tibljТуберкулез и болезни легкихTuberculosis and Lung Diseases2075-12302542-1506Медицинские знания и технологии10.21292/2075-1230-2022-100-5-64-70tiblj-1644Research ArticleОБЗОРREVIEWИнгибиторы DprE1 – перспективная мишень для разработки противотуберкулезных препаратовDprE1 inhibitors – a prospective target for development of antituberculosis drugsКукурикаА. В.KukurikaA. V.

Кукурика Анастасия Владимировна, врач-фтизиатр

г. Макеевка, ул. Сормовская, д. 7

Anastasia V. Kukurika, Makeevka Municipal TB Dispensary, Phthisiologist

7, Sormovskaya St., Makeevka

nastya_kukurika@mail.ruГородской противотуберкулезный диспансер г. МакеевкиУкраинаMakeevka Municipal TB DispensaryUkraine20221006202210056470Copyright © Кукурика А.В., 20222022Кукурика А.В.Kukurika A.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.tibl-journal.com/jour/article/view/1644

В литературном обзоре рассмотрены и проанализированы 63 научные публикации, посвященные новым классам противотуберкулезных препаратов – ингибиторам DprE1. На текущий момент на разных стадиях клинических испытаний находятся соединения BTZ-043, PBTZ-169 (макозинон), TBA-7371 и OPC-167832. Ингибиторы DprE1 относятся к многообещающим препаратам с противотуберкулезной активностью, что обусловливает необходимость дальнейших клинических испытаний.

The article reviews and analyzes 63 scientific publications devoted to new classes of antituberculosis drugs – DprE1 inhibitors. Currently, compounds BTZ-043, PBTZ-169 (makozinone), TBA-7371 and OPC-167832 are tested at different stages of clinical trials. DprE1 inhibitors are promising drugs with antituberculosis activity, which requires further clinical trials.

DprE1противотуберкулезные препаратыBTZ-043PBTZ-169TBA-7371OPC-167832туберкулез с множественной/широкой лекарственной устойчивостьюDprE1antituberculosis drugsBTZ-043PBTZ-169TBA-7371OPC-167832multiple/extensive drug resistant tuberculosisReferencesМарьяндышев А. О., Хохлов А. Л., Смердин С. В., Щербакова В. С., Игумнова О. В., Озерова И. В., Болгарина А. А., Никитина Н. А. Основные результаты клинических исследований эффективности, безопасности и фармакокинетики перспективного противотуберкулезного препарата макозинон (PBTZ169) // Терапевтический архив. – 2020. – Т. 92, №3. – С. 61-72.Maryandyshev А.O., Khokhlov А.L., Smerdin S.V., Scherbakova V.S., Igumnova O.V., Ozerova I.V., Bolgarina А.А., Nikitina N.А. The main results of clinical trials of the efficacy, safety and pharmacokinetics of the prespective anti-tuberculosis drug makozinone (PBTZ169). Terapevticheskiy Arkhiv, 2020, vol. 92, no. 3, pp. 61-72. (In Russ.)Рузанов Д. Ю., Скрягина Е. М., Буйневич И. В., Гопоняко С. В., БаласанянцГ. С., Химова Е. С. Новые схемы и новые препараты в лечении туберкулеза: шагаем в ногу? // Клиническая микробиология и антимикробная химиотерапия. – 2021. – Т. 23, № 1. – С. 27-42.Ruzanov D.Yu., Skryagina E.M., Buynevich I.V., Goponyako S.V., Balasanyants G.S., Khimova E.S. New regimens and new medications in the treatment of tuberculosis: keeping step? Klinicheskaya Mikrobiologiya i Antimikrobnaya Khimioterapiya, 2021, vol. 23, no. 1, pp. 27-42. (In Russ.)Хохлов А. Л., Марьяндышев А. О., Щербакова В. С., Озерова И. В., Казаишвили Ю. Г., Игумнова О. В., Болгарина А. А., Рудой Б. А. Влияние физико-химических свойств на фармакокинетические параметры нового представителя бензотиазинонов – противотуберкулезного препарата макозинон // Терапевтический архив. – 2020. – Т. 92, № 12. – С. 165-171.Khokhlov А.L., Maryandyshev А.O., Scherbakova V.S., Ozerova I.V., Kazaishvili Yu.G., Igumnova O.V., Bolgarina А.А., Rudoy B.А. Effect of physicochemical properties on the pharmacokinetic parameters of the new representative of benzothiazinones antituberculosis drug macozinonе. Terapevticheskiy Arkhiv, 2020, vol. 92, no. 12, pp. 165-171. (In Russ.)Batt S. M., Jabeen T., Bhowruth V., Quill L., Lund P. A., Eggeling L., Alderwick L. J., Fütterer K., Besra G. S. Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors // Proc. Natl. Acad. Sci. USA. ‒ 2012. ‒ № 109. ‒ Р. 11354-11359.Batt S.M., Jabeen T., Bhowruth V., Quill L., Lund P.A., Eggeling L., Alderwick L.J., Fütterer K., Besra G.S. Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors. Proc. Natl. Acad. Sci. USA, 2012, no. 109, pp. 11354-11359.Bhutani I., Loharch S., Gupta P., Madathil R., Parkesh R. Structure, dynamics, and interaction of Mycobacterium tuberculosis (Mtb) DprE1 and DprE2 examined by molecular modeling, simulation, and electrostatic studies // PLoS One. ‒ 2015. ‒ Vol. 10, № 3. ‒ Р. e0119771.Bhutani I., Loharch S., Gupta P., Madathil R., Parkesh R. Structure, dynamics, and interaction of Mycobacterium tuberculosis (Mtb) DprE1 and DprE2 examined by molecular modeling, simulation, and electrostatic studies. PLoS One, 2015, vol. 10, no. 3, pp. e0119771.Borthwick J. A., Alemparte C., Wall I., Whitehurst B. C., Argyrou A., Burley G., de Dios-Anton P., Guijarro L., Monteiro M. C., Ortega F., SucklingC. J., Pichel J. C., Cacho M., Young R. J. Mycobacterium tuberculosis decaprenylphosphoryl-β-d-ribose oxidase inhibitors: expeditious reconstruction of suboptimal hits into a series with potent in vivo activity // J.Med. Chem. ‒ 2020. ‒ Vol. 63, № 5. ‒ Р. 2557-2576.Borthwick J.A., Alemparte C., Wall I., Whitehurst B.C., Argyrou A., Burley G., de Dios-Anton P., Guijarro L., Monteiro M.C., Ortega F., SucklingC.J., Pichel J.C., Cacho M., Young R.J. Mycobacterium tuberculosis decaprenylphosphoryl-β-d-ribose oxidase inhibitors: expeditious reconstruction of suboptimal hits into a series with potent in vivo activity. J.Med. Chem., 2020, vol. 63, no. 5, pp. 2557-2576.Brecik M., Centárova I., Mukherjee R., Kolly G. S., Huszár S., Bobovská A., Kilacsková E., Mokošová V., Svetlíková Z., Šarkan M., Neres J., Korduláková J., Cole S. T., Mikušová K. DprE1 is a vulnerable tuberculosis drug target due to its cell wall localization // ACS Chem. Biol. ‒ 2015. ‒ Vol. 10, № 7. ‒ Р. 1631-1636.Brecik M., Centárova I., Mukherjee R., Kolly G.S., Huszár S., Bobovská A., Kilacsková E., Mokošová V., Svetlíková Z., Šarkan M., Neres J., Korduláková J., Cole S.T., Mikušová K. DprE1 is a vulnerable tuberculosis drug target due to its cell wall localization. ACS Chem. Biol., 2015, vol. 10, no. 7, pp. 1631-1636.Buroni S., Pasca M. R., de Jesus Lopes Ribeiro A. L., Degiacomi G., MolteniE., Riccardi G. Antituberculars which target decaprenylphosphoryl-β-D-ribofu ranose 2'-oxidase DprE1: state of art // Appl. Microbiol. Biotechnol. ‒ 2012. ‒ Vol. 94, № 4. ‒ Р. 907-916.Buroni S., Pasca M.R., de Jesus Lopes Ribeiro A.L., Degiacomi G., Molteni E., Riccardi G. Antituberculars which target decaprenylphosphoryl-β-D-ribofur anose 2'-oxidase DprE1: state of art. Appl. Microbiol. Biotechnol., 2012, vol. 94, no. 4, pp. 907-916Chikhale R. V., Barmade M. A., Murumkar P. R., Yadav M. R. Overview of the development of DprE1 inhibitors for combating the menace of tuberculosis // J. Med. Chem. ‒ 2018. ‒ Vol. 61, № 19. ‒ Р. 8563-8593.Chikhale R.V., Barmade M.A., Murumkar P.R., Yadav M.R. Overview of the development of DprE1 inhibitors for combating the menace of tuberculosis. J.Med. Chem., 2018, vol. 61, no. 19, pp. 8563-8593.ClinicalTrials.gov. A Phase 1 Study to Evaluate Safety, Tolerability, PK, and PK Interactions of TBA-7371. Bethesda (MD): National Library of Medicine(US); 2000.ClinicalTrials.gov. A Phase 1 Study to Evaluate Safety, Tolerability, PK, and PK Interactions of TBA-7371. Bethesda (MD), National Library of Medicine (US), 2000.ClinicalTrials.gov. A Phase 1/2 Trial of Multiple Oral Doses of OPC-167832 for Uncomplicated Pulmonary Tuberculosis. Bethesda (MD): National Library of Medicine (US); 2000.ClinicalTrials.gov. A Phase 1/2 Trial of Multiple Oral Doses of OPC-167832 for Uncomplicated Pulmonary Tuberculosis. Bethesda (MD), National Library of Medicine (US), 2000.ClinicalTrials.gov. BTZ-043 ‒ Multiple Ascending Dose (MAD) to Evaluate Safety, Tolerability and Early Bactericidal Activity (EBA). Bethesda (MD): National Library of Medicine (US); 2000.ClinicalTrials.gov. BTZ-043 ‒ Multiple Ascending Dose (MAD) to Evaluate Safety, Tolerability and Early Bactericidal Activity (EBA). Bethesda (MD), National Library of Medicine (US), 2000.ClinicalTrials.gov. Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis. Bethesda (MD): National Library of Medicine (US); 2000.ClinicalTrials.gov. Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis. Bethesda (MD), National Library of Medicine (US), 2000.ClinicalTrials.gov. Phase 1 Study of PBTZ169. Bethesda (MD): National Library of Medicine (US); 2000.ClinicalTrials.gov. Phase 1 Study of PBTZ169. Bethesda (MD), National Library of Medicine (US), 2000.ClinicalTrials.gov. Phase 2a Study of PBTZ169. Bethesda (MD): National Library of Medicine (US); 2000.ClinicalTrials.gov. Phase 2a Study of PBTZ169. Bethesda (MD), National Library of Medicine (US), 2000.ClinicalTrials.gov. Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Ex-vivo Antitubercular Activity of PBTZ169 Formulation. Bethesda (MD): National Library of Medicine (US); 2000.ClinicalTrials.gov. Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Ex-vivo Antitubercular Activity of PBTZ169 Formulation. Bethesda (MD): National Library of Medicine (US); 2000.Foo C. S., Lechartier B., Kolly G. S., Boy-Röttger S., Neres J., Rybniker J., Lupien A., Sala C., Piton J., Cole S. T. Characterization of DprE1-mediated benzothiazinone resistance in Mycobacterium tuberculosis // Antimicrob. Agents Chemother. ‒ 2016. ‒ Vol. 60, № 11. ‒ Р. 6451-6459.Foo C.S., Lechartier B., Kolly G.S., Boy-Röttger S., Neres J., Rybniker J., Lupien A., Sala C., Piton J., Cole S.T. Characterization of DprE1-mediated benzothiazinone resistance in Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2016, vol. 60, no. 11, pp. 6451-6459.Gawad J., Bonde С. Decaprenyl-phosphoryl-ribose 2'-epimerase (DprE1): challenging target for antitubercular drug discovery // Chem. Centr. J. ‒ 2018.‒ № 12. ‒ Р. 72.Gawad J., Bonde С. Decaprenyl-phosphoryl-ribose 2'-epimerase (DprE1): challenging target for antitubercular drug discovery. Chem. Centr. J., 2018, no. 12, pp. 72.Global tuberculosis report 2020. Geneva: World Health Organization, 2020.Global tuberculosis report 2020. Geneva, World Health Organization, 2020.González-Martínez N. A., Lozano-Garza H. G., Castro-Garza J., DeOsio-Cortez A., Vargas-Villarreal J., Cavazos-Rocha N. In vivo activity of the benzothiazinones PBTZ169 and BTZ043 against nocardia brasiliensis // PLoS Negl. Trop. Dis. ‒ 2015. ‒ Vol. 9, № 10. ‒ Р. e0004022.González-Martínez N.A., Lozano-Garza H.G., Castro-Garza J., DeOsio-CortezA., Vargas-Villarreal J., Cavazos-Rocha N. In vivo activity of the benzothiazinones PBTZ169 and BTZ043 against nocardia brasiliensis. PLoS Negl. Trop. Dis., 2015, vol. 9, no. 10, pp. e0004022.Hariguchi N., Chen X., Hayashi Y., Kawano Y., Fujiwara M., Matsuba M., Shimizu H., Ohba Y., Nakamura I., Kitamoto R., Shinohara T., Uematsu Y., Ishikawa S., Itotani M., Haraguchi Y., Takemura I., Matsumoto M. OPC-167832, a novel carbostyril derivative with potent antituberculosis activity as a DprE1 inhibitor // Antimicrob. Agents Chemother. ‒ 2020. ‒ № 64. ‒ Р. e02020-19.Hariguchi N., Chen X., Hayashi Y., Kawano Y., Fujiwara M., Matsuba M., Shimizu H., Ohba Y., Nakamura I., Kitamoto R., Shinohara T., Uematsu Y., Ishikawa S., Itotani M., Haraguchi Y., Takemura I., Matsumoto M. OPC-167832, a novel carbostyril derivative with potent antituberculosis activity as a DprE1 inhibitor. Antimicrob. Agents Chemother., 2020, no. 64, pp. e02020-19.Imran M., Alshrari A. S., Thabet H. K., Abida, Bakht M. A. Synthetic molecules as DprE1 inhibitors: a patent review // Expert. Opin. Ther. Pat. ‒ 2021. doi: 10.1080/13543776.2021.1902990. Online ahead of print.Imran M., Alshrari A.S., Thabet H.K., Abida, Bakht M.A. Synthetic molecules as DprE1 inhibitors: a patent review. Expert. Opin. Ther. Pat., 2021. doi: 10.1080/13543776.2021.1902990. Online ahead of print.Incandela M. L., Perrin E., Fondi M., de Jesus Lopes Ribeiro A. L., Mori G., Moiana A., Gramegna M., Fani R., Riccardi G., Pasca M. R. DprE1, a new taxonomic marker in mycobacteria // FEMS Microbiol. Lett. ‒ 2013. ‒ Vol. 348, № 1. ‒ Р. 66-73.Incandela M.L., Perrin E., Fondi M., de Jesus Lopes Ribeiro A.L., Mori G., Moiana A., Gramegna M., Fani R., Riccardi G., Pasca M.R. DprE1, a new taxonomic marker in mycobacteria. FEMS Microbiol. Lett., 2013, vol. 348, no. 1, pp. 66-73.Kloss F., Krchnak V., Krchnakova A., Schieferdecker S., Dreisbach J., Krone V., Möllmann U., Hoelscher M., Miller M. J. In vivo dearomatization of the potent antituberculosis agent BTZ043 via meisenheimer complex formation // Angew. Chem. Int. Ed. Engl. ‒ 2017. ‒ Vol. 56, № 8. ‒ Р. 2187-2191.Kloss F., Krchnak V., Krchnakova A., Schieferdecker S., Dreisbach J., Krone V., Möllmann U., Hoelscher M., Miller M.J. In vivo dearomatization of the potent antituberculosis agent BTZ043 via meisenheimer complex formation. Angew. Chem. Int. Ed., Engl., 2017, vol. 56, no. 8, pp. 2187-2191.Kumar N., Srivastava R., Prakash A., Lynn A. M. Virtual screening and free energy estimation for identifying Mycobacterium tuberculosis flavoenzyme DprE1 inhibitors // J. Mol. Graph. Model. ‒ 2021. ‒ № 102. ‒ Р. 107770.Kumar N., Srivastava R., Prakash A., Lynn A.M. Virtual screening and free energy estimation