RU2770598C1 - Application of antifungal agent based on 2-((4-r1-5-r2-3-(ethoxycarbonyl)thiophene-2-il)amino)-4-oxo-4-r3-but-2-eno acids in relation to candida aldicans - Google Patents
Application of antifungal agent based on 2-((4-r1-5-r2-3-(ethoxycarbonyl)thiophene-2-il)amino)-4-oxo-4-r3-but-2-eno acids in relation to candida aldicans Download PDFInfo
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- 241000222120 Candida <Saccharomycetales> Species 0.000 title claims abstract 4
- 229940121375 antifungal agent Drugs 0.000 title description 2
- 239000003429 antifungal agent Substances 0.000 title description 2
- 239000004599 antimicrobial Substances 0.000 claims abstract 2
- 239000002253 acid Substances 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 5
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 13
- 230000000843 anti-fungal effect Effects 0.000 abstract description 9
- 231100000053 low toxicity Toxicity 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 241000222122 Candida albicans Species 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229940095731 candida albicans Drugs 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 2
- -1 2-((2-(dimethylamino)ethyl)amino)-N-(2,6-dimethylphenyl)-4-(3,4-dimethoxyphenyl)-4-oxobut-2-enoic acid amide Chemical compound 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 2
- 229960002722 terbinafine Drugs 0.000 description 2
- 229940099259 vaseline Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GEJWJZPYTVXVBZ-UHFFFAOYSA-N 2-[(3-ethoxycarbonyl-4-methyl-5-phenylthiophen-2-yl)amino]-4-(4-methylphenyl)-4-oxobut-2-enoic acid Chemical compound CCOC(C1=C(NC(C(O)=O)=CC(C2=CC=C(C)C=C2)=O)SC(C2=CC=CC=C2)=C1C)=O GEJWJZPYTVXVBZ-UHFFFAOYSA-N 0.000 description 1
- OHMLBZKIUZTEOC-UHFFFAOYSA-N 2-aminothiophene-3-carboxylic acid Chemical compound NC=1SC=CC=1C(O)=O OHMLBZKIUZTEOC-UHFFFAOYSA-N 0.000 description 1
- HTYHIFXQHMFHEB-UHFFFAOYSA-N 4-(4-methylphenyl)-2,4-dioxobutanoic acid Chemical compound CC1=CC=C(C(=O)CC(=O)C(O)=O)C=C1 HTYHIFXQHMFHEB-UHFFFAOYSA-N 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- YEZSWHPLZBZVLH-UHFFFAOYSA-N Formylpyruvate Chemical class OC(=O)C(=O)CC=O YEZSWHPLZBZVLH-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 235000019256 formaldehyde Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/66—Nitrogen atoms not forming part of a nitro radical
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Изобретения относятся к области органической и медицинской химии, а именно к применению биологически активных веществ класса замещенных 2-амино-4-арил-4-оксобутановых кислот, а именно к 2-((4-R1-5-R2-3-(этоксикарбонил)тиофен-2-ил)амино)-4-оксо-4-R3-бут-2-еновым кислотам 1а, б общей формулы:The inventions relate to the field of organic and medicinal chemistry, namely to the use of biologically active substances of the class of substituted 2-amino-4-aryl-4-oxobutanoic acids, namely to 2-((4-R 1 -5-R 2 -3- (ethoxycarbonyl)thiophen-2-yl)amino)-4-oxo-4-R 3 -but-2-enoic acids 1a, b of the general formula:
в медицине в качестве лекарственного средства с противогрибковыми свойствами и низкой токсичностью.in medicine as a drug with antifungal properties and low toxicity.
Аналогом по структуре заявляемым соединениям является амид 2-((2-(диметиламино)этил)амино)-N-(2,6-диметилфенил)-4-(3,4-диметоксифенил)-4-оксобут-2-еновой кислоты 2, обладающий противогрибковой активностью [Чернов И.Н., Мельникова Н.А., Зубов П.В., Игидов Н.М., Одегова Т.Ф., Махмудов P.P., Чащина С.В. (2013). биологическая активность енаминоамидов ароилпировиноградных кислот. Фармация. №6, 49-50] формулы:The structural analogue of the claimed compounds is 2-((2-(dimethylamino)ethyl)amino)-N-(2,6-dimethylphenyl)-4-(3,4-dimethoxyphenyl)-4-oxobut-2-enoic acid amide 2 having antifungal activity [Chernov I.N., Melnikova N.A., Zubov P.V., Igidov N.M., Odegova T.F., Makhmudov P.R., Chashchina S.V. (2013). biological activity of aroylpyruvic acid enaminoamides. Pharmacy. No. 6, 49-50] formulas:
Эталоном сравнения биологической активности был выбран тербинафин формулы:Terbinafine of the formula was chosen as the standard for comparing biological activity:
который широко применяется в лечебной практике, и является аналогом по действию [Машковский М.Д. Лекарственные средства. - 16-е изд., перераб., испр. и доп. - М.: Новая волна, 2012. - с. 925].which is widely used in medical practice, and is analogous in action [Mashkovsky M.D. Medicines. - 16th ed., revised, corrected. and additional - M.: New wave, 2012. - p. 925].
