pmedpharmФармация и фармакологияPharmacy & Pharmacology2307-92662413-2241Pyatigorsk Medical and Pharmaceutical Institute - branch of Volgograd State Medical Univer10.19163/2307-9266-2021-9-2-114-129pmedpharm-829Research ArticleФАРМАЦЕВТИЧЕСКАЯ И ТОКСИКОЛОГИЧЕСКАЯ ХИМИЯPHARMACEUTICAL AND TOXICOLOGICAL CHEMISTRYХАРАКТЕРИЗАЦИЯ И ИССЛЕДОВАНИЕ МЕХАНИЗМА ДЕЙСТВИЯ 1-[2-(2-БЕНЗОИЛФЕНОКСИ)ЭТИЛ]-6-МЕТИЛУРАЦИЛАCHARACTERISATION AND STUDY OF 1- [2- (2-BENZOYLPHENOXY) ETHYL] -6-METHYLURACIL MECHANISM OF ACTIONhttps://orcid.org/0000-0003-0283-8598Джайн (Корсакова)Е. А.Jain (Korsakova)E. A.

аспирант кафедры фармацевтической химии, фармакогнозии и организации фармацевтического дела, факультет фундаментальной медицины

Postgraduate student of the Department of Pharmaceutical Chemistry, Pharmacognosy and Organization of Pharmaceutical Business, Faculty of Fundamental Medicine

ekaterina.korsa@gmail.comhttps://orcid.org/0000-0003-3856-3936ДемченкоД. В.DemchenkoD. V.

кандидат фармацевтических наук, руководитель группы ГЛС 

Candidate of Sciences (Pharmacy), the Head of the GLS

demchenko.dv@doclinika.ruhttps://orcid.org/0000-0002-4721-0959ОзеровА. А.OzerovA. A.

доктор химических наук, профессор, заведующий кафедрой фармацевтической и токсикологической химии

Doctor of Sciences (Chemistry), Professor, the Head of the Department of Pharmaceutical and Toxicological Chemistry 

prof_ozerov@yahoo.comhttps://orcid.org/0000-0003-3176-6386МакароваМ. Н.MakarovaM. N.

доктор медицинских наук, заместитель генерального директора по науке 

Doctor of Sciences (Medicine), Deputy General Director, Director of Research

makarova.mn@doclinika.ruhttps://orcid.org/0000-0002-2447-7888МакаровВ. Г.MakarovV. G.

доктор медицинских наук, профессор, генеральный директор 

Doctor of Sciences (Medicine), Professor, General Director 

makarov.vg@doclinika.ruhttps://orcid.org/0000-0002-5744-7060БалабаньянВ. Ю.BalabanyanV. Yu.

доктор фармацевтических наук, доцент кафедры фармацевтической технологии,факультет фундаментальной медицины

Doctor of Sciences (Pharmacy), Associate Professor of the Department of Pharmaceutical Technology, Faculty of Fundamental Medicine

bal.pharm@mail.ruФедеральное государственное бюджетное образовательное учреждение высшего образования «Московский государственный университет имени М.В. Ломоносова», 119991, Россия, г. Москва, Ломоносовский пр-т., дом 27, корп. 1РоссияMoscow State University named after M.V. Lomonosov, Bldg. 1, 27, Lomonosov Ave., Moscow, Russia, 119991Russian FederationЗакрытое акционерное общество «Санкт-Петербургский институт фармации» 188663, Россия, Ленинградская обл., Всеволожский район, г.п. Кузьмоловский, ул. Заводская, дом 3, корп. 245.РоссияSt. Petersburg Institute of Pharmacy, Bldg. 245, 3, Zavodskaya St., Vil. Kuzmolovsky, Vsevolozhsky district, Leningrad region, Russia, 188663Russian FederationФедеральное государственное бюджетное образовательное учреждение высшего образования «Волгоградский государственный медицинский университет» Министерства здравоохранения Российской Федерации, 400131, Россия, г. Волгоград, площадь Павших Борцов, д. 1РоссияVolgograd State Medical University, 1, Pavshikh Bortsov Sq., Volgograd, Russia, 400131Russian Federation20212107202192114129Copyright © Джайн (Корсакова) Е.А., Демченко Д.В., Озеров А.А., Макарова М.Н., Макаров В.Г., Балабаньян В.Ю., 20212021Джайн (Корсакова) Е.А., Демченко Д.В., Озеров А.А., Макарова М.Н., Макаров В.Г., Балабаньян В.Ю.Jain (Korsakova) E.A., Demchenko D.V., Ozerov A.A., Makarova M.N., Makarov V.G., Balabanyan V.Y.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmpharm.ru/jour/article/view/829

Цель – идентификация 1-[2-(2-бензоилфенокси)этил]-6-метилурацила с использованием различных методов анализа, а также исследование его механизма действия в отношении дикого типа и мутантных форм обратной транскриптазы (ОТ) ВИЧ-1.

