RU2785142C1 - Application of (5-(methoxycarbonyl)-[1,1'-biphenyl]-3-yl)-l-proline as an anti-tuberculosis agent - Google Patents
Application of (5-(methoxycarbonyl)-[1,1'-biphenyl]-3-yl)-l-proline as an anti-tuberculosis agent Download PDFInfo
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- -1 5-(methoxycarbonyl)-[1,1'-biphenyl]-3-yl Chemical group 0.000 title claims abstract description 10
- 229940121383 antituberculosis agents Drugs 0.000 title claims description 3
- 239000000814 tuberculostatic agent Substances 0.000 title claims description 3
- 230000000694 effects Effects 0.000 abstract description 10
- 230000002365 anti-tubercular Effects 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 3
- 229940079593 drugs Drugs 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 5
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 4
- 235000015097 nutrients Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- AQYAHPDSJAFBOS-UHFFFAOYSA-N methyl 2,4-dioxo-4-phenylbutanoate Chemical compound COC(=O)C(=O)CC(=O)C1=CC=CC=C1 AQYAHPDSJAFBOS-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- 201000008827 tuberculosis Diseases 0.000 description 3
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 2
- 229940010383 Mycobacterium tuberculosis Drugs 0.000 description 2
- 229960002429 Proline Drugs 0.000 description 2
- 230000001580 bacterial Effects 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- HUOIDCCHUGUZQS-UHFFFAOYSA-N ethyl 3H-benzimidazole-5-carboxylate Chemical class CCOC(=O)C1=CC=C2N=CNC2=C1 HUOIDCCHUGUZQS-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000010490 three component reaction Methods 0.000 description 2
- XFDUHJPVQKIXHO-UHFFFAOYSA-N 3-Aminobenzoic acid Chemical class NC1=CC=CC(C(O)=O)=C1 XFDUHJPVQKIXHO-UHFFFAOYSA-N 0.000 description 1
- JYZIHLWOWKMNNX-UHFFFAOYSA-N Benzimidazole Chemical compound C1=C[CH]C2=NC=NC2=C1 JYZIHLWOWKMNNX-UHFFFAOYSA-N 0.000 description 1
- 229940072185 DRUGS FOR TREATMENT OF TUBERCULOSIS Drugs 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241001646725 Mycobacterium tuberculosis H37Rv Species 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229940099259 Vaseline Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000001355 anti-mycobacterial Effects 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 238000007392 microtiter assay Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- IVGPGQSSDLDOLH-UHFFFAOYSA-M sodium;10-oxido-7-oxophenoxazin-10-ium-3-olate Chemical compound [Na+].C1=CC(=O)C=C2OC3=CC([O-])=CC=C3[N+]([O-])=C21 IVGPGQSSDLDOLH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000005429 turbidity Methods 0.000 description 1
Abstract
Description
Изобретение относится к области фармакологии и медицины, в частности фтизиатрии, а именно к применению индивидуального соединения класса м-карбоксианилинов (5-(метоксикарбонил)-[1,1'-бифенил]-3-ил)-L-пролина, обладающего противотуберкулезной активностью, который может найти применение в фармакологии и медицине в качестве противотуберкулезного средства.The invention relates to the field of pharmacology and medicine, in particular phthisiology, and in particular to the use of an individual compound of the m-carboxyaniline class (5-(methoxycarbonyl)-[1,1'-biphenyl]-3-yl)-L-proline, which has anti-tuberculosis activity , which can be used in pharmacology and medicine as an anti-tuberculosis agent.