for identifying Mycobacterium tuberculosis flavoenzyme DprE1 inhibitors. J. Mol. Graph. Model., 2021, no. 102, pp. 107770.Lechartier B., Hartkoorn R. C., Cole S. T. In vitro combination studies of benzothiazinone lead compound BTZ043 against Mycobacterium tuberculosis // Antimicrob. Agents Chemother. ‒ 2012. ‒ Vol. 56, № 11. ‒ Р. 5790-5793.Lechartier B., Hartkoorn R.C., Cole S.T. In vitro combination studies of benzothiazinone lead compound BTZ043 against Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2012, vol. 56, no. 11, pp. 5790-5793.Li L., Lv K., Tao Z., Wang A., Wang H., Geng Y., Liu M., Guo H., Sun J., YangY., Wang B., Lu Y. Identification of N benzyl 3,5-dinitrobenzamides derived from PBTZ169 as antitubercular agents // ACS Med.Chem. Letters. ‒ 2018. ‒ Vol. 9, № 7. ‒ Р. 741-745.Li L., Lv K., Tao Z., Wang A., Wang H., Geng Y., Liu M., Guo H., Sun J., YangY., Wang B., Lu Y. Identification of N benzyl 3,5-dinitrobenzamides derived from PBTZ169 as antitubercular agents. ACS Med.Chem. Letters, 2018, vol. 9, no. 7, pp. 741-745.Li P., Wang B., Zhang X., Batt S. M., Besra G. S., Zhang, T., Ma C., ZhangD., Lin Z., Li G., Huang H., Lu Y. Identification of novel benzothiopyranone compounds against Mycobacterium tuberculosis through scaffold morphing from benzothiazinones // Eur. J. Med. Chem. ‒ 2018. ‒ № 160. ‒ Р. 157-170.Li P., Wang B., Zhang X., Batt S.M., Besra G.S., Zhang, T., Ma C., Zhang D., Lin Z., Li G., Huang H., Lu Y. Identification of novel benzothiopyranone compounds against Mycobacterium tuberculosis through scaffold morphing from benzothiazinones. Eur. J. Med. Chem., 2018, no. 160, pp. 157-170.Libardo M. D. J., Boshoff H. I., Barry C. E. The present state of the tuberculosis drug development pipeline // Curr. Opin. Pharmacol. ‒ 2018. ‒ № 42. ‒ Р. 81-94.Libardo M.D.J., Boshoff H.I., Barry C.E. The present state of the tuberculosis drug development pipeline. Curr. Opin. Pharmacol., 2018, no. 42, pp. 81-94.Liu L., Kong C., Fumagalli M., Savková K., Xu Y., Huszár S., Sammartino J. C., Fan D., Chiarelli L. R., Mikušová K., Sun Z., Qiao C. Design, synthesis and evaluation of covalent inhibitors of DprE1 as antitubercular agents // Eur. J. Med. Chem. ‒ 2020. ‒ № 208. ‒ Р. 112773.Liu L., Kong C., Fumagalli M., Savková K., Xu Y., Huszár S., Sammartino J.C., Fan D., Chiarelli L.R., Mikušová K., Sun Z., Qiao C. Design, synthesis and evaluation of covalent inhibitors of DprE1 as antitubercular agents. Eur. J. Med. Chem., 2020, no. 208, pp. 112773.Liu R., Krchnak V., Brown S. N., Miller M. J. Deuteration of BTZ043 extends the lifetime of meisenheimer intermediates to the antituberculosis nitroso oxidation state // ACS Med. Chem. Lett. ‒ 2019. ‒ Vol. 10, № 10. ‒ Р. 1462-1466.Liu R., Krchnak V., Brown S.N., Miller M.J. Deuteration of BTZ043 extends the lifetime of meisenheimer intermediates to the antituberculosis nitroso oxidation state. ACS Med. Chem. Lett., 2019, vol. 10, no. 10, pp. 1462-1466.Liu R., Lyu X., Batt S. M., Hsu M.-H., Harbut M. B., Vilcheze' C., ChengB., AjayiK., Yang B., Yang Y., Guo H., Lin C., Gan F., Wang C., Franzblau S.G., Jacobs W.R.Jr., Besra G. S., Johnson E. F., Petrassi M., Chatterjee A. K., Fütterer K., Wang, F. Determinants of the inhibition of DprE1 and CYP2C9 by antitubercular thiophenes // Angew. Chem., Int. Ed. ‒ 2017. ‒ № 56. ‒ Р. 13011-13015.Liu R., Lyu X., Batt S.M., Hsu M.-H., Harbut M.B., Vilcheze ' C., ChengB., AjayiK., Yang B., Yang Y., Guo H., Lin C., Gan F., Wang C., FranzblauS.G., JacobsW.R.Jr., Besra G.S., Johnson E.F., Petrassi M., Chatterjee A.K., FüttererK., Wang, F. Determinants of the inhibition of DprE1 and CYP2C9 by antitubercular thiophenes. Angew. Chem. Int. Ed., 2017, no. 56, pp. 13011-13015.Lupien A., Vocat A., Foo C. S.-Y., Blattes E., Gillon J.-Y., Makarov V., ColeS.T. Optimized background regimen for treatment of active tuberculosis with the next-generation benzothiazinone macozinone (PBTZ169) // Antimicrob. Agents Chemother. ‒ 2018. ‒ № 62. ‒ Р. e00840-e008418.Lupien A., Vocat A., Foo C. S.-Y., Blattes E., Gillon J.