CHARACTERISATION AND STUDY OF 1- [2- (2-BENZOYLPHENOXY) ETHYL] -6-METHYLURACIL MECHANISM OF ACTION


如何引用文章

全文:

详细

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. 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. 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. 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.

作者简介

E. Jain

Moscow State University named after M.V. Lomonosov

Email: ekaterina.korsa@gmail.com
Bldg. 1, 27, Lomonosov Ave., Moscow, Russia, 119991

D. Demchenko

St. Petersburg Institute of Pharmacy

Email: demchenko.dv@doclinika.ru
Bldg. 245, 3, Zavodskaya St., Vil. Kuzmolovsky, Vsevolozhsky district, Leningrad region, Russia, 188663

A. Ozerov

Volgograd State Medical University

Email: prof_ozerov@yahoo.com
1, Pavshikh Bortsov Sq., Volgograd, Russia, 400131

M. Makarova

St. Petersburg Institute of Pharmacy

Email: makarova.mn@doclinika.ru
Bldg. 245, 3, Zavodskaya St., Vil. Kuzmolovsky, Vsevolozhsky district, Leningrad region, Russia, 188663

V. Makarov

St. Petersburg Institute of Pharmacy

Email: makarov.vg@doclinika.ru
Bldg. 245, 3, Zavodskaya St., Vil. Kuzmolovsky, Vsevolozhsky district, Leningrad region, Russia, 188663

V. Balabanyan

Moscow State University named after M.V. Lomonosov

Email: bal.pharm@mail.ru
Bldg. 1, 27, Lomonosov Ave., Moscow, Russia, 119991

参考

  1. Chen B. Molecular Mechanism of HIV-1 Entry// Trends Microbiol. - 2019. - Vol.27, №10. -P. 878-891. doi: 10.1016/j.tim.2019.06.002.
  2. 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.
  3. 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/s12955-017-0778-6
  4. Eggleton J.S., Nagalli S. Highly Active Antiretroviral Therapy (HAART). 2021. In: StatPearls// Treasure Island (FL): StatPearls Publishingю - 2021
  5. Dionne 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. De Corte BL. From 4,5,6,7-tetrahydro-5-methylimidazo(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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. Novikov 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-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.
  24. 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.
  25. Озеров А.А., Новиков М.С., Луганченко А.И., Хартман Т., Букхайт Р.У. Новые N-производные нуклеиновых оснований -синтез и анти-ВИЧ-1 активность in vitro // Волгоградский научно-мед. журн.- 2012. - №4. - С. 15-18.
  26. 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.2013.04.016
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. 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.
  32. 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.
  33. 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.
  34. 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.
  35. 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.
  36. 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.
  37. 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.

版权所有 © Jain E.A., Demchenko D.V., Ozerov A.A., Makarova M.N., Makarov V.G., Balabanyan V.Y., 2021

Creative Commons License
此作品已接受知识共享署名 4.0国际许可协议的许可
 
##common.cookie##