Заявленное соединение (5-(метоксикарбонил)-[1,1'-бифенил]-3-ил)-L-пролин (1) и способ его синтеза известны из уровня техники. Соединение (1) получается в результате трехкомпонентной реакции L-пролина (2), метил бензоилпирувата (3) и ацетона (4) (Synthesis of meta-substituted anilines via a three-component reaction of acetone, amines, and 1, 3-diketones / A.R. Galeev, M.V. Dmitriev, I.G. Mokrushin, I.V. Mashevskaya, A.N. Maslivets, M. Rubin // Organic & Biomolecular Chemistry. - 2019. - Vol. 17. - P. 10030-10044. DOI: 10.1039/C9OB02120E), согласно схеме, представленной ниже:The claimed compound (5-(methoxycarbonyl)-[1,1'-biphenyl]-3-yl)-L-proline (1) and the method of its synthesis are known from the prior art. Compound (1) is obtained as a result of a three-component reaction of L-proline (2), methyl benzoylpyruvate (3) and acetone (4) (Synthesis of meta-substituted anilines via a three-component reaction of acetone, amines, and 1, 3-diketones / A.R. Galeev, M.V. Dmitriev, I.G. Mokrushin, I.V. Mashevskaya, A.N. Maslivets, M. Rubin // Organic & Biomolecular Chemistry. - 2019. - Vol. 17. - P. 10030-10044. DOI: 10.1039/C9OB02120E), according to the scheme below:
Противотуберкулезные свойства (5-(метоксикарбонил)-[1,1'-бифенил]-3-ил)-L-пролина (1) или его близких аналогов не изучены. Из уровня техники можно выделить производные этил 1H-бензо[d]имидазол-5-карбоксилата (5) (Synthesis and evaluation of antimycobacterial activity of new benzimidazole aminoesters. / Y.K. Yoon, M.A. Ali, A.C. Wei, T.S. Choon, R. Ismail // European journal of medicinal chemistry. - 2015. - Vol. 93 - P.614-624. DOI: 10.1016/j.ejmech.2013.06.025), обладающие активностью в отношении М. tuberculosis штамма H37Rv в концентрации 50-100 мкг/мл (МИК).The antituberculous properties of (5-(methoxycarbonyl)-[1,1'-biphenyl]-3-yl)-L-proline (1) or its close analogs have not been studied. Derivatives of ethyl 1H-benzo[d]imidazole-5-carboxylate (5) can be distinguished from the prior art (Synthesis and evaluation of antimycobacterial activity of new benzimidazole aminoesters. / YK Yoon, MA Ali, AC Wei, TS Choon, R. Ismail / / European journal of medicinal chemistry. - 2015. - Vol. 93 - P.614-624. DOI: 10.1016/j.ejmech.2013.06.025), which have activity against M. tuberculosis strain H 37 Rv at a concentration of 50-100 μg/ml (MIC).
Целью изобретения является изыскание новых соединений, обладающих ингибирующей активностью в отношении Mycobacterium tuberculosis, что позволит расширить ассортимент потенциальных противотуберкулезных препаратов.The aim of the invention is to find new compounds with inhibitory activity against Mycobacterium tuberculosis, which will expand the range of potential anti-tuberculosis drugs.
Поставленная цель решается изучением противотуберкулезной активности (5-(метоксикарбонил)-[1,1'-бифенил]-3-ил)-L-пролина (1), который обладает противотуберкулезной активностью: минимальная ингибирующая концентрация (МИК) в отношении М. tuberculosis штамма H37R-V составляет 25.0 мкг/мл. Изобретение иллюстрируется следующими примерами.This goal is solved by studying the anti-tuberculosis activity of (5-(methoxycarbonyl)-[1,1'-biphenyl]-3-yl)-L-proline (1), which has anti-tuberculosis activity: the minimum inhibitory concentration (MIC) against M. tuberculosis strain H 37 RV is 25.0 µg/ml. The invention is illustrated by the following examples.
Пример 1. Получение (5-(метоксикарбонил)-[1,1'-бифенил]-3-ил)-L-пролина (1).Example 1 Preparation of (5-(methoxycarbonyl)-[1,1'-biphenyl]-3-yl)-L-proline (1).
К раствору 2.0 ммоль метил бензоилпирувата (3) в 2 мл ацетона (4) последовательно добавляли 0.6 ммоль уксусной кислоты, 1.0 г молекулярных сит 4А и 2.2 ммоль L-пролина (2). Реакционную массу выдерживали при 55°С в течение 24 ч. Затем растворитель отгоняли на ротационном испарителе, к остатку добавляли 5 мл NaHCO3 (насыщ.) и смесь экстрагировали диэтиловым эфиром (3×5 мл). Водный слой подкисляли HCl (конц.) до рН 1-2, полученный осадок золотисто-оранжевого цвета отфильтровывали. Выход 51%, т.пл. 69-72°С. Соединение (1) C19H19NO4. Устойчиво при хранении в обычных условиях.To a solution of 2.0 mmol of methyl benzoylpyruvate (3) in 2 ml of acetone (4), 0.6 mmol of acetic acid, 1.0 g of 4A molecular sieves, and 2.2 mmol of L-proline (2) were successively added. The reaction mass was kept at 55°C for 24 hours Then the solvent was distilled off on a rotary evaporator, 5 ml of NaHCO 3 (sat.) was added to the residue and the mixture was extracted with diethyl ether (3×5 ml). The aqueous layer was acidified with HCl (conc.) to pH 1-2, the resulting golden-orange precipitate was filtered off. Yield 51%, m.p. 69-72°C. Compound (1) C 19 H 19 NO 4 . Stable under normal storage conditions.