-Y., Makarov V., Cole S.T. Optimized background regimen for treatment of active tuberculosis with the next-generation benzothiazinone macozinone (PBTZ169). Antimicrob. Agents Chemother., 2018, no. 62, pp. e00840-e008418.Lv K., You X., Wang B., Wei Z., Chai Y., Wang B., Wang A., Huang G., Liu M., LuY. Identification of better pharmacokinetic benzothiazinone derivatives as new antitubercular agents // ACS Med. Chem. Lett. ‒ 2017. ‒ Vol. 8, №6. ‒ Р. 636-641.Lv K., You X., Wang B., Wei Z., Chai Y., Wang B., Wang A., Huang G., Liu M., LuY. Identification of better pharmacokinetic benzothiazinone derivatives as new antitubercular agents. ACS Med. Chem. Lett., 2017, vol. 8, no. 6, pp. 636-641.Ma X., Han B., Gu J., Yang L., Lv K., Wang A., Zhang K., Huang M., ChowdhuryK. Identification of benzothiazones containing a hexahydropyrrolo[3,4-c]pyrrol moiety as antitubercular agents against MDR-MTB // RSC Advances. ‒ 2020.‒ Vol. 10, № 24. ‒ Р. 14410-14414.Ma X., Han B., Gu J., Yang L., Lv K., Wang A., Zhang K., Huang M., Chowdhury K. Identification of benzothiazones containing a hexahydropyrrolo[3,4-c]pyrrol moiety as antitubercular agents against MDR-MTB. RSC Advances, 2020, vol. 10, no. 24, pp. 14410-14414.Madikizela B., Eckhardt T., Goddard R., Richter A., Lins A., Lehmann C., Imming P., Seidel R. W. Synthesis, structural characterization and antimycobacterial evaluation of several halogenated non-nitro benzothiazinones // Med. Chem. Res. ‒ 2021. ‒ Р. 1-11.Madikizela B., Eckhardt T., Goddard R., Richter A., Lins A., Lehmann C., Imming P., Seidel R.W. Synthesis, structural characterization and antimycobacterial evaluation of several halogenated non-nitro benzothiazinones. Med. Chem. Res., 2021, pp. 1-11.Makarov V., Lechartier B., Zhang M., Neres J., van der Sar A. M., RaadsenS.A., Hartkoorn R. C., Ryabova O. B., Vocat A., Decosterd L. A., Widmer N., Buclin T., Bitter W., Andries K., Pojer F., Dyson P. J., Cole S. T. Towards a new combination therapy for tuberculosis with next generation benzothiazinones // EMBO Mol. Med. ‒ 2014. ‒ № 3. ‒ Р. 372-383.Makarov V., Lechartier B., Zhang M., Neres J., van der Sar A.M., Raadsen S.A., Hartkoorn R.C., Ryabova O.B., Vocat A., Decosterd L.A., Widmer N., Buclin T., Bitter W., Andries K., Pojer F., Dyson P.J., Cole S.T. Towards a new combination therapy for tuberculosis with next generation benzothiazinones. EMBO Mol. Med., 2014, no. 3, pp. 372-383.Makarov V., Manina G., Mikusova K., Möllmann U., Ryabova O., Saint-JoanisB., Dhar N., Pasca M. R., Buroni S., Lucarelli A. P., Milano A., De Rossi E., BelanovaM., Bobovska A., Dianiskova P., Kordulakova J., Sala C., Fullam E., Schneider P., McKinney J. D., Brodin P., Christophe T., Waddell S., ButcherP., Albrethsen J., Rosenkrands I., Brosch R., Nandi V., Bharath S., Gaonkar S., Shandil R. K., Balasubramanian V., Balganesh T., Tyagi S., Grosset J., RiccardiG., Cole S. T. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis // Science. ‒ 2009. ‒ Vol. 324 (5928). ‒ Р. 801-804.Makarov V., Manina G., Mikusova K., Möllmann U., Ryabova O., Saint-JoanisB., Dhar N., Pasca M.R., Buroni S., Lucarelli A.P., Milano A., De Rossi E., BelanovaM., Bobovska A., Dianiskova P., Kordulakova J., Sala C., Fullam E., Schneider P., McKinney J.D., Brodin P., Christophe T., Waddell S., ButcherP., Albrethsen J., Rosenkrands I., Brosch R., Nandi V., Bharath S., Gaonkar S., Shandil R.K., Balasubramanian V., Balganesh T., Tyagi S., Grosset J., RiccardiG., Cole S.T. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science, 2009, vol. 324 (5928), pp. 801-804.Makarov V., Mikušová K. Development of Macozinone for TB treatment: AnUpdate // Appl. Sci. ‒ 2020. ‒ № 10. ‒ Р. 2269.Makarov V., Mikušová K. Development of Macozinone for TB treatment: AnUpdate. Appl. Sci., 2020, no. 10, pp. 2269.Makarov V., Neres J., Hartkoorn R. C., Ryabova O. B., Kazakova E., ŠarkanM., Huszár S., Piton J., Kolly G. S., Vocat A., Conroy T. M., Mikušová K., ColeS.T. The 8-pyrrole-benzothiazinones are noncovalent inhibitors of DprE1 from Mycobacterium tuberculosis // Antimicrob. Agents Chemother. ‒ 2015.‒ №59.‒ Р. 4446-4452.Makarov V., Neres J., Hartkoorn R.C., Ryabova O.B., Kazakova E., Šarkan M., Huszár S., Piton J., Kolly G.S., Vocat A., Conroy T.M., Mikušová K., Cole S.T. The 8-pyrrole-benzothiazinones are noncovalent inhibitors of DprE1 from Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2015, no. 59, pp. 4446-4452.Manina G., Pasca M. R., Buroni S., De Rossi E., Riccardi G. Decaprenylphosphoryl-β-D-ribose 2'-epimerase from Mycobacterium tuberculosis is a magic drug targe // Curr. Med. Chem. ‒ 2010. ‒ Vol. 17, №27.