Материалы и методы

Материалы и методы. Для характеризации структуры исследуемого вещества использовали рентгеноструктурный анализ, элементный анализ, термический анализ, а также УФ-, ИК- и ЯМР- спектроскопии. Изучение механизма действия соединения, как потенциального лекарственного средства, проводили путем оценки ингибирующей активности в отношении ОТ ВИЧ-1 дикого типа и ее мутантных форм, соответствующих лекарственно-устойчивым штаммам вируса.

Результаты

Результаты. Проведены исследования, подтверждающие структуру 1-[2-(2-бензоилфенокси)этил]-6-метилурацила. УФ-спектр имеет выраженный максимум поглощения при измерении раствора субстанции в тетрагидрофуране в концентрации 0,10 мг/мл, в ИК спектре наблюдаются специфичные полосы в области 4000–370 см–1, что позволяет использовать УФ и ИК спектры для идентификации исследуемого вещества в субстанции. Также было установлено, что количество и взаимное расположение функциональных групп, интегральная интенсивность сигналов в спектре 1H-ЯМР, а также строение углеродного скелет, соответствуют структуре 1-[2-(2-бензоилфенокси)этил]-6-метилурацила. Результаты изучения механизма действия показали, что исследуемое соединение является эффективным ингибитором ОТ ВИЧ-1 дикого типа с константой ингибирования 0,2 µM, а также ингибитором фермента (мутация G190A) с константой ингибирования 8 µM; фермента (мутация Y181C) с константой ингибирования 10 µM, а также ингибитором ОТ (мутация L100I, K103N, V106A) и двойном мутанте K103N/Y181C с константой ингибирования более 20 µM.

Заключение

Заключение. В результате проведенных рентгеноструктурного, элементного, 1Н-ЯМР и 13С-ЯМР анализов была подтверждена структура 1-[2-(2-бензоилфенокси)этил]-6-метилурацила. Показана возможность применения УФ-, ИК- и ЯМР- спектроскопии, а также термических анализов для подтверждения подлинности при входном контроле качества 1-[2-(2-бензоилфенокси)этил]-6-метилурацила. Разработанные методы могут быть использованы в контроле качества и включены в проект НД на исследуемую субстанцию. Исследования механизма действия соединения в отношении ОТ ВИЧ-1 показали, что данное соединение относится к группе ненуклеозидных ингибиторов обратной транскриптазы (ННИОТ) ВИЧ-1.

The aim of the study is to identify 1-[2-(2-benzoylphenoxy) ethyl]-6-methyluracil using various methods of analysis, as well as to study its action mechanism against wild-type and mutant forms of HIV-1 reverse transcriptase (RT).

Materials and methods

Materials and methods. To characterize the structure of the test substance, a few kinds of analysis (X-ray diffraction, elemental, thermal) as well as a few kinds of spectroscopy (UV, IR, and NMR) have been used. The study of the action mechanism of the compound as a potential drug was carried out by evaluating the inhibitory activity against HIV-1 RT wild-type and its mutant forms corresponding to drug-resistant viral strains.

Results

Results. The studies have been carried out to confirm the structure of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil. The UV spectrum has a pronounced absorption maximum when measuring a solution of the substance in tetrahydrofuran at the concentration of 0.10 mg / ml. In the IR spectrum, there are specific bands in the range of 4000-370 cm–1. These factors make it possible to use UV and IR spectra to identify the test compound in the substance. It has also been established that the number and mutual arrangement of functional groups, the integrated intensity of signals in the 1H-NMR spectrum, as well as the structure of the carbon skeleton, correspond to the structure of 1-[2-(2-benzoylphenoxy) ethyl]-6-methyluracil. The results of studying the action mechanism showed that the test compound is an effective inhibitor of wild-type HIV-1 RT with an inhibition constant of 0.2 µM, as well as an enzyme inhibitor (mutation G190A) with an inhibition constant of 8 µM; enzyme (mutation Y181C) with an inhibition constant of 10 µM, as well as a reverse transcriptase (RT) inhibitor (mutation L100I, K103N, V106A) and a double mutant K103N / Y181C with an inhibition constant of more than 20 µM.

