RU2809158C1 - Use of n-(2-oxo-6-(3,4,5-trimethoxyphenyl)-2h-pyran-3-yl)benzamide as an anti-microbial agent - Google Patents
Use of n-(2-oxo-6-(3,4,5-trimethoxyphenyl)-2h-pyran-3-yl)benzamide as an anti-microbial agent Download PDFInfo
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- 239000004599 antimicrobial Substances 0.000 title claims abstract description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 title 1
- -1 N-(2-oxo-6-(3,4,5-trimethoxyphenyl)-2H-pyran-3-yl)benzamide Chemical compound 0.000 claims abstract description 6
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- IBNFFIKIHHCABM-XPPMVYLVSA-N 6-[(E,4S)-4-hydroxy-3-oxopent-1-enyl]pyran-2-one Chemical compound C[C@H](O)C(=O)\C=C\c1cccc(=O)o1 IBNFFIKIHHCABM-XPPMVYLVSA-N 0.000 description 2
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- QGZCUOLOTMJILH-UHFFFAOYSA-N 2h-tetrazol-2-ium;bromide Chemical compound [Br-].C1=N[NH+]=NN1 QGZCUOLOTMJILH-UHFFFAOYSA-N 0.000 description 1
- 125000000972 4,5-dimethylthiazol-2-yl group Chemical group [H]C([H])([H])C1=C(N=C(*)S1)C([H])([H])[H] 0.000 description 1
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- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
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- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
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Abstract
Description
Изобретение относится к области органической химии, к новым биологически активным веществам класса пиран-2-онов, а именно к N-(2-оксо-6-(3,4,5-триметоксифенил)-2Н-пиран-3-ил)бензамиду (1):The invention relates to the field of organic chemistry, to new biologically active substances of the class of pyran-2-ones, namely N-(2-oxo-6-(3,4,5-trimethoxyphenyl)-2H-pyran-3-yl)benzamide (1):
Данное соединение обладает противомикробной активностью в отношении золотистого стафилокока (S.aureus) и кишечной палочки (E.coli) что позволяет предположить его использование в медицине в качестве противомикробного средства.This compound has antimicrobial activity against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli), which suggests its use in medicine as an antimicrobial agent.
Известен структурный аналог заявляемым соединениям - (S,E)-6-(4-гидрокси-3-оксопент-1-ен-1-ил)-2H-пиран-2-он (2) выделенный из Полыни арги (Artemisia argyi) обладающий умеренным противомикробным действием(Gu Н, Zhang S., Liu L., Yang Z., Zhao F., Tian Y. Antimicrobial Potential of Endophytic Fungi From Artemisia argyi and Bioactive Metabolites From Diaporthe sp.AC1. // Frontiers in Microbiology - 2022. - 13, 908836.).(Таблица 1).A known structural analogue of the claimed compounds is (S,E)-6-(4-hydroxy-3-oxopent-1-en-1-yl)-2H-pyran-2-one (2) isolated from Wormwood (Artemisia argyi) having a moderate antimicrobial effect (Gu H, Zhang S., Liu L., Yang Z., Zhao F., Tian Y. Antimicrobial Potential of Endophytic Fungi From Artemisia argyi and Bioactive Metabolites From Diaporthe sp.AC1. // Frontiers in Microbiology - 2022. - 13, 908836.).(Table 1).
Эталоном сравнения был выбран фенилсалицилат формулы 3:Phenyl salicylate of formula 3 was chosen as the standard of comparison:
который широко применяется в лечебной практике, и являются аналогами по действию [Машковский М.Д. Лекарственные средства. - 16-е изд., перераб., испр. и доп. - М.: ООО «Новая волна», 2010 - с. 472].which is widely used in medical practice, and are analogues in action [Mashkovsky M.D. Medicines. - 16th ed., revised, corrected. and additional - M.: New Wave LLC, 2010 - p. 472].
