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Synthesis and activity of (+)-usnic acid and (−)-usnic acid derivatives containing 1,3-thiazole cycle against Mycobacterium tuberculosis

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Abstract

New usnic acid (UA) derivatives were investigated in vitro to elucidate their potential inhibitory activities on the growth of Mycobacterium smegmatis and Mycobacterium tuberculosis. Seven pairs of enantiomers of thiazole UA derivatives were tested using the M. smegmatis strain mc2 155 test system, and the “structure–activity” relationship was established. The most active compounds were (+)-3 and (−)-3, and their kinase inhibitory activities were investigated. The results obtained using the Streptomyces lividans APHVIII+ and M. smegmatis APHVIII+ test systems indicated the significant protein kinase activity of these compounds and revealed the species specificity of the actions of the dextro- and levorotatory isomers. Both isomers, (+)-3 and (−)-3, possess similar inhibitory activity against M. tuberculosis H37Rv. The action of the isomers on eukaryotic cells was also investigated, and the results demonstrate that the dextrorotatory isomer (+)-3 leads to the lysis of intact macrophages to a degree higher than that obtained spontaneously and significantly higher than that obtained with the levorotatory isomer.

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References

  • Andries K, Verhasselt P, Guillemont J, Göhlmann HW, Neefs JM, Winkler H, Van Gestel J, Timmerman P, Zhu M, Lee E, Williams P, de Chaffoy D, Huitric E, Hoffner S, Cambau E, Truffot-Pernot C, Lounis N, Jarlier V (2005) A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307(5707):223–227

    Article  CAS  PubMed  Google Scholar 

  • Balabanova Y, Radiulyte B, Davidaviciene E, Hooper R, Ignatyeva O, Nikolayevskyy V, Drobniewski FA (2011) Survival of drug resistant tuberculosis patients in Lithuania: retrospective national cohort study. Br Med J Open 1:e000351. doi:10.1136/bmjopen-2011-000351

    Google Scholar 

  • Bekker OB, Elizarov SM, Alekseeva MT, Lyubimova IK, Danilenko VN (2008) Ca2+-dependent modulation of antibiotic resistance in Streptomyces lividans 66 and Streptomyces coelicolor A3 (2). Microbiology 77:559–567

    Article  CAS  Google Scholar 

  • Bekker OB, Alekseeva MG, Osolodkin DI, Palyulin VA, Elizarov SM, Zefirov NS, Danilenko VN (2010) New test system for serine/threonine protein kinase inhibitors screening: E. coli APHVIII/Pk25 design. Acta Nat 2:110–121

    CAS  Google Scholar 

  • Blokpoel MCJ, Murphy HN, O’Toole R, Wiles S, Runn ESC, Stewart GR, Young DB, Robertson BD (2005) Tetracycline-inducible gene regulation in mycobacteria. Nucleic Acids Res 33:e22. doi:10.1093/nar/gni023

    Article  PubMed Central  PubMed  Google Scholar 

  • Casali N, Nikolayevskyy V, Balabanova Y, Ignatyeva O, Kontsevaya I, Harris SR, Bentley SD, Parkhill J, Nejentsev S, Hoffner SE, Horstmann RD, Brown T, Drobniewski F (2012) Microevolution of extensively drug-resistant tuberculosis in Russia. Genome Res 22:735–745

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cetin H, Tufan-Cetin O, Turk AO, Tay T, Candan M, Yanikoglu A, Sumbul H (2008) Insecticidal activity of major lichen compounds, (−)- and (+)-usnic acid, against the larvae of house mosquito, Culex pipiens L. Parasitol Res 102:1277–1279

    Article  PubMed  Google Scholar 

  • Cocchietto M, Skert N, Nimis P, Sava G (2002) A review on usnic acid, an interesting natural compound. Naturwissenschaften 89:137–146