Conclusion

Conclusion. As a result of the performed X-ray structural, elemental, 1H-NMR and 13C-NMR analyzes, the structure of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil has been confirmed. The possibility of using UV, IR and NMR spectroscopy, as well as thermal analyzes to confirm the authenticity during the verification of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil, has been shown. The developed methods can be used in the quality control and included in the draft of practice guidelines for the investigated substance. The studies of the action mechanism of the compound of HIV-1 RT reverse transcriptase have shown that this compound belongs to the group of non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1.

1-[2-(2-бензоилфенокси)этил]-6-метилурацилидентификациярентгеноструктурный анализтермическийанализэлементный анализУФ-спектроскопияИК-спектроскопияЯМР-спектроскопиямеханизм действияобратная транскриптаза ВИЧ-11-[2-(2-benzoylphenoxy)ethyl]-6-methyluracilidentificationX-ray structural analysisthermal analysiselemental analysisUV spectroscopyIR spectroscopyNMR spectroscopyaction mechanismHIV-1 reverse transcriptaseРабота выполнена при финансовой поддержке государства в лице Минобрнауки России (ГК №14.N08.11.0154 от 02 июня 2017 г., Уникальный идентификатор контракта RF-N0817X0148).This work was carried out with a financial support from the state on behalf of the Ministry of Education and Science of Russia (GK No. 14.N08.11.0154 dated June 02, 2017, Unique contract identifier RF-N0817X0148).ReferencesChen B. Molecular Mechanism of HIV-1 Entry// Trends Microbiol. – 2019. – Vol.27, №10. -P. 878-891. DOI: 10.1016/j.tim.2019.06.002.Chen B. Molecular Mechanism of HIV-1 Entry. Trends Microbiol. 2019 Oct;27(10):878-891. DOI: 10.1016/j.tim.2019.06.002.Gulick R.M., Flexner C. Long-Acting HIV Drugs for Treatment and Prevention // Annu Rev Med. – 2019. – Vol.70. – P.137-150. DOI: 10.1146/annurev-med-041217-013717.Gulick RM, Flexner C. Long-Acting HIV Drugs for Treatment and Prevention. Annu Rev Med. 2019 Jan 27;70:137-150. DOI: 10.1146/annurev-med-041217-013717.Cooper V. Clatworthy J., Harding R., Whetham J; Emerge Consortium. Measuring quality of life among people living with HIV: a systematic review of reviews // Health Qual Life Outcomes. – 2017. - Vol.15 , No.1.– P. 220. DOI: 10.1186/s12955-017-0778-6Cooper V, Clatworthy J, Harding R, Whetham J; Emerge Consortium. Measuring quality of life among people living with HIV: a systematic review of reviews. Health Qual Life Outcomes. 2017 Nov 15;15(1):220. DOI: 10.1186/s12955-017-0778-6.Eggleton J.S., Nagalli S. Highly Active Antiretroviral Therapy (HAART). 2021. In: StatPearls [Электронный доступ] // Treasure Island (FL): StatPearls Publishingю - 2021Eggleton JS, Nagalli S. Highly Active Antiretroviral Therapy (HAART). 2021 Apr 7. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021Dionne B. Key Principles of Antiretroviral Pharmacology // Infect Dis Clin North Am. – 2019. – Vol.33, No.3. – P.787-805. DOI: 10.1016/j.idc.2019.05.006.Dionne B. Key Principles of Antiretroviral Pharmacology. Infect Dis Clin North Am. 2019 Sep;33(3):787-805. DOI: 10.1016/j.idc.2019.05.006.Gupta R.K., Gregson J., Parkin N., Haile-Selassie H., Tanuri A., Andrade Forero L., Kaleebu P., Watera C., Aghokeng A., Mutenda N., Dzangare J., Hone S., Hang Z.Z., Garcia J., Garcia Z., Marchorro P., Beteta E., Giron