Задачей изобретения является поиск веществ с выраженным противомикробным и действием, и низкой токсичностью.The objective of the invention is to search for substances with a pronounced antimicrobial effect and low toxicity.
Пример 1. Заявляемое соединение 1 синтезируется в 2 стадии, включающих в себя взаимодействие 3,4,5-триметоксиацетофенона 4 с диметилформамид-диметилацеталем с получением соответствующего (Е)-3-(диметиламино)-1-(3,4,5-триметоксифенил)проп-2-ен-1-она 5, взаимодействие соединения 5 с гиппуровой кислотой в присутствии уксусного ангидрида с образованием соответствующего N-(2-оксо-6-(3,4,5-триметоксифенил)-2H-пиран-3-ил)бензамида 1.Example 1. The claimed compound 1 is synthesized in 2 stages, including the interaction of 3,4,5-trimethoxyacetophenone 4 with dimethylformamide-dimethylacetal to obtain the corresponding (E)-3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl )prop-2-en-1-one 5, reaction of compound 5 with hippuric acid in the presence of acetic anhydride to form the corresponding N-(2-oxo-6-(3,4,5-trimethoxyphenyl)-2H-pyran-3- yl)benzamide 1.
Получение соединения 1. Стадия 1. 3,4,5-Триметоксиацетофенон 4 (1,0 экв.) и диметилацеталь N,N-диметилформамида (DMF-DMA) (2,0 экв.) кипятили с обратным холодильником до тех пор, пока исходные материалы не были израсходованы. За протеканием реакции следили с помощью метода тонкослойной хроматографии. По завершении реакции, реакционную смесь охлаждали до комнатной температуры. Все летучие компоненты удаляли при пониженном давлении и полученный (Е)-3-(диметиламино)-1-(3,4,5-триметоксифенил)проп-2-ен-1-она 5 в дальнейшем синтезе использовали без дополнительной очистки. Выход 95%. Стадия 2. Эквимолярное количество гиппуровой кислоты и (Е)-3-(диметиламино)-1-(3,4,5-триметоксифенил)проп-2-ен-1-она 5 нагревали при 90°С необходимое количество времени. По истечении заданного времени уксусный ангидрид отгоняли при пониженном давлении. Остаток растворяли в CHCl3 и остатки уксусного ангидрида нейтрализовали насыщенным водным раствором NaHCO3, промывали водой и насыщенным водным раствором NaCl. Органический слой отделяли, сушили над безводным Na2SO4. Растворитель упаривали при пониженном давлении и полученный неочищенный остаток очищали с помощью перекристаллизации из этанола. Выход 87%. C16H22O2. Спектр ЯМР 1H, (400 МГц, CDCl3), δ, м.д.: 1Н NMR (400 MHz, CDCl3), δ, м.д.: 8.73 (с, 1Н), 8.56 (д, J=7.7 Hz, 1Н), 7.93 (д, 2Н), 7.60 (т, 1Н), 7.53 (т, 2Н), 7.03 (с, J=6.9 Hz, 2Н), 6.73 (д, J=6.8 Hz, 3Н), 3.96 (с, 6Н), 3.92 (с, 3Н). Спектр ЯМР 13С (100 МГц, CDCl3), δ, м.д.:166.0, 159.66, 153.75, 140.42, 133.72, 132.44, 128.92, 127.14, 126.56, 124.38, 123.88, 102.71, 101.84, 60.96, 56.44, 14.3. Полученное соединение 1 представляет собой желтое кристаллическое вещество, растворимое в хлороформе, ацетоне, этилацетате.Preparation of compound 1. Step 1. 