895-898. DOI: 10.1007/s11094-020-02096-z.
21. Kizimova I.A., Igidov N.M., Kiselev M.A., Dmitriev M.V., Chashchina S.V., Siutkina A.I. Synthesis of new 2-amino-pyrrole derivatives by reaction of furan-2,3-diones 3-acylhy-drazones with CH-nucleophiles. Russ. J. Gen. Chem. 2020. V. 90. N 2. P. 182-186. DOI: 10.1134/S1070363220020036.
22. Taiseer Abdul-Kader S., Rafah Razooq Hameed A.-S., Noor Essam A.-R. The antioxidant and antimicrobial activity for some new synthesized Schiff bases derived from Ascorbic acid. IJRPS. 2019. V. 10. N 2. P. 1510-1515. DOI: 10.26452/ijrps.v10i2.730.
23. Arzyamova E.M., Ibragimova D.N., Fedotova O.V., Pchelintseva N.V. 5-(R)benzylidene-2,2-dimethyl-1,3-diox-ane-4,6-diones insynthesisof aromatic oximes, thiosemicarba-zones and hydrazones. ChemChemTech [Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol.J. 2021. V. 64. N 6. P. 20-24 (in Russian). DOI: 10.6060/ivkkt.20216406.6353.
24. Mokhonova I.D., Maksimov E.A., Ledenyona I.V., Yego-rova A.Y., Shikhaliev K.S. Reactions of 3H-furan-2-ones and 2H-chromen-2-ones with pyrazole-3(5)-diazonium salts. Heterocyc.Commun. 2018. V. 24. N 4. P. 183-185. DOI: 10.1515/hc-2017-0192.
25. Maiorova O.A., Babkina N.V., Egorova A.Y. Studies of Stereochemistry of 3-(Arylhydrazono)Furan-2(3H)-Ones, Synthesis of 4-(Arylhydrazono)Pyridazin-3(1H)-Ones. Chem. Heterocycl. Compd. 2015. V. 51. N 6. P. 514-517. DOI: 10.1007/s10593-015-1730-5.
26. Шипиловских С.А., Рубцов А.Е. Синтез новых замещенных 3-(тиофен-2-ил)имино-3H-фуран-2-онов. ЖОХ. 2020. Т. 90. Вып. 6. С. 837-842. DOI: 10.31857/S0044460X20060037.
27. Maigali S.S., El-Hussieny M., Soliman F.M. Chemistry of Phosphorus Ylides. Part 37. The Reaction of Phosphonium Ylides with Indoles and Naphthofurans. Synthesis of Phos-phanylidenes, Pyrans, Cyclobutenes, and Pyridazine as Antitumor Agents. J. Heterocycl. Chem. 2015. V. 52. N 1. P. 15-23. DOI: 10.1002/jhet.1911.
28. Гавкус Д.Н., Майорова О.А., Борисов М.Ю., Егорова А.Ю. Азосочетание 5-R-фуран-2(3H)-онов и 5-R-2H-пиррол-2-онов с солями арил(гетарил)диазо-ния. ЖОрХ. 2012. Т. 48. Вып. 9. С. 1230-1233. DOI: 10.1134/S107042801209014X.
29. Shipilovskikh S.A., Rubtsov A.E. Synthesis of substituted 2-((2-oxofuran-3(2H)-ylidene)amino)-4,5,6,7-tetra-hydrobenzo[b]thiophene-3-carboxamide. AIP Conf. Proc. 2020. V. 2280. N 1. P. 030016. DOI: 10.1063/5.0018486.
30. Миронов А.Н. Руководство по проведению доклинических исследований лекарственных средств. М.: Гриф и К. 2013. 202 с.
31. Беленький МЛ. Элементы количественной оценки фармакологического эффекта. Л.: Медгиз. 1963. 146 с.
32. Козьминых В.О., Игидов HM., Березина E.C, Козь-миных E.H, Касаткина Ю.С. Пивалоилпировиноград-ная кислота как новый ацилирующий агент для аминов. Изв. Ак. Наук. Сер. Хим. 2000. Т. 49. Вып. 9. С. 1564-1568. DOI: 10.1007/BF02495160.
33. Комарова О.А., Игидов Н.М., Корягина Н.Н., Макаров АС., Токсарова Ю.С., Рубцов А.Е. Химия иминофуранов. VI. Синтез и строение 2'2-метилензамещенных производных 4-арил-2-гидразино-4-оксобут-2-еновых и 5,5-диме-тил-2-гидразино-4-оксогекс-2-еновых кислот. ЖОрХ. 2011. Т. 47. Вып. 1. С. 110-115. DOI: 10.1134/S1070428011010131.