A., Hamers R., Inzaule S., Frenkel L.M., Chung M.H., de Oliveira T., Pillay D., Naidoo K., Kharsany A., Kugathasan R., Cutino T., Hunt G., Avila Rios S., Doherty M., Jordan M.R., Bertagnolio S. HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis // Lancet Infect Dis. – 2018. – Vol.18, No.3. – P.346-355. DOI: 10.1016/S1473-3099(17)30702-8.Gupta RK, Gregson J, Parkin N, Haile-Selassie H, Tanuri A, Andrade Forero L, Kaleebu P, Watera C, Aghokeng A, Mutenda N, Dzangare J, Hone S, Hang ZZ, Garcia J, Garcia Z, Marchorro P, Beteta E, Giron A, Hamers R, Inzaule S, Frenkel LM, Chung MH, de Oliveira T, Pillay D, Naidoo K, Kharsany A, Kugathasan R, Cutino T, Hunt G, Avila Rios S, Doherty M, Jordan MR, Bertagnolio S. HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis. Lancet Infect Dis. 2018 Mar;18(3):346-355. DOI: 10.1016/S1473-3099(17)30702-8.Wang Y., De Clercq E., Li G. Current and emerging non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV-1 treatment // Expert Opin Drug Metab Toxicol. – 2019. – Vol.15, No.10. – P.813-829. DOI: 10.1080/17425255.2019.1673367.Wang Y, De Clercq E, Li G. Current and emerging non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV-1 treatment. Expert Opin Drug Metab Toxicol. 2019 Oct;15(10):813-829. DOI: 10.1080/17425255.2019.1673367.Das K., Martinez S.E., DeStefano J.J., Arnold E. Structure of HIV-1 RT/dsRNA initiation complex prior to nucleotide incorporation // Proc Natl Acad Sci U S A. – 2019. – Vol.116, No.15. – P.7308-7313. DOI: 10.1073/pnas.1814170116.Das K, Martinez SE, DeStefano JJ, Arnold E. Structure of HIV-1 RT/dsRNA initiation complex prior to nucleotide incorporation. Proc Natl Acad Sci U S A. 2019 Apr 9;116(15):7308-7313. DOI: 10.1073/pnas.1814170116.Das K., Arnold E. HIV-1 reverse transcriptase and antiviral drug resistance // Part 2. Curr Opin Virol. – 2013. – Vol.3, No.2. – P.119-28. DOI: 10.1016/j.coviro.2013.03.014.Das K, Arnold E. HIV-1 reverse transcriptase and antiviral drug resistance. Part 2. Curr Opin Virol. 2013 Apr;3(2):119-28. DOI: 10.1016/j.coviro.2013.03.014.Das K., Martinez S.E., Bauman J.D., Arnold E. HIV-1 reverse transcriptase complex with DNA and nevirapine reveals non-nucleoside inhibition mechanism // Nat Struct Mol Biol. – 2012. – Vol.19, No.2. – P.253-259. DOI: 10.1038/nsmb.2223.Das K, Martinez SE, Bauman JD, Arnold E. HIV-1 reverse transcriptase complex with DNA and nevirapine reveals non-nucleoside inhibition mechanism. Nat Struct Mol Biol. 2012 Jan 22;19(2):253-9. DOI: 10.1038/nsmb.2223.Liu S., Abbondanzieri E.A., Rausch J.W., Le Grice S.F., Zhuang X. Slide into action: dynamic shuttling of HIV reverse transcriptase on nucleic acid substrates // Science. – 2008. – Vol.322, No.5904. – P.1092-1097. DOI: 10.1126/science.1163108.Liu S, Abbondanzieri EA, Rausch JW, Le Grice SF, Zhuang X. Slide into action: dynamic shuttling of HIV reverse transcriptase on nucleic acid substrates. Science. 