3,4,5-Trimethoxyacetophenone 4 (1.0 eq.) and N,N-dimethylformamide dimethyl acetal (DMF-DMA) (2.0 eq.) were refluxed until no raw materials were consumed. The reaction progress was monitored using thin layer chromatography. Upon completion of the reaction, the reaction mixture was cooled to room temperature. All volatile components were removed under reduced pressure, and the resulting (E)-3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one 5 was used in further synthesis without additional purification. Yield 95%. Step 2. An equimolar amount of hippuric acid and (E)-3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one 5 was heated at 90°C for the required amount of time. After a given time, acetic anhydride was distilled off under reduced pressure. The residue was dissolved in CHCl 3 and the remaining acetic anhydride was neutralized with saturated aqueous NaHCO 3 solution, washed with water and saturated aqueous NaCl solution. The organic layer was separated and dried over anhydrous Na 2 SO 4 . The solvent was evaporated under reduced pressure and the resulting crude residue was purified by recrystallization from ethanol. Yield 87%. C16H22O2 . _ NMR spectrum 1 H, (400 MHz, CDCl 3 ), δ, ppm: 1 H NMR (400 MHz, CDCl 3 ), δ, ppm: 8.73 (s, 1H), 8.56 (d, J =7.7 Hz, 1H), 7.93 (d, 2H), 7.60 (t, 1H), 7.53 (t, 2H), 7.03 (s, J=6.9 Hz, 2H), 6.73 (d, J=6.8 Hz, 3H ), 3.96 (s, 6H), 3.92 (s, 3H). 13 C NMR spectrum (100 MHz, CDCl 3 ), δ, ppm: 166.0, 159.66, 153.75, 140.42, 133.72, 132.44, 128.92, 127.14, 126.56, 124.38, 123.88, 10 2.71, 101.84, 60.96, 56.44, 14.3 . The resulting compound 1 is a yellow crystalline substance, soluble in chloroform, acetone, and ethyl acetate.
Пример 2. Определение антимикробной активности проводили методом двукратных серийных разведений [Першин Г.Н. «Методы экспериментальной химиотерапии, 1971, с. 109] на музейных тест - культурах: Staphylococcus aurous, штамм 906; Escherichia coli, штамм 1257 (ФГБУ «Научный центр экспертизы средств медицинского применения», г. Москва). В опытах использовали 18 часовые агаровые тест - культуры (5*105 микробных тел в 1 мл среды). Для исследования брали растворы соединения 1 в диметилформамиде (ДМФА).Example 2. Determination of antimicrobial activity was carried out by the method of two-fold serial dilutions [Pershin G.N. “Methods of experimental chemotherapy, 1971, p. 109] on museum test cultures: Staphylococcus aurous, strain 906; Escherichia coli, strain 1257 (FGBU "Scientific Center for Expertise of Medicinal Products", Moscow). In the experiments, 18-hour agar test cultures were used (5*10 5 microbial bodies in 1 ml of medium). Solutions of compound 1 in dimethylformamide (DMF) were taken for the study.
Максимальная из испытанных концентраций была 1000 мкг/мл. Пробирки инкубировали при 37°C с последующим высевом через 20 часов и 7 суток в пробирки со скошенным мясопептонным агаром. Учет результатов проводили по наличию и характерному росту культур микроорганизмов на питательной среде. (Таблица 1.)The highest concentration tested was 1000 μg/ml. The tubes were incubated at 37°C, followed by seeding after 20 hours and 7 days into tubes with slanted meat peptone agar. The results were recorded based on the presence and characteristic growth of microorganism cultures on a nutrient medium. (Table 1.)