Из уровня техники известны структурные формулы соединений 1а, б (Shipilovskikh, S.A., Makhmudov, R.R., Lupach, D.Y., Pavlov, P.Т., Babushkina, E. V., & Rubtsov, A. E. (2013). Synthesis and Analgesic Activity of Substituted 4-(Het)aryl-4-oxo-2-thienylaminobut-2-enoic Acids. Pharmaceutical Chemistry Journal, 47(7), 366-370. doi:10.1007/s11094-013-0960-z). Осуществлен способ получения соединений 1а, б взаимодействием замещенных производных 2,4-диоксобутановой кислоты с 4,5-дизамещенными этиловыми эфирами 2-амино-тиофен-3-карбоновой кислоты в среде этилового спирта при 60°С с последующим выделением целевых продуктов известными методами по схеме:The structural formulas of compounds 1a, b are known from the prior art (Shipilovskikh, S.A., Makhmudov, R.R., Lupach, D.Y., Pavlov, P.T., Babushkina, E.V., & Rubtsov, A.E. (2013). Synthesis and Analgesic Activity of Substituted 4- (Het)aryl-4-oxo-2-thienylaminobut-2-enoic Acids Pharmaceutical Chemistry Journal, 47(7), 366-370 doi:10.1007/s11094-013-0960-z). A method for preparing compounds 1a, 1b was carried out by reacting substituted derivatives of 2,4-dioxobutanoic acid with 4,5-disubstituted ethyl esters of 2-amino-thiophene-3-carboxylic acid in ethanol at 60°C, followed by isolation of the target products by known methods according to scheme:
Однако из патентной и научно-технической литературы не выявлено применение соединений 1а, б в качестве средств с противогрибковыми свойствами.However, from the patent and scientific and technical literature, the use of compounds 1a, b as agents with antifungal properties has not been revealed.
Задачей изобретения является расширение арсенала противогрибковых средств по отношению к кандидозу, в частности разработка средства, обладающего выраженной противогрибковой активностью по отношению к Candida albicans, низкой токсичностью и превышающего по указанной активности применяемые в медицинской практике препараты.The objective of the invention is to expand the arsenal of antifungal agents in relation to candidiasis, in particular, the development of an agent with a pronounced antifungal activity against Candida albicans, low toxicity and exceeding the indicated activity of drugs used in medical practice.
Поставленная задача достигается применением 2-[(4-метил-5-фенил-3-(этоксикарбонил)тиофен-2-ил)амино]-4-(4-метилфенил)-4-оксобут-2-еновой кислоты и 2-[(4,5-диметил-3-(этоксикарбонил)тиофен-2-ил)амино]-4-оксо-4-(4-хлорфенил)бут-2-еновой кислоты, которые обладают противогрибковой активностью.This task is achieved by using 2-[(4-methyl-5-phenyl-3-(ethoxycarbonyl)thiophen-2-yl)amino]-4-(4-methylphenyl)-4-oxobut-2-enoic acid and 2-[ (4,5-dimethyl-3-(ethoxycarbonyl)thiophen-2-yl)amino]-4-oxo-4-(4-chlorophenyl)but-2-enoic acid, which have antifungal activity.
Технический результат: получены соединения с высокими выходами, обладающие выраженной противогрибковой активностью, а также низкой токсичностью.EFFECT: obtained compounds with high yields, with pronounced antifungal activity, as well as low toxicity.
Изобретение иллюстрируется примерами исследования фармакологических свойств.The invention is illustrated by examples of the study of pharmacological properties.