2008 Nov 14;322(5904):1092-7. DOI: 10.1126/science.1163108.Schauer G.D., Huber K.D., Leuba S.H., Sluis-Cremer N. Mechanism of allosteric inhibition of HIV-1 reverse transcriptase revealed by single-molecule and ensemble fluorescence // Nucleic Acids Res. – 2014. – Vol.42, No.18. – P.11687-11696. DOI: 10.1093/nar/gku819.Schauer GD, Huber KD, Leuba SH, Sluis-Cremer N. Mechanism of allosteric inhibition of HIV-1 reverse transcriptase revealed by single-molecule and ensemble fluorescence. Nucleic Acids Res. 2014 Oct;42(18):11687-96. DOI: 10.1093/nar/gku819.Wang J., Smerdon S.J., Jäger J., Kohlstaedt L.A., Rice P.A., Friedman J.M., Steitz T.A. Structural basis of asymmetry in the human immunodeficiency virus type 1 reverse transcriptase heterodimer // Proc Natl Acad Sci U S A. – 1994. – Vol.91, No.15. – P.7242-7246. DOI: 10.1073/pnas.91.15.7242.Wang J, Smerdon SJ, Jäger J, Kohlstaedt LA, Rice PA, Friedman JM, Steitz TA. Structural basis of asymmetry in the human immunodeficiency virus type 1 reverse transcriptase heterodimer. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7242-6. DOI: 10.1073/pnas.91.15.7242.De Corte BL. From 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk](1,4)benzodiazepin-2(1H)-one (TIBO) to etravirine (TMC125): fifteen years of research on non-nucleoside inhibitors of HIV-1 reverse transcriptase // J Med Chem. – 2005. – Vol. 48, No.6. – P.1689-1696. DOI: 10.1021/jm040127p.De Corte BL. From 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk](1,4)benzodiazepin-2(1H)-one (TIBO) to etravirine (TMC125): fifteen years of research on non-nucleoside inhibitors of HIV-1 reverse transcriptase. J Med Chem. 2005 Mar 24;48(6):1689-96. DOI: 10.1021/jm040127p.Schafer J.J., Short W.R. Rilpivirine, a novel non-nucleoside reverse transcriptase inhibitor for the management of HIV-1 infection: a systematic review // Antivir Ther. – 2012. – Vol.17, No.8. – P.1495-1502. DOI: 10.3851/IMP2254.Schafer JJ, Short WR. Rilpivirine, a novel non-nucleoside reverse transcriptase inhibitor for the management of HIV-1 infection: a systematic review. Antivir Ther. 2012;17(8):1495-502. DOI: 10.3851/IMP2254.Hofstra L.M., Sauvageot N., Albert J., et al. Transmission of HIV Drug Resistance and the Predicted Effect on Current First-line Regimens in Europe // Clin Infect Dis. – 2016. – Vol.62, №5 – P.655-663.Hofstra LM, Sauvageot N, Albert J, et al. Transmission of HIV Drug Resistance and the Predicted Effect on Current First-line Regimens in Europe. Clin Infect Dis. 2016 Mar 1;62(5):655-663. DOI: 10.1093/cid/civ963.Tang M.W., Shafer R.W. HIV-1 antiretroviral resistance: scientific principles and clinical applications // Drugs. – 2012. – Vol.72, No.9. P. e1-25. DOI: 10.2165/11633630-000000000-00000.Tang MW, Shafer RW. HIV-1 antiretroviral resistance: scientific principles and clinical applications. Drugs. 2012 Jun 18;72(9):e1-25. DOI: 10.2165/11633630-000000000-00000.Bruccoleri A. Positional adaptability in the design of mutation-resistant nonnucleoside HIV-1 reverse transcriptase inhibitors: a supramolecular perspective. AIDS Res Hum Retroviruses. 2013 Jan;29(1):4-12. DOI: 10.1089/AID.2012.0141.Bruccoleri A. Positional adaptability in the design of mutation-resistant nonnucleoside HIV-1 reverse transcriptase inhibitors: a supramolecular perspective. AIDS Res Hum Retroviruses. 2013 Jan;29(1):4-12. DOI: 10.1089/AID.2012.0141.La Regina G., Coluccia A., Silvestri R. Looking for an active conformation of the future HIV type-1 non-nucleoside reverse transcriptase inhibitors // Antivir Chem Chemother. – 2010. – Vol.20, No.6. – P.213-37. DOI: 10.3851/IMP1607.La Regina G, Coluccia A, Silvestri R. Looking for an active conformation of the future HIV type-1 non-nucleoside reverse transcriptase inhibitors. Antivir Chem Chemother. 