    Article  CAS  PubMed  Google Scholar 

  • Danilenko V, Simonov A, Lakatosh S, Kubbutat M, Totzke F, Schaechtele C, Elizarov S, Bekker O, Printsevskaya S, Luzikov Y, Reznikova M, Shtil A, Preobrazhenskaya M (2008) Search for inhibitors of bacterial and human protein kinases among derivatives of diazepines[1,4] annelated with maleimide and indole cycles. J Med Chem 51:7731–7736

    Article  CAS  PubMed  Google Scholar 

  • Danilenko VN, Osolodkin DI, Lakatosh SA, Preobrazhenskaya MN, Shtil AA (2011) Bacterial eukaryotic type serine–threonine protein kinases: from structural biology to targeted anti-infective drug design. Curr Top Med Chem 11:1352–1369

    Article  CAS  PubMed  Google Scholar 

  • Dover LG, Coxon GD (2011) Current status and research strategies in tuberculosis drug development: miniperspective. J Med Chem 54:6157–6165

    Article  CAS  PubMed  Google Scholar 

  • Elizarov SM, Alekseeva MG, Novikov FN, Chilov GG, Maslov DA, Shtil AA, Danilenko VN (2012) Identification of phosphorylation sites in aminoglycoside phosphotransferase VIII from Streptomyces rimosus. Biochemistry (Mosc) 77:1258–1265. doi:10.1134/S0006297912110041

    Article  CAS  Google Scholar 

  • Forrellad MA, Klepp LI, Gioffre A, Sabio y García GJ, Morbidoni HR, de la Paz Santangelo M, Cataldi AA, Bigi F (2013) Virulence factors of the Mycobacterium tuberculosis complex. Virulence 4:3–66

    Article  PubMed Central  PubMed  Google Scholar 

  • Honda NK, Pavan FR, Coelho RG, De Andrade Leite SR, Micheletti C, Lopes TIB, Misutsu MY, Beatriz A, Brum RL, Leite CQF (2010) Antimycobacterial activity of lichen substances. Phytomedicine 17:328–332

    Article  CAS  PubMed  Google Scholar 

  • Koul A, Arnoult E, Lounis N, Guillemont J, Andries K (2011) The challenge of new drug discovery for tuberculosis. Nature 469:483–490

    Article  CAS  PubMed  Google Scholar 

  • Leibert E, Danckers M, Rom WN (2014) New drugs to treat multidrug-resistant tuberculosis: the case for bedaquiline. Ther Clin Risk Manag 10:597–602. doi:10.2147/TCRM.S37743 eCollection

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liao JJ (2007) Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. J Med Chem 50:409–424

    Article  CAS  PubMed  Google Scholar 

  • Luzina OA, Sokolov DN, Shernyukov AV, Salakhutdinov NF (2012) Synthesis of aurones based on usninic acid. Chem Nat Compd 48:385–391

    Article  CAS  Google Scholar 

  • Matyugina E, Khandazhinskaya A, Chernousova L, Andreevskaya S, Smirnova T, Chizhov A, Karpenko I, Kochetkov S, Alexandrova L (2012) The synthesis and antituberculosis activity of 5′-nor carbocyclic uracil derivatives. Bioorg Med Chem 20:6680–6686

    Article  CAS  PubMed  Google Scholar 

  • Meissner A, Boshoff HI, Vasan M, Duckworth BP, Barry CE III, Aldrich CC (2013) Structure–activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis. Bioorg Med Chem 21:6385–6397

    Article  CAS  PubMed  Google Scholar 

  • Polovinka MP, Salakhutdinov NF, Panchenko MY (2008) Russian Federation Patent 2317076

  • Prozorov AA, Zaichikova MV, Danilenko VN (2012) Mycobacterium tuberculosis mutants with multidrug resistance: history of origin, genetic and molecular mechanisms of resistance, and emerging challenges. Russ J Genet 48(1):1–14

    Article  CAS  Google Scholar 

  • Ramón-García S, Ng C, Anderson H, Chao JD, Zheng X, Pfeifer T, Av-Gay Y, Roberge M, Thompson CJ (2011) Synergistic drug combinations for tuberculosis therapy identified by a novel high-throughput screen. Antimicrob Agents Chemother 55:3861–3869