HRMS (ESI+)m/z рассчитано для C19H20NO4 +(М+Н)+: 326.1387, найдено: 326.1389.HRMS (ESI+)m/z calculated for C 19 H 20 NO 4 + (M+H) + : 326.1387, found: 326.1389.
ИК спектр (в вазелиновом масле), ν, см-1: 1717, 1598.IR spectrum (in vaseline oil), ν, cm -1 : 1717, 1598.
Спектр 1H ЯМР (400 МГц, CDCl3) δ, м.д.: 8.15 (уш. с, 1H), 7.64 (д, J=1.3 Гц, 1H), 7.57 (д, J=7.1 Гц, 2Н), 7.41 (т, J=7.4 Гц, 2Н), 7.36-7.30 (м, 1Н), 7.25 (д, J=1.8 Гц, 1H), 6.95 (т, J=1.9 Гц, 1H), 4.38 (дд, J=8.3, 2.6 Гц, 1H), 3.90 (с, 3Н), 3.66 (тд, J=8.4, 3.1 Гц, 1H), 3.44 (кв, J=8.0 Гц, 1H), 2.45-2.23 (м, 2Н), 2.22-1.91 (м, 2Н). Спектр 13С ЯМР (101 МГц, CDCl3) δ, м.д.: 178.6, 167.7, 147.2, 142.7, 141.1, 131.7, 128.9 (2С), 127.7, 127.4 (2С), 117.5, 115.3, 112.2, 61.0, 52.2, 48.9, 31.1, 23.9. 1 H NMR spectrum (400 MHz, CDCl 3 ) δ, ppm: 8.15 (br. s, 1H), 7.64 (d, J=1.3 Hz, 1H), 7.57 (d, J=7.1 Hz, 2H) , 7.41 (t, J=7.4 Hz, 2H), 7.36-7.30 (m, 1H), 7.25 (d, J=1.8 Hz, 1H), 6.95 (t, J=1.9 Hz, 1H), 4.38 (dd, J=8.3, 2.6Hz, 1H), 3.90(s, 3H), 3.66(td, J=8.4, 3.1Hz, 1H), 3.44(kv, J=8.0Hz, 1H), 2.45-2.23(m, 2H ), 2.22-1.91 (m, 2H). 13C NMR spectrum (101 MHz, CDCl3 ) δ, ppm: 178.6, 167.7, 147.2, 142.7, 141.1, 131.7, 128.9 (2С), 127.7, 127.4 (2С), 117.5, 115.3, 112.2, 61.0, 52.2, 48.9, 31.1, 23.9.
Пример 2. Исследование (5-(метоксикарбонил)-[1,1'-бифенил]-3-ил)-L-пролина (1) на противотуберкулезную активность.Example 2. Study of (5-(methoxycarbonyl)-[1,1'-biphenyl]-3-yl)-L-proline (1) for anti-tuberculosis activity.
Исследование противотуберкулезной активности производилось микрометодом двукратных серийных разведений в жидкой питательной среде с использованием индикатора роста резазурина натриевой соли [Resazurin Microtiter Assay Plate: Simple and Inexpensive Method for Detection of Drug Resistance in Mycobacterium tuberculosis. / J. C. Palomino, A. Martin, M. Camacho, H. Guerra, J. Swings, F. Portaels // Antimicrobail Agents and Chemotherapy. - 2002. - Vol. 46 N.8. - P.2720-2722. DOI: 10.1128/ААС.46.8.2720].The study of anti-tuberculosis activity was carried out by a micromethod of two-fold serial dilutions in a liquid nutrient medium using a growth indicator of resazurin sodium salt [Resazurin Microtiter Assay Plate: Simple and Inexpensive Method for Detection of Drug Resistance in Mycobacterium tuberculosis. / J. C. Palomino, A. Martin, M. Camacho, H. Guerra, J. Swings, F. Portaels // Antimicrobail Agents and Chemotherapy. - 2002. - Vol. 46 N.8. - P.2720-2722. DOI: 10.1128/AAC.46.8.2720].