2010 Aug 11;20(6):213-37. DOI: 10.3851/IMP1607.Huo Z., Zhang H., Kang D., Zhou Z., Wu G., Desta S., Zuo X., Wang Z., Jing L., Ding X., Daelemans D., De Clercq E., Pannecouque C., Zhan P., Liu X. Discovery of Novel Diarylpyrimidine Derivatives as Potent HIV-1 NNRTIs Targeting the "NNRTI Adjacent" Binding Site // ACS Med Chem Lett. – 2018. – Vol.9, No.4. – P. 334-338. DOI: 10.1021/acsmedchemlett.7b00524.Huo Z, Zhang H, Kang D, Zhou Z, Wu G, Desta S, Zuo X, Wang Z, Jing L, Ding X, Daelemans D, De Clercq E, Pannecouque C, Zhan P, Liu X. Discovery of Novel Diarylpyrimidine Derivatives as Potent HIV-1 NNRTIs Targeting the "NNRTI Adjacent" Binding Site. ACS Med Chem Lett. 2018 Feb 27;9(4):334-338. DOI: 10.1021/acsmedchemlett.7b00524.Kang D., Wang Z., Zhang H., Wu G., Zhao T., Zhou Z., Huo Z., Huang B., Feng D., Ding X., Zhang J., Zuo X., Jing L., Luo W., Guma S., Daelemans D., Clercq E., Pannecouque C., Zhan P., Liu X. Further Exploring Solvent-Exposed Tolerant Regions of Allosteric Binding Pocket for Novel HIV-1 NNRTIs Discovery // ACS Med Chem Lett. – 2018. – Vol.9, No.4. – P. 370-375. DOI: 10.1021/acsmedchemlett.8b00054.Kang D, Wang Z, Zhang H, Wu G, Zhao T, Zhou Z, Huo Z, Huang B, Feng D, Ding X, Zhang J, Zuo X, Jing L, Luo W, Guma S, Daelemans D, Clercq E, Pannecouque C, Zhan P, Liu X. Further Exploring Solvent-Exposed Tolerant Regions of Allosteric Binding Pocket for Novel HIV-1 NNRTIs Discovery. ACS Med Chem Lett. 2018 Mar 1;9(4):370-375. DOI: 10.1021/acsmedchemlett.8b00054.Озеров А.А., Новиков М.С., Тимофеева Ю.А., Лобачев А.А., Луганченко А.И., Гейсман А.Н. Пиримидиновые ненуклеозидные ингибиторы обратной транскриптазы ВИЧ-1 – история разработки и перспективы // Вестник ВолгГМУ. – 2012.– №3. – 10-17.Ozerov MA, Novikov A.S, Timofeeva YuA, Lobachev AA, Luganchenko AI, Heisman AN. Pyrimidine non-nucleoside hiv-1 inhibitors: history of their development and perspectives. Journal of Volgograde State Medical University. - 2012.– No. 3. – P.10-17. RussianNovikov M.S., Ivanova O.N., Ivanov A.V., Ozerov A.A., Valuev-Elliston V.T., Temburnikar K., Gurskaya G.V., Kochetkov S.N., Pannecouque C., Balzarini J., Seley-Radtke K.L. 1-[2-(2-Benzoyl- and 2-benzylphenoxy)ethyl]uracils as potent anti-HIV-1 agents // Bioorg Med Chem. – 2011. – Vol.19, No.19. – P.5794-5802. DOI: 10.1016/j.bmc.2011.08.025.Novikov MS, Ivanova ON, Ivanov AV, Ozerov AA, Valuev-Elliston VT, Temburnikar K, Gurskaya GV, Kochetkov SN, Pannecouque C, Balzarini J, Seley-Radtke KL. 1-[2-(2-Benzoyl- and 2-benzylphenoxy)ethyl]uracils as potent anti-HIV-1 agents. Bioorg Med Chem. 2011 Oct 1;19(19):5794-802. DOI: 10.1016/j.bmc.2011.08.025.Петров В.И., Новиков М.С., Луганченко А.И., Озеров А.А., Рогова Н.В. Кластерный подход к созданию биотехнологических лекарственных средств // Медицинская этика. – 2014. – №1. – С. 28-31.Petrov VI, Novikov MS, Luganchenko AI, Ozerov AA, Rogova NV. Klasternyj podhod k sozdaniyu biotekhnologicheskih lekarstvennyh sredstv. Medicinskaya etika. 2014;1:28-31. RussianОзеров А.А., Новиков М.С., Луганченко А.И., Хартман Т., Букхайт Р.У. Новые N-[2-(Бензоилфенокси)этил] производные нуклеиновых оснований –синтез и анти-ВИЧ-1 активность in vitro // Волгоградский научно-мед. журн.– 2012. – №4. – С. 15-18.Ozerov A. A., Novikov M. S., Luganchenko A. I., Hartman T., Buckheit R. W. Novel n-[2-(benzoylphenoxy)ethyl] nucleic bases deriv atives - synthesis and anti-hiv-1 activity in vitro. Volgograd Journal of Medical Research.2012;4:15-18.Siddiqui M.R., Al Othman Z.A., Rahman N. Analytical techniques in pharmaceutical analysis: A review // Arabian Journal of Chemistry. – 2017. – Vol.10, No.2. – P.1409-1421. DOI: 10.1016/j.arabjc.2013.04.016Arabian Journal of Chemistry. 