    Article  PubMed Central  PubMed  Google Scholar 

  • Riccardi G, Pasca MR (2014) Trends in discovery of new drugs for tuberculosis therapy. J Antibiot (Tokyo) 67(9):655–659. doi:10.1038/ja.2014.109

    Article  CAS  Google Scholar 

  • Siddiqi SH (2005) MGIT procedure manual for BACTEC MGIT 960 TB system. Becton Dickinson, Sparks, pp 81–84

    Google Scholar 

  • Sokolov DN, Luzina OA, Salakhutdinov NF (2012) Usnic acid: preparation, structure, properties and chemical transformations. Russ Chem Rev 81:747–768

    Article  CAS  Google Scholar 

  • Thakur M, Chakraborti PK (2006) GTPase activity of mycobacterial FtsZ is impaired due to its transphosphorylation by the eukaryotic-type Ser/Thr kinase, PknA. J Biol Chem 281:40107–40113

    Article  CAS  PubMed  Google Scholar 

  • Udwadia ZF (2012) MDR, XDR, TDR tuberculosis: ominous progression. Thorax 67:286–288

    Article  PubMed  Google Scholar 

  • World Health Organization (2012) Global Tuberculosis Report

  • Zakharevich NV, Osolodkin DI, Artamonova II, Palyulin VA, Zefirov NS, Danilenko VN (2012) Signatures of the ATP-binding pocket as a basis for structural classification of the serine/threonine protein kinases of gram-positive bacteria. Proteins 80:1363–1376

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Yew WW (2009) Mechanisms of drug resistance in Mycobacterium tuberculosis. Int J Tuberc Lung Dis 13:1320–1330

    CAS  PubMed  Google Scholar 

  • Zumla AI, Gillespie SH, Hoelscher M, Philips PP, Cole ST, Abubakar I, McHugh TD, Schito M, Maeurer M, Nunn AJ (2014) New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospects. Lancet Infect Dis 14(4):327–340. doi:10.1016/S1473-3099(13)70328-1

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by the Russian Foundation for Basic Research (Grant No. 13-03-00810) and Russia Federation Contract 2012 No. 12411.1008799.13.002.

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Authors and Affiliations

  1. Vavilov Institute of General Genetics, Russian Academy of Sciences, Gubkin str., 3, 119991, Moscow, Russia

    Olga B. Bekker, Dmitry A. Maslov & Valery. N. Danilenko

  2. N. N. Vorozhtzov Novosibirsk Institute of Organic Chemistry of the Siberian Branch of Russian Academy of Sciences, Lavrent’eva ave., 9, 630090, Novosibirsk, Russia

    Dmitry N. Sokolov, Olga A. Luzina, Nina I. Komarova, Yuriy V. Gatilov & Nariman F. Salakhutdinov

  3. Federal State Budgetary Institution “Central Tuberculosis Research Institute” under the Russian Academy of Medical Sciences, Yauzskaya alley, 2, 107564, Moscow, Russia

    Sofia N. Andreevskaya, Tatiana G. Smirnova & Larisa N. Chernousova

Authors
  1. Olga B. Bekker
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  2. Dmitry N. Sokolov
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  3. Olga A. Luzina
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  4. Nina I. Komarova
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  5. Yuriy V. Gatilov
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  6. Sofia N. Andreevskaya
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  7. Tatiana G. Smirnova
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  8. Dmitry A. Maslov
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  9. Larisa N. Chernousova
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  10. Nariman F. Salakhutdinov
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  11. Valery. N. Danilenko
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Corresponding author

Correspondence to Olga A. Luzina.

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Bekker, O.B., Sokolov, D.N., Luzina, O.A. et al. Synthesis and activity of (+)-usnic acid and (−)-usnic acid derivatives containing 1,3-thiazole cycle against Mycobacterium tuberculosis . Med Chem Res 24, 2926–2938 (2015). https://doi.org/10.1007/s00044-015-1348-2

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