Пример 1. Получение соединения 1а. К раствору 2.06 г (0.01 моль) 4-(4-метилфенил)-2,4-диоксобутановой кислоты в 10 мл этилового спирта прибавляют раствор 2.61 г (0.01 моль) этилового эфира 2-амино-4-метил-5-фенилтиофен-3-карбоновой кислоты в 10 мл того же растворителя и выдерживают при комнатной температуре 24 часа. Смесь охлаждают до 0°С, выпавший осадок отфильтровывают и перекристаллизовывают из ацетонитрила. Выход 73%. Тразл.=189-172°С. Найдено, %: С 66.82, Н 5.13, N 3.10, S 7.15. C25H23NO5S. Вычислено, %: С 66.80, Н 5.16, N 3.12, S 7.13. ИК спектр (ФСМ 1202, вазелиновое масло, ν, см-1): 1673 уш. (COOEt), 3401 (NH). Спектр ЯМP 1Н, (Varian Mercury300, 300 МГц, DMSOd6), δ, м.д.: 1.28 (т, J 7.2 Гц, 3Н, Me), 2.25 (с, 3Н, Me), 2.39 (с, 3Н, Me), 4.21 (кв, J 7.2 Гц, 2Н, CH2O), 6.61 (с, 1Н, С=СН), 7.38 (м, 7Н, HAr), 7.98 (м, J 8.1 Гц, 2Н, HAr), 12.83 (с, 1Н, NH). Полученное соединение 1а представляет собой красное кристаллическое вещество, растворимое в хлороформе, толуоле, ацетоне, не растворимое в воде и гексане.Example 1 Preparation of Compound 1a. To a solution of 2.06 g (0.01 mol) of 4-(4-methylphenyl)-2,4-dioxobutanoic acid in 10 ml of ethanol is added a solution of 2.61 g (0.01 mol) of 2-amino-4-methyl-5-phenylthiophene-3 ethyl ester -carboxylic acid in 10 ml of the same solvent and kept at room temperature for 24 hours. The mixture is cooled to 0°C, the precipitate is filtered off and recrystallized from acetonitrile. Yield 73%. T diff. =189-172°C. Found, %: C 66.82, H 5.13, N 3.10, S 7.15. C 25 H 23 NO 5 S. Calculated, %: C 66.80, H 5.16, N 3.12, S 7.13. IR spectrum (FSM 1202, vaseline oil, ν, cm -1 ): 1673 br. (COOEt), 3401 (NH). 1H NMR spectrum, (Varian Mercury300 , 300 MHz, DMSO d6 ), δ, ppm: 1.28 (t, J 7.2 Hz, 3H, Me), 2.25 (s, 3H, Me), 2.39 (s, 3H , Me), 4.21 (q, J 7.2 Hz, 2H, CH 2 O), 6.61 (s, 1H, C=CH), 7.38 (m, 7H, H Ar ), 7.98 (m, J 8.1 Hz, 2H, H Ar ), 12.83 (s, 1H, NH). The resulting compound 1a is a red crystalline substance, soluble in chloroform, toluene, acetone, insoluble in water and hexane.
Пример 2. Соединение 1б получают аналогично. Выход 89%. Тразл=155-158°С (этанол). Найдено, %: С 55.97, Н 4.43, N 3.45, S 7.82. C19H18ClNO5S. Вычислено, %: С 55.95, Н 4.45, N 3.43, S 7.86. ИК спектр (ФСМ 1202, вазелиновое масло, ν, см-1): 1732 (COOEt), 3397 (NH). Спектр ЯМP 1H, (Varian Mercury300, 300 МГц, DMSOd6), δ, м.д.: 1.33 (т, J 7.1 Гц, 3Н, Me), 2.19 (с, 3Н, Me), 2.25 (с, 3Н, Me), 4.33 (кв, J 7.1 Гц, 2Н, CH2O), 6.49 (с, 1H С=СН), 7.63 (м, J 8.6 Гц, 2Н, HAr), 8.01 (м, J 8.6 Гц, 2Н, HAr), 12.71 (с, 1Н, NH). Полученное соединение 1б представляет собой красное кристаллическое вещество, растворимое в хлороформе, толуоле, ацетоне, не растворимое в воде и гексане.Example 2 Compound 1b was obtained in a similar way. Yield 89%. T decom =155-158°C (ethanol). Found, %: C 55.97, H 4.43, N 3.45, S 7.82. C 19 H 18 ClNO 5 S. Calculated, %: C 55.95, H 4.45, N 3.43, S 7.86. IR spectrum (FSM 1202, vaseline oil, ν, cm -1 ): 1732 (COOEt), 3397 (NH). 1H NMR spectrum, (Varian Mercury300 , 300 MHz, DMSO d6 ), δ, ppm: 1.33 (t, J 7.1 Hz, 3H, Me), 2.19 (s, 3H, Me), 2.25 (s, 3H , Me), 4.33 (q, J 7.1 Hz, 2Н, CH2O), 6.49 (s, 1H С = CH), 7.63 (m, J 8.6 Hz, 2Н, H Ar ), 8.01 (m, J 8.6 Hz , 2Н, H Ar ), 12.71 (s, 1Н, NH). The obtained compound 1b is a red crystalline substance, soluble in chloroform, toluene, acetone, insoluble in water and hexane.