‒ Р. 3099-30108.Manina G., Pasca M.R., Buroni S., De Rossi E., Riccardi G. Decaprenylphosphoryl-β-D-ribose 2'-epimerase from Mycobacterium tuberculosis is a magic drug targe. Curr. Med. Chem., 2010, vol. 17, no. 27, pp. 3099-30108.Manjunatha M. R., Shandil R., Panda M., Sadler C., Ambady A., PandugaV., Kumar N., Mahadevaswamy J., Sreenivasaiah M., Narayan A., Guptha S., SharmaS., Sambandamurthy V. K., Ramachandran V., Mallya M., CooperC., Mdluli K., Butler S., Tommasi R., Iyer P. S., Narayanan S., Chatterji M., ShirudeP.S. Scaffold morphing to identify novel DprE1 inhibitors with antimycobacterial activity // ACS Med. Chem. Lett. ‒ 2019. ‒ Vol. 10, № 10.‒ Р. 1480-1485.Manjunatha M.R., Shandil R., Panda M., Sadler C., Ambady A., PandugaV., Kumar N., Mahadevaswamy J., Sreenivasaiah M., Narayan A., Guptha S., SharmaS., Sambandamurthy V.K., Ramachandran V., Mallya M., Cooper C., Mdluli K., Butler S., Tommasi R., Iyer P.S., Narayanan S., Chatterji M., ShirudeP.S. Scaffold morphing to identify novel DprE1 inhibitors with antimycobacterial activity. ACS Med. Chem. Lett., 2019, vol. 10, no. 10, pp. 1480-1485.Mikusová K., Makarov V., Neres J. DprE1 – from the discovery to the promising tuberculosis drug target // Curr. Pharm. Des. ‒ 2014. ‒ Vol. 20, №27. ‒ Р. 4379-4403.Mikusová K., Makarov V., Neres J. DprE1 – from the discovery to the promising tuberculosis drug target. Curr. Pharm. Des., 2014, vol. 20, no. 27, pp. 4379-4403.Panda M., Ramachandran S., Ramachandran V, Shirude P. S., HumnabadkarV., Nagalapur K., Sharma S., Kaur P., Guptha S., Narayan A., MahadevaswamyJ., Ambady A., Hegde N., Rudrapatna S. S., HosagraharaV.P., SambandamurthyV.K., Raichurkar A. Discovery of pyrazolopyridones as a novel class of noncovalent DprE1 inhibitor with potent anti-mycobacterial activity // J. Med. Chem. ‒ 2014. ‒ № 57. ‒ Р. 4761-4771.Panda M., Ramachandran S., Ramachandran V, Shirude P.S., Humnabadkar V., Nagalapur K., Sharma S., Kaur P., Guptha S., Narayan A., Mahadevaswamy J., Ambady A., Hegde N., Rudrapatna S.S., Hosagrahara V.P., SambandamurthyV.K., Raichurkar A. Discovery of pyrazolopyridones as a novel class of noncovalent DprE1 inhibitor with potent anti-mycobacterial activity. J. Med. Chem., 2014, no. 57, pp. 4761-4771.Patel A., Redinger N., Richter A., Woods A., Neumann P. R., Keegan G., Childerhouse N., Imming P., Schaible U. E., Forbes B., Dailey L. A. In vitro and in vivo antitubercular activity of benzothiazinone-loaded human serum albumin nanocarriers designed for inhalation // J. Control. Release. ‒ 2020. ‒ №328. ‒ Р. 339-349.Patel A., Redinger N., Richter A., Woods A., Neumann P.R., Keegan G., Childerhouse N., Imming P., Schaible U.E., Forbes B., Dailey L.A. In vitro and in vivo antitubercular activity of benzothiazinone-loaded human serum albumin nanocarriers designed for inhalation. J. Control Release, 2020, no. 328, pp. 339-349.Piton J., Vocat A., Lupien A., Foo C. S., Riabova O., Makarov V., Cole S. T. Structure-based drug design and characterization of sulfonyl-piperazine benzothiazinone inhibitors of DprE1 from Mycobacterium tuberculosis // Antimicrob. Agents Chemother. ‒ 2018. ‒ Vol. 62, № 10. ‒ Р. e00681-e006818.Piton J., Vocat A., Lupien A., Foo C.S., Riabova O., Makarov V., Cole S.T. Structure-based drug design and characterization of sulfonyl-piperazine benzothiazinone inhibitors of DprE1 from Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2018, vol. 62, no. 10, pp. e00681-e006818.Piton J., Foo C. S., Cole S. T. Structural studies of Mycobacterium tuberculosis DprE1 interacting with its inhibitors // Drug. Discov. Today. ‒ 2017. ‒ Vol. 22, № 3. ‒ Р. 526-533.Piton J., Foo C.S., Cole S.T. Structural studies of Mycobacterium tuberculosis DprE1 interacting with its inhibitors. Drug. Discov. Today, 2017, vol. 22, no. 3, pp. 526-533.Riccardi G., Pasca M. R., Chiarelli L. R., Manina G., Mattevi A., Binda C. The DprE1 enzyme, one of the most vulnerable targets of Mycobacterium tuberculosis // Appl. Microbiol. Biotechnol. ‒ 2013. ‒ № 97. ‒ Р. 8841-8848.Riccardi G., Pasca M.R., Chiarelli L.R., Manina G., Mattevi A., Binda C. The DprE1 enzyme, one of the most vulnerable targets of Mycobacterium tuberculosis. Appl. Microbiol. Biotechnol., 2013, no. 97, pp. 8841-8848.Richter A., Goddard R., Schlegel T., Imming P., Seidel R. W. 2-Chloro-3-nitro-5-(tri-fluoro-meth-yl)benzoic acid and -benzamide: structural characterization of two precursors for anti-tubercular benzothiazinones // Acta Crystallogr. E Crystallogr. Commun. ‒ 2021. ‒ Vol. 77 (Pt 2). ‒ Р. 142-147.Richter A., Goddard R., Schlegel T., Imming P., Seidel R.W. 2-Chloro-3-nitro-5-(tri-fluoro-meth-yl)benzoic acid and -benzamide: structural characterization of two precursors for anti-tubercular benzothiazinones. Acta Crystallogr. E Crystallogr. Commun., 2021, vol. 77 (Pt 2), pp. 142-147.Richter A., Rudolph I., Möllmann U., Voigt K., Chung C. W., Singh O. M.P., Rees M., Mendoza-Losana A., Bates R., Ballell L., Batt S., Veerapen N., FüttererK., Besra G., Imming P., Argyrou A. Novel insight into the reaction of nitro, nitroso and hydroxylamino benzothiazinones and of benzoxacinones with Mycobacterium tuberculosis DprE1 // Sci. Rep. ‒ 2018. ‒ Vol. 8, № 1. ‒ Р. 13473.Richter A., Rudolph I., Möllmann U., Voigt K., Chung C.W., Singh O.M.P., Rees M., Mendoza-Losana A., Bates R., Ballell L., Batt S., Veerapen N., FüttererK., Besra G., Imming P., Argyrou A. Novel insight into the reaction of nitro, nitroso and hydroxylamino benzothiazinones and of benzoxacinones with Mycobacterium tuberculosis DprE1. Sci. Rep., 2018, vol. 8, no. 1, pp. 13473.Rogacki M. K., Pitta E., Balabon O., Huss S., Lopez-Roman E. M., ArgyrouA., Blanco-Ruano D., Cacho M., Vande Velde C. M. L.,0 Augustyns K., BallellL., Barros D., Bates R. H., Cunningham F., Van der Veken P. Identification and profiling of hydantoins a novel class of potent antimycobacterial DprE1 inhibitors // J. Med. Chem. ‒ 2018. ‒ № 61. ‒ Р. 11221-112490.Rogacki M.K., Pitta E., Balabon O., Huss S., Lopez-Roman E.M., ArgyrouA., Blanco-Ruano D., Cacho M., Vande Velde C.M.L., Augustyns K., BallellL., Barros D., Bates R.H., Cunningham F., Van der Veken P. Identification and profiling of hydantoins a novel class of potent antimycobacterial DprE1 inhibitors. J. Med. Chem., 2018, no. 61, pp. 11221-112490.Shi J., Lu J., Wen S., Zong Z., Huo F., Luo J., Liang Q., Li Y., Huang H., PangY. In vitro activity of PBTZ169 against multiple Mycobacterium species // Antimicrob. Agents Chemother. ‒ 2018. ‒ № 62. ‒ Р. e01314- e013118.Shi J., Lu J., Wen S., Zong Z., Huo F., Luo J., Liang Q., Li Y., Huang H., PangY. Invitro activity of PBTZ169 against multiple Mycobacterium species. Antimicrob. Agents Chemother., 2018, no. 62, pp. e01314- e013118.Shirude P. S., Shandil R., Sadler C., Naik M., Hosagrahara V., HameedS., ShindeV., Bathula C., Humnabadkar V., Kumar N., Reddy J., PandugaV., Sharma S., AmbadyA., Hegde N., Whiteaker J., McLaughlin R. E., GardnerH., MadhavapeddiP., Ramachandran V., Kaur P., Narayan A., Guptha S., AwasthyD., Narayan C., Mahadevaswamy J., Vishwas K. G., Ahuja V., SrivastavaA., PrabhakarK.R., Bharath S., Kale R., Ramaiah M., ChoudhuryN.R., Sambandamurthy V. K., Solapure S., Iyer P. S., Narayanan S., Chatterji M. Azaindoles: noncovalent DprE1 inhibitors from scaffold morphing efforts, kill Mycobacterium tuberculosis and are efficacious in vivo // J. Med. Chem. ‒ 2013.‒ Vol. 56, № 23. ‒ Р. 9701-9708.Shirude P.S., Shandil R., Sadler C., Naik M., Hosagrahara V., Hameed S., Shinde V., Bathula C., Humnabadkar V., Kumar N., Reddy J., Panduga V., Sharma S., Ambady A., Hegde N., Whiteaker J., McLaughlin R.E., GardnerH., MadhavapeddiP., Ramachandran V., Kaur P., Narayan A., Guptha S., AwasthyD., Narayan C., Mahadevaswamy J., Vishwas K.G., Ahuja V., Srivastava A., Prabhakar K.R., Bharath S., Kale R., Ramaiah M., Choudhury N.R., Sambandamurthy V.K., Solapure S., Iyer P.S., Narayanan S., Chatterji M. Azaindoles: noncovalent DprE1 inhibitors from scaffold morphing efforts, kill Mycobacterium tuberculosis and are efficacious in vivo. J. Med. Chem., 2013, vol. 56, no. 23, pp. 9701-9708.Suma K. B., Kumari А., Shetty D., Fernandes E., Chethan D. V., Jays J., Murahari М. Structure based pharmacophore modelling approach for the design of azaindole derivatives as DprE1 inhibitors for tuberculosis // J. Molec. Graph. Model. ‒ 2020. ‒ № 101. ‒ Р. 107718.Suma K.B., Kumari А., Shetty D., Fernandes E., Chethan D.V., Jays J., Murahari М. Structure based pharmacophore modelling approach for the design of azaindole derivatives as DprE1 inhibitors for tuberculosis. J. Molec. Graph. Model., 2020, no. 101, pp. 107718.Tiwari R., Miller P. A., Chiarelli L. R., Mori G., Šarkan M., Centárová I., Cho S., Mikušová K., Franzblau S. G., Oliver A. G., Miller M. J. Design, Syntheses, and Anti-TB Activity of 1,3-Benzothiazinone Azide and Click Chemistry Products Inspired by BTZ043 // ACS Med. Chem Lett. ‒ 2016. ‒ Vol. 7, № 3. ‒ Р. 266-270.Tiwari R., Miller P.A., Chiarelli L.R., Mori G., Šarkan M., Centárová I., Cho S., Mikušová K., Franzblau S.G., Oliver A.G., Miller M.J. Design, Syntheses, and Anti-TB