В лунках стерильного 96 луночного плоскодонного микропланшета готовили два параллельных ряда двукратных серийных разведений соединения (1) в питательной жидкой среде Мидлбрук 7Н, содержащей ростовую добавку ВАСТЕС MGIT OADC. Предварительно соединение (1) было растворено в ДМСО. В каждой лунке содержалось 150 мкл определенной концентрации испытуемого вещества.In the wells of a sterile 96-well flat-bottomed microplate, two parallel rows of two-fold serial dilutions of compound (1) were prepared in Middlebrook 7H nutrient liquid medium containing BASTEC MGIT OADC growth supplement. Compound (1) was preliminarily dissolved in DMSO. Each well contained 150 µl of a certain concentration of the test substance.
Из 14-ти суточной культуры М. tuberculosis штамм H37RV готовили бактериальную суспензию, которая была стандартизирована по оптическому стандарту мутности Мак-Фарланда №2 с использованием денситометра, после чего инокулят разводили 1:20 в питательной среде Мидлбрук 7Н9 и вносили в каждую лунку планшета по 150 мкл.From a 14-day culture of M. tuberculosis strain H 37 RV, a bacterial suspension was prepared, which was standardized according to the McFarland optical turbidity standard No. 2 using a densitometer, after which the inoculum was diluted 1:20 in Middlebrook 7H9 nutrient medium and added to each well tablet 150 µl.
В последних рядах содержалась питательная среда и культура в равных объемах (контроль). Максимально испытанная концентрация соответствовала 100.0 мкг/мл, минимальная - 0.1 мкг/мл.The last rows contained nutrient medium and culture in equal volumes (control). The maximum tested concentration corresponded to 100.0 μg/ml, the minimum - 0.1 μg/ml.
Планшеты запечатывали в полиэтиленовые пакеты и инкубировали при 37°С в течение 7 суток. После 7 дней инкубации в каждую лунку добавляли 50 мкл 0,02% раствора резазурина, культивировали при 37°С в течение 24 часов, затем оценивали визуально изменение окраски резазурина. Изменение цвета указывает на снижение резазурина и, следовательно, рост бактерий. МИК - минимальная концентрация химических веществ, которая предотвращала изменение цвета.The plates were sealed in plastic bags and incubated at 37°C for 7 days. After 7 days of incubation, 50 μl of 0.02% resazurin solution was added to each well, cultured at 37°C for 24 hours, then the color change of resazurin was visually assessed. A change in color indicates a decrease in resazurin and therefore bacterial growth. MIC is the minimum concentration of chemicals that prevented color change.
Проведенные исследования показали (см. таблицу), что соединение (1) проявляет ингибирующее действие в отношении М. tuberculosis штамма H37RV в концентрации - 25.0 мкг/мл.Studies have shown (see table) that the compound (1) exhibits an inhibitory effect against M. tuberculosis strain H37RV at a concentration of 25.0 µg/ml.
Предлагаемое соединение (5-(метоксикарбонил)-[1,1'-бифенил]-3-ил)-L-пролин (1) обладает противотуберкулезной активностью и может найти применение в фармакологии в качестве потенциального лекарственного средства. The proposed compound (5-(methoxycarbonyl)-[1,1'-biphenyl]-3-yl)-L-proline (1) has anti-tuberculosis activity and can be used in pharmacology as a potential drug.
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| RU2785142C1 true RU2785142C1 (en) | 2022-12-05 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013033240A1 (en) * | 2011-08-29 | 2013-03-07 | Ptc Therapeutics, Inc. | Antibacterial compounds and methods for use |
| RU2748748C1 (en) * | 2020-06-25 | 2021-05-31 | Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" (ПГНИУ) | Anti-tuberculosis drug based on (z)-3-(3,3-dimethyl-2-oxobutylidene) -3,4-dihydro-2h-1,4-benzoxazin-2-one and a method for its synthesis |
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013033240A1 (en) * | 2011-08-29 | 2013-03-07 | Ptc Therapeutics, Inc. | Antibacterial compounds and methods for use |
| RU2748748C1 (en) * | 2020-06-25 | 2021-05-31 | Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" (ПГНИУ) | Anti-tuberculosis drug based on (z)-3-(3,3-dimethyl-2-oxobutylidene) -3,4-dihydro-2h-1,4-benzoxazin-2-one and a method for its synthesis |
Non-Patent Citations (1)
| Title |
|---|
| Galeev, A. R. et al, "Synthesis of meta-Substituted Anilines via Three-Component Reaction of Acetone, Amines, and 1,3-Diketones", 2019, Organic & Biomolecular Chemistry, 17, 10030-10044. * |
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