Пример 3 Цитотоксичность определяли по отношению HEK-293 (эмбриональные клетки почки человека). Линии клеток HEK-293 (эмбриональные клетки почки человека) культивировали в среде DMEM с добавлением 10% эмбриональной телячьей сыворотки, 2 мМ L-глутамина и 1% пенициллина-стрептомицина в качестве антибиотика при 37°С и 5% CO2 во влажной атмосфере. Цитотоксичность синтезированного соединения определяли с помощью МТТ-теста [1]. Суспензии клеток в концентрации 1×104 клеток/200 мкл высевали в 96-луночный планшет (SPL Life Sciences, Корея) и культивировали при 37°С во влажной атмосфере с 5% CO2 в инкубаторе 460-СЕ (Thermo Fisher Scientific, США). Через 24 часа инкубации к культурам клеток добавляли исследуемые соединения, растворенные в ДМСО, в диапазоне концентраций от 3,125 до 100 мкмоль⋅л-1. После добавления соединения клетки культивировали в указанных выше условиях. В качестве контроля использовали лунки с добавлением ДМСО, конечная концентрация которого не превышала 1% и не была токсична для клеток. Выживаемость клеток оценивали через 72 часа инкубации с исследуемым соединением путем добавления 20 мкл раствора МТТ (3-[4,5-диметилтиазол-2-ил]-2,5-дидифенил тетразолия бромид, 5 мг/мл) в каждую лунку. После инкубирования клеток с раствором МТТ в течение 4 часов, среду из планшетов удаляли и в каждую лунку добавляли 100 мкл ДМСО для растворения образовавшихся кристаллов формазана. С помощью планшетного спектрофотометра FLUOstar Optima (BMG Labtech, Германия) определяли оптическую плотность при 544 нм. Данные сравнивали с отрицательным контролем (1% раствор ДМСО), в качестве положительного контроля служил доксорубицин (Tocris Bioscience, США). Значение 50% ингибирующей концентрации (IC50) определяли на основе дозозависимых кривых с помощью программного обеспечения GraphPad Prism 6.0.Example 3 Cytotoxicity was determined against HEK-293 (human embryonic kidney cells). HEK-293 cell lines (human embryonic kidney cells) were cultured in DMEM supplemented with 10% fetal bovine serum, 2 mM L-glutamine and 1% penicillin-streptomycin antibiotic at 37°C and 5% CO 2 in a humidified atmosphere. The cytotoxicity of the synthesized compound was determined using the MTT test [1]. Cell suspensions at a concentration of 1x104 cells/200 μl were seeded in a 96-well plate (SPL Life Sciences, Korea) and cultured at 37°C in a humidified atmosphere with 5% CO2 in a 460-CE incubator (Thermo Fisher Scientific, USA) . After 24 hours of incubation, the test compounds dissolved in DMSO were added to the cell cultures in a concentration range from 3.125 to 100 µmol⋅l -1 . After adding the compound, the cells were cultured under the above conditions. As a control, we used wells with the addition of DMSO, the final concentration of which did not exceed 1% and was not toxic to cells. Cell survival was assessed after 72 hours of incubation with the test compound by adding 20 μl of MTT solution (3-[4,5-dimethylthiazol-2-yl]-2,5-didiphenyl tetrazolium bromide, 5 mg/ml) to each well. After incubating the cells with the MTT solution for 4 hours, the medium was removed from the plates and 100 μl of DMSO was added to each well to dissolve the formed formazan crystals. The optical density at 544 nm was determined using a FLUOstar Optima plate spectrophotometer (BMG Labtech, Germany). The data were compared with a negative control (1% DMSO solution); doxorubicin (Tocris Bioscience, USA) served as a positive control. The 50% inhibitory concentration (IC 50 ) value was determined from dose-response curves using GraphPad Prism 6.0 software.
Как видно из таблицы, заявляемое соединение 1 превышает по противомикробной активности препарат сравнения (Фенилсалицилат) и наиболее близкий структурный аналог. И не воздействует на здоровые клетки человека. Таким образом, N-(2-оксо-6-(3,4,5-триметоксифенил)-2Н-пиран-3-ил)бензамид проявляет более высокую активность, что делает возможным использовать его для создания новых лекарственных средств, целенаправленного действия.As can be seen from the table, the claimed compound 1 exceeds the reference drug (Phenyl salicylate) and the closest structural analogue in antimicrobial activity. And it does not affect healthy human cells. Thus, N-(2-oxo-6-(3,4,5-trimethoxyphenyl)-2H-pyran-3-yl)benzamide exhibits higher activity, which makes it possible to use it to create new drugs with targeted action.
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