Activity of 1,3-Benzothiazinone Azide and Click Chemistry Products Inspired by BTZ043. ACS Med. Chem Lett., 2016, vol. 7, no. 3, pp. 266-270.Tiwari R., Miller P. A., Cho S., Franzblau S. G., Miller M. J. Syntheses and Antituberculosis Activity of 1,3-Benzothiazinone Sulfoxide and Sulfone Derived from BTZ043 // ACS Med. Chem. Lett. ‒ 2014. ‒ Vol. 6, № 2. ‒ Р. 128-133.Tiwari R., Miller P.A., Cho S., Franzblau S.G., Miller M.J. Syntheses andAntituberculosis Activity of 1,3-Benzothiazinone Sulfoxide and Sulfone Derived from BTZ043. ACS Med. Chem. Lett., 2014, vol. 6, no. 2, pp. 128-133.Tiwari R., Möllmann U., Cho S., Franzblau S. G., Miller P. A., Miller M. J. Design and syntheses of anti-tuberculosis agents inspired by BTZ043 using a scaffold simplification strategy // ACS Med. Chem. Lett. ‒ 2014. ‒ Vol. 5, №5.‒ Р. 587-591. doi: 10.1021/ml500039g.Tiwari R., Möllmann U., Cho S., Franzblau S.G., Miller P.A., Miller M.J. Design and syntheses of anti-tuberculosis agents inspired by BTZ043 using a scaffold simplification strategy. ACS Med. Chem. Lett., 2014, vol. 5, no. 5, pp. 587-591. doi: 10.1021/ml500039g.Tiwari R., Moraski G. C., Krchňák V., Miller P. A., Colon-Martinez M., HerreroE., Oliver A. G., Miller M. J. Thiolates chemically induce redox activation of BTZ043 and related potent nitroaromatic anti-tuberculosis agents // J. Am. Chem. Soc. ‒ 2013. ‒ Vol. 135, № 9. ‒ Р. 3539-3549. doi: 10.1021/ja311058q.Tiwari R., Moraski G.C., Krchňák V., Miller P.A., Colon-Martinez M., HerreroE., Oliver A.G., Miller M.J. Thiolates chemically induce redox activation of BTZ043 and related potent nitroaromatic anti-tuberculosis agents. J. Am. Chem. Soc., 2013, vol. 135, no. 9, pp. 3539-3549. doi: 10.1021/ja311058q.Trefzer C., Škovierová H., Buroni S., Bobovská A., Nenci S., Molteni E., PojerF., Pasca M. R., Makarov V., Cole S. T., Riccardi G., Mikušová K., Johnsson K. Benzothiazinones are suicide inhibitors of mycobacterial decaprenylphospho ryl-β-D-ribofuranose 2'-oxidase DprE1 // J. Am. Chem. Soc. ‒ 2012. ‒ Vol. 134, № 2. ‒ Р. 912-915. doi: 10.1021/ja211042r.Trefzer C., Škovierová H., Buroni S., Bobovská A., Nenci S., Molteni E., PojerF., Pasca M.R., Makarov V., Cole S.T., Riccardi G., Mikušová K., Johnsson K. Benzothiazinones are suicide inhibitors of mycobacterial decaprenylphospho ryl-β-D-ribofuranose 2'-oxidase DprE1. J. Am. Chem. Soc., 2012, vol. 134, no. 2, pp. 912-915. doi: 10.1021/ja211042r.Wang P., Batt S. M., Wang B., Fu L., Qin R., Lu Y., Li G., Besra G. S., HuangH. Discovery of novel thiophene-arylamide derivatives as DprE1 Inhibitors with potent antimycobacterial activities // J. Med. Chem. ‒ 2021. ‒ Vol. 64, № 9. ‒ Р. 6241-6261. doi: 10.1021/acs.jmedchem.1c00263.Wang P., Batt S.M., Wang B., Fu L., Qin R., Lu Y., Li G., Besra G.S., HuangH. Discovery of novel thiophene-arylamide derivatives as DprE1 Inhibitors with potent antimycobacterial activities. J. Med. Chem., 2021, vol. 64, no. 9, pp. 6241-6261. doi: 10.1021/acs.jmedchem.1c00263.Xiong L., Gao C., Shi Y. J., Tao X., Rong J., Liu K. L., Peng C. T., Lei Q., Zhang Y. W., Yu L. T., Wei Y. Q., Wang N. Y. Identification of a new series of benzothiazinone derivatives with excellent antitubercular activity and improved pharmacokinetic profiles // RSC Advances. ‒ 2018. ‒ Vol. 8, № 20. ‒ Р. 11163-11176.Xiong L., Gao C., Shi Y.J., Tao X., Rong J., Liu K.L., Peng C.T., Lei Q., Zhang Y.W., Yu L.T., Wei Y.Q., Wang N.Y. Identification of a new series of benzothiazinone derivatives with excellent antitubercular activity and improved pharmacokinetic profiles. RSC Advances, 2018, vol. 8, no. 20, pp. 11163-11176.Zhang G., Aldrich C. C., Howe M. Spirocyclic and bicyclic 8 nitrobenzothiazinones for tuberculosis with improved physicochemical and pharmacokinetic properties // ACS Med. Chem. Letters. ‒ 2019. ‒ Vol. 10, №3. ‒ Р. 348-351.Zhang G., Aldrich C.C., Howe M. Spirocyclic and bicyclic 8 nitrobenzo thiazinones for tuberculosis with improved physicochemical and pharmacokinetic properties. ACS Med. Chem. Letters, 2019, vol. 10, no. 3, pp. 348-351.Zhang G., Guo S., Cui H., Qi J. Virtual screening of small molecular inhibitors against DprE1 // Molecules. ‒ 2018. ‒ Vol. 23, № 3. ‒ Р. 524. doi: 10.3390/molecules23030524.Zhang G., Guo S., Cui H., Qi J. Virtual screening of small molecular inhibitors against DprE1. Molecules, 2018, vol. 23, no. 3, pp. 524. doi: 10.3390/molecules23030524.

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