Пример 3. Для характеристики противогрибковой активности соединений использовали стандартные параметры: минимальная подавляющая концентрация (МПК), которую определяли модифицированным методом двукратных серийных разведений [МУК 4.2.1890-04 Определение чувствительности микроорганизмов к антибактериальным препаратам] и минимальная бактерицидная концентрация (МБК) [Медицинские лабораторные технологии: Руководство по клинической лабораторной диагностике, п/р Каприщенко, 2013, Т. 2, стр. 407]. Тесты проводили с использованием культуры модельного микроорганизма Candida albicans АТСС 10231 (Всероссийская коллекция патогенных микроорганизмов) на питательной среде Мюллера-Хинтона с добавлением 0,4% глюкозы в 96-луночных полистироловых планшетах. Концентрация микроорганизмов в лунках перед началом культивирования составляла 5*105 КОЕ/мл. Культивирование проводили при 37°С без перемешивания. Определение МПК и высевы для определения МБК производили через 24 ч. Исследуемые соединения растворяли в диметилсульфоксиде (ДМСО) в концентрации 20 мг/мл до полного растворения. Максимальная действующая концентрация составляла 1000 мкг/млExample 3. To characterize the antifungal activity of the compounds, standard parameters were used: the minimum inhibitory concentration (MIC), which was determined by a modified method of two-fold serial dilutions [MUK 4.2.1890-04 Determination of the sensitivity of microorganisms to antibacterial drugs] and the minimum bactericidal concentration (MBC) [Medical laboratory technology: Guidelines for clinical laboratory diagnostics, p / r Kaprischenko, 2013, Vol. 2, p. 407]. The tests were carried out using a culture of the model microorganism Candida albicans АТСС 10231 (All-Russian Collection of Pathogenic Microorganisms) on a Muller-Hinton nutrient medium supplemented with 0.4% glucose in 96-well polystyrene plates. The concentration of microorganisms in the wells before cultivation was 5*10 5 CFU/ml. Cultivation was carried out at 37°C without stirring. Determination of the MIC and seeding for the determination of MBC was carried out after 24 hours. The test compounds were dissolved in dimethyl sulfoxide (DMSO) at a concentration of 20 mg/ml until complete dissolution. The maximum effective concentration was 1000 µg/ml
Пример 4. Острую токсичность (ЛД50, мг/мл) соединений 1а, б определяли по методу Г. Н. Першина [Першин Г.Н. Методы экспериментальной химиотерапии // М., С. 100, 109-117 (1971)]. Соединения 1а, б вводили внутрибрюшинно белым мышам массой 16-18 г в виде взвеси в 2% крахмальной слизи и наблюдали за поведением и гибелью животных в течение 10 суток. Для исследуемых соединений 1а, б ЛД50 составляет > 1500 мг/кг.Example 4. Acute toxicity (LD 50 , mg/ml) of compounds 1a, b was determined by the method of G. N. Pershin [Pershin G.N. Methods of experimental chemotherapy // M., S. 100, 109-117 (1971)]. Compounds 1a, b were administered intraperitoneally to white mice weighing 16-18 g as a suspension in 2% starch mucus, and the behavior and death of the animals were observed for 10 days. For the studied compounds 1a, b LD 50 is > 1500 mg/kg.
Согласно классификации токсичности препаратов соединения 1а, б относятся к V классу практически нетоксичных препаратов [Измеров Н.Ф., Саноцкий И.В., Сидоров К.К. Параметры токсикометрии промышленных ядов при однократном воздействии: Справочник. М., 1977. - с. 196]. Результаты испытаний представлены в таблице:According to the toxicity classification of drugs, compounds 1a, b belong to the V class of practically non-toxic drugs [Izmerov N.F., Sanotsky I.V., Sidorov K.K. Parameters of toxicometry of industrial poisons at a single exposure: a Handbook. M., 1977. - p. 196]. The test results are presented in the table:
Как видно из таблицы, заявляемые соединения 1а, б превышют по противогрибковой активности препарат сравнения (тербинафин) в 3 раза по отношению к Candida albicans АТСС 10231, а также показывают низкую токсичность. Таким образом, 2-((4-R1-5-R2-3-(этоксикарбонил)тиофен-2-ил)амино)-4-оксо-4-R3-бут-2-еновые кислоты 1а, б проявляет более высокую активность по сравнению со структурным аналогом и эталоном сравнения, что делает возможным их использование для создания новых лекарственных средств целенаправленного действия.As can be seen from the table, the claimed compounds 1a, b exceed the antifungal activity of the reference drug (terbinafine) by 3 times in relation to Candida albicans ATCC 10231, and also show low toxicity. Thus, 2-((4-R 1 -5-R 2 -3-(ethoxycarbonyl)thiophen-2-yl)amino)-4-oxo-4-R 3 -but-2-enoic acids 1a, b exhibits higher activity in comparison with the structural analog and reference standard, which makes it possible to use them to create new targeted drugs.
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| EA033736B1 (en) * | 2014-12-05 | 2019-11-20 | Pulmocide Ltd | Antimycotic compound |
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