2017;10(2):S1409-S1421. DOI: 10.1016/j.arabjc.2013.04.016Rai M.A., Pannek S., Fichtenbaum C.J. Emerging reverse transcriptase inhibitors for HIV-1 infection // Expert Opin Emerg Drugs. – 2018. – Vol.23, No.2. – P.149-157. DOI: 10.1080/14728214.2018.1474202.Rai M.A., Pannek S., Fichtenbaum C.J. Emerging reverse transcriptase inhibitors for HIV-1 infection // Expert Opin Emerg Drugs. – 2018. – Vol.23, No.2. – P.149-157. DOI: 10.1080/14728214.2018.1474202.de Bethune, M.P. Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989-2009) // Antiviral Res. - 2010. - Vol. 85, No. 1. - P. 75-90. DOI: 10.1016/j.antiviral.2009.09.008.de Béthune MP. Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989-2009). Antiviral Res. 2010 Jan;85(1):75-90. DOI: 10.1016/j.antiviral.2009.09.008.Maga G., Amacker M., Ruel N., Hübscher U., Spadari S. Resistance to nevirapine of HIV-1 reverse transcriptase mutants: loss of stabilizing interactions and thermodynamic or steric barriers are induced by different single amino acid substitutions. // J Mol Biol. - 1997. - Vol. 274, No. 5. - P. 738-747. DOI: 10.1006/jmbi.1997.1427.Maga G, Amacker M, Ruel N, Hübscher U, Spadari S. Resistance to nevirapine of HIV-1 reverse transcriptase mutants: loss of stabilizing interactions and thermodynamic or steric barriers are induced by different single amino acid substitutions. J Mol Biol. 1997 Dec 19;274(5):738-47. DOI: 10.1006/jmbi.1997.1427.Mackie N. Resistance to non-nucleoside reverse transcriptase inhibitors. In: Geretti AM, editor. Antiretroviral Resistance in Clinical Practice. Изд-во- London: Mediscript; 2006. Chapter 2.Mackie N. Resistance to non-nucleoside reverse transcriptase inhibitors. In: Geretti AM, editor. Antiretroviral Resistance in Clinical Practice. London: Mediscript; 2006. Chapter 2.Sato A., Hammond J., Alexander T.N., Graham J.P., Binford S., Sugita K., Sugimoto H., Fujiwara T., Patick A.K.. In vitro selection of mutations in human immunodeficiency virus type 1 reverse transcriptase that confer resistance to capravirine, a novel nonnucleoside reverse transcriptase inhibitor // Antiviral Res. - 2006. - Vol. 70, No.2. - P. 66-74. DOI: 10.1016/j.antiviral.2006.01.001.Sato A, Hammond J, Alexander TN, Graham JP, Binford S, Sugita K, Sugimoto H, Fujiwara T, Patick AK. In vitro selection of mutations in human immunodeficiency virus type 1 reverse transcriptase that confer resistance to capravirine, a novel nonnucleoside reverse transcriptase inhibitor. Antiviral Res. 2006 Jun;70(2):66-74. DOI: 10.1016/j.antiviral.2006.01.001.Corbau R., Mori J., Phillips C., Fishburn L., Martin A., Mowbray C., Panton W., Smith-Burchnell C., Thornberry A., Ringrose H., Knöchel T., Irving S., Westby M., Wood A., Perros M. Lersivirine, a nonnucleoside reverse transcriptase inhibitor with activity against drug-resistant human immunodeficiency virus type 1 // Antimicrob Agents Chemother. - 2010. -Vol. 54, No.10. - P. 4451-4463. DOI: 10.1128/AAC.01455-09.Corbau R, Mori J, Phillips C, Fishburn L, Martin A, Mowbray C, Panton W, Smith-Burchnell C, Thornberry A, Ringrose H, Knöchel T, Irving S, Westby M, Wood A, Perros M. Lersivirine, a nonnucleoside reverse transcriptase inhibitor with activity against drug-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2010 Oct;54(10):4451-63. DOI: 