34. Тюнева А.В., Игидов Н.М., Корягина Н.Н., Бородин А.Ю., Захматов А.В., Макаров А.С., Токсарова Ю.С., Рубцов А.Е. Химия иминофуранов VII. Внутримолекулярная циклизация 2-Ы-арилзамещенных производных 2-амино-4-арил-4-оксобут-2-еновых и 2-амино-5,5-ди-метил-4-оксогекс-2-еновых кислот. ЖОрХ. 2011. Т. 47. Вып. 2. С. 266-272. DOI: 10.1134/S1070428011020163.
35. Сюткина А.И., Игидов Н.М., Дмитриев М.В., Махмудов Р.Р., Новикова В.В. Синтез и биологическая активность N-арил(алкил)-2-[2-(9H-Ффлуорен-9-илиден)гидразоно]-5,5-диметил-4-оксогексанамидов. ЖОХ. 2019. Т. 89. Вып. 7. С. 1026-1032. DOI: 10.1134/S0044460X19070060.
25. Maiorova O.A., Babkina N.V., Egorova A.Y. Studies of Stereochemistry of 3-(Arylhydrazono)Furan-2(3H)-Ones, Synthesis of 4-(Arylhydrazono)Pyridazin-3(1H)-Ones. Chem. Heterocycl. Compd. 2015. V. 51. N 6. P. 514-517. DOI: 10.1007/s10593-015-1730-5.
26. Shipilovskikh S.A., Rubtsov A.E. Synthesis ofNew Substituted 3-(Thien-2-yl)imino-3H-fUran-2-ones. Russ. J. Gen. Chem. 2020. V. 90. N 6. P. 943-947. DOI: 10.1134/S1070363220060031.
27. Maigali S.S., El-Hussieny M., Soliman F.M Chemistry of Phosphorus Ylides. Part 37. The Reaction of Phosphonium Ylides with Indoles and Naphthofurans. Synthesis of Phos-phanylidenes, Pyrans, Cyclobutenes, and Pyridazine as Antitumor Agents. J. Heterocycl. Chem. 2015. V. 52. N 1. P. 15-23. DOI: 10.1002/jhet.1911.
28. Gavkus D.N., Maiorova O.A., Borisov M.Y., Egorova A.Y. Azo coupling of 5-substituted furan-2(3H)-ones and 1H-pyrrol-2(3H)-ones with arene(hetarene)diazonium salts. Russ. J. Org. Chem. 2012. V. 48. N 9. P. 1229-1232. DOI: 10.1134/S107042801209014X.
29. Shipilovskikh S.A., Rubtsov A.E. Synthesis of substituted 2-((2-oxofuran-3(2H)-ylidene)amino)-4,5,6,7-tetrahydrobenzo[b]thio-phene-3-carboxamide. AIP Conf. Proc. 2020. V. 2280. N 1. P. 030016. DOI: 10.1063/5.0018486.
30. Mironov A.N. Guidelines for conducting preclinical studies of drugs. M.: Grif and K. 2012. 944 p. (in Russian).
31. Belenky M.L. Elements of quantitative evaluation of the pharmacological effect. L.: Medgiz. 1963. 146 p. (in Russian).
32. Koz'minykh V.O., Igidov N.M., Berezina E.S., Koz'minykh E.N., Kasatkina Yu.S. Pivaloylpyruvic acid as a new acylating reagent for amines. Russ. Chem. Bull. 2000. V. 49. N 9. P. 1552-1556. DOI: 10.1007/BF02495160.
33. Komarova O.A., Igidov N.M., Koryagina N.N., Makarov AS., Toksarova Yu.S., Rubtsov A.E. Chemistry of iminofu-rans: VI. Synthesis and structure of 2-(2-ylidenehydrazino)-substituted 4-aryl-4-oxobut-2-enoic and 5,5-dimethyl-4-oxohex-2-enoic acids. Russ. J. Org. Chem. 2011. V. 47. N 1. P. 109-114. DOI: 10.1134/S1070428011010131.
34. Tyuneva A.V., Igidov N.M., Koryagina N.N., Borodin AY., Zakhmatov A.V., Makarov AS., Toksarova Y.C., Rubtsov A.E. Iminofuran chemistry: VII. Intramolecular cy-clization of 2-N-aryl-substituted derivatives of 2-amino-4-aryl-4-oxobut-2-enoic and 2-amino-5,5-dimethyl4-oxohex-2-enoic acids. Russ. J. Org. Chem. 2011. V. 47. N 2. P. 258-264. DOI: 10.1134/S1070428011020163.
35. Siutkina A.I., Igidov N.M., Dmitriev M.V., Makhmudov R.R., Novikova V.V. Synthesis and Biological Activity of N-Aryl(alkyl)-2-[2-(9H-fluoren-9-ylidene)hydrazinylidene]-5,5-dimethyl-4-oxohexanamides. Russ. J. Gen. Chem. 2019. V. 89. N 7. P. 1388-1393. DOI: 10.1134/S1070363219070065.
Поступила в редакцию 06.10.2021 Принята к опубликованию 21.12.2021
Received 06.10.2021 Accepted 21.12.2021