10.1128/AAC.01455-09.Chan J.H., Freeman G.A., Tidwell J.H., Romines K.R., Schaller L.T., Cowan J.R., Gonzales S.S., Lowell G.S., Andrews C.W. 3rd, Reynolds D.J., St. Clair M., Hazen R.J., Ferris R.G., Creech K.L., Roberts G.B., Short S.A., Weaver K., Koszalka G.W., Boone L.R.. Novel benzophenones as non-nucleoside reverse transcriptase inhibitors of HIV-1 // J Med Chem. – 2004. – Vol.47, No.5. – P.1175-1182. DOI: 10.1021/jm030255y.Chan JH, Freeman GA, Tidwell JH, Romines KR, Schaller LT, Cowan JR, Gonzales SS, Lowell GS, Andrews CW 3rd, Reynolds DJ, St Clair M, Hazen RJ, Ferris RG, Creech KL, Roberts GB, Short SA, Weaver K, Koszalka GW, Boone LR. Novel benzophenones as non-nucleoside reverse transcriptase inhibitors of HIV-1. J Med Chem. 2004 Feb 26;47(5):1175-82. DOI: 10.1021/jm030255y.Hsiou Y., Das K., Ding J., Clark A.D. Jr., Kleim J.P., Rösner M., Winkler I., Riess G., Hughes S.H., Arnold E. Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance // J Mol Biol. - 1998. - V. 284, No.2. - P. 313-323. DOI: 10.1006/jmbi.1998.2171.Hsiou Y, Das K, Ding J, Clark AD Jr, Kleim JP, Rösner M, Winkler I, Riess G, Hughes SH, Arnold E. Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance. J Mol Biol. 1998 Nov 27;284(2):313-23. doi: 10.1006/jmbi.1998.2171.Kertesz D.J., Brotherton-Pleiss C., Yang M., Wang Z., Lin X., Qiu Z., Hirschfeld D.R., Gleason S., Mirzadegan T., Dunten P.W., Harris S.F., Villaseñor A.G., Hang J.Q., Heilek G.M., Klumpp K. Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-benzyl derivatives with broad potency against resistant mutant viruses // Bioorg Med Chem Lett. - 2010. - Vol. 20, No.14. - P. 4215-4218. DOI: 10.1016/j.bmcl.2010.05.040.Kertesz DJ, Brotherton-Pleiss C, Yang M, Wang Z, Lin X, Qiu Z, Hirschfeld DR, Gleason S, Mirzadegan T, Dunten PW, Harris SF, Villaseñor AG, Hang JQ, Heilek GM, Klumpp K. Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-benzyl derivatives with broad potency against resistant mutant viruses. Bioorg Med Chem Lett. 2010 Jul 15;20(14):4215-8. DOI: 10.1016/j.bmcl.2010.05.040.Hsiou Y., Ding J., Das K., Clark A.D. Jr., Boyer P.L., Lewi P., Janssen P.A., Kleim J.P., Rösner M., Hughes S.H., Arnold E. The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance // J Mol Biol. - 2001. - Vol. 309, No. 2. - P. 437-445. DOI: 0.1006/jmbi.2001.4648.Hsiou Y, Ding J, Das K, Clark AD Jr, Boyer PL, Lewi P, Janssen PA, Kleim JP, Rösner M, Hughes SH, Arnold E. The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance. J Mol Biol. 2001 Jun 1;309(2):437-45. DOI: 10.1006/jmbi.2001.4648.Ren J., Nichols C.E., Chamberlain P.P., Weaver K.L., Short S.A., Chan J.H., Kleim J.P., Stammers D.K. Relationship of potency and resilience to drug resistant mutations for GW420867X revealed by crystal structures of inhibitor complexes for wild-type, Leu100Ile, Lys101Glu, and Tyr188Cys mutant HIV-1 reverse transcriptases // J Med Chem. - 2007. - Vol. 50, No.10. - P. 2301-2309. DOI: 10.1021/jm061117m.Ren J, Nichols CE, Chamberlain PP, Weaver KL, Short SA, Chan JH, Kleim JP, Stammers DK. Relationship of potency and resilience to drug resistant mutations for GW420867X revealed by crystal structures of inhibitor complexes for wild-type, Leu100Ile, Lys101Glu, and Tyr188Cys mutant HIV-1 reverse transcriptases. J Med Chem. 2007 May 17;50(10):2301-9. DOI: 10.1021/jm061117m.

The authors declare that there are no conflicts of interest present.