Skip to main content

Advertisement

SpringerLink
Log in

Thieno[2,3-b]pyridine derivatives: a new class of antiviral drugs against Mayaro virus

  • Original Article
  • Published:
Archives of Virology Aims and scope Submit manuscript

Abstract

Mayaro virus (MAYV) is an arthropod-borne virus and a member of the family Togaviridae, genus Alphavirus. Its infection leads to an acute illness accompanied by long-lasting arthralgia. To date, there are no antiviral drugs or vaccines against infection with MAYV and resources for the prevention or treatment of other alphaviruses are very limited. MAYV has served as a model to study the antiviral potential of several substances on alphavirus replication. In this work we evaluated the antiviral effect of seven new derivatives of thieno[2,3-b]pyridine against MAYV replication in a mammalian cell line. All derivatives were able to reduce viral production effectively at concentrations that were non-toxic for Vero cells. Molecular modeling assays predicted low toxicity risk and good oral bioavailability of the substances in humans. One of the molecules, selected for further study, demonstrated a strong anti-MAYV effect at early stages of replication, as it protected pre-treated cells and also during the late stages, affecting virus morphogenesis. This study is the first to demonstrate the antiviral effect of thienopyridine derivatives on MAYV replication in vitro, suggesting the potential application of these substances as antiviral molecules against alphaviruses. Additional in vivo research will be needed to expand the putative therapeutic applications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Marcondes CB, Ximenes MF (2015) Zika virus in Brazil and the danger of infestation by Aedes (Stegomyia) mosquitoes. Rev Soc Bras Med Trop. doi:10.1590/0037-8682-0220-2015

    PubMed  Google Scholar 

  2. Figueiredo ML, Figueiredo LT (2014) Emerging alphaviruses in the Americas: Chikungunya and Mayaro. Rev Soc Bras Med Trop 47(6):677–683. doi:10.1590/0037-8682-0246-2014

    Article  PubMed  Google Scholar 

  3. Tesh RB, Watts DM, Russell KL, Damodaran C, Calampa C, Cabezas C, Ramirez G, Vasquez B, Hayes CG, Rossi CA, Powers AM, Hice CL, Chandler LJ, Cropp BC, Karabatsos N, Roehrig JT, Gubler DJ (1999) Mayaro virus disease: an emerging mosquito-borne zoonosis in tropical South America. Clin Infect Dis 28(1):67–73. doi:10.1086/515070

    Article  CAS  PubMed  Google Scholar 

  4. Long KC, Ziegler SA, Thangamani S, Hausser NL, Kochel TJ, Higgs S, Tesh RB (2011) Experimental transmission of Mayaro virus by Aedes aegypti. Am J Trop Med Hyg 85(4):750–757. doi:10.4269/ajtmh.2011.11-0359

    Article  PubMed  PubMed Central  Google Scholar 

  5. Vasconcelos PF, Calisher CH (2016) Emergence of human arboviral diseases in the Americas, 2000–2016. Vector Borne Zoonotic Dis 16(5):295–301. doi:10.1089/vbz.2016.1952

    Article  PubMed  Google Scholar 

  6. Vieira CJ, Silva DJ, Barreto ES, Siqueira CE, Colombo TE, Ozanic K, Schmidt DJ, Drumond BP, Mondini A, Nogueira ML, Bronzoni RV (2015) Detection of Mayaro virus infections during a dengue outbreak in Mato Grosso, Brazil. Acta Trop 147:12–16. doi:10.1016/j.actatropica.2015.03.020

    Article  PubMed  Google Scholar 

  7. Ferreira DF, Santo MP, Rebello MA, Rebello MC (2000) Weak bases affect late stages of Mayaro virus replication cycle in vertebrate cells. J Med Microbiol 49(4):313–318

    Article  CAS  PubMed  Google Scholar 

  8. Burlandy FM, Rebello MA (2001) Inhibition of Mayaro virus replication by prostaglandin A(1) in Vero cells. Intervirology 44(6):344–349 (pii: int44344)

    Article  CAS  PubMed  Google Scholar 

  9. Da Costa LJ, Rebello MA (1999) Effect of brefeldin A on Mayaro virus replication in Aedes albopictus and Vero cells. Acta Virol 43(6):357–360

    PubMed  Google Scholar 

  10. De Campos RM, Ferreira DF, Da Veiga VF, Rebello MA, Rebello MC (2003) Effect of monensin on Mayaro virus replication in monkey kidney and Aedes albopictus cells. Acta Virol 47(2):113–119

    PubMed  Google Scholar 

  11. Bernardino AM, da Silva Pinheiro LC, Rodrigues CR, Loureiro NI, Castro HC, Lanfredi-Rangel A, Sabatini-Lopes J, Borges JC, Carvalho JM, Romeiro GA, Ferreira VF, Frugulhetti IC, Vannier-Santos MA (2006) Design, synthesis, SAR, and biological evaluation of new 4-(phenylamino)thieno[2,3-b]pyridine derivatives. Bioorg Med Chem 14(16):5765–5770. doi:10.1016/j.bmc.2006.03.013

    Article  CAS  PubMed  Google Scholar 

  12. dos Santos AE, Kuster RM, Yamamoto KA, Salles TS, Campos R, de Meneses MD, Soares MR, Ferreira D (2014) Quercetin and quercetin 3-O-glycosides from Bauhinia longifolia (Bong.) Steud. show anti-Mayaro virus activity. Parasit Vectors 7:130. doi:10.1186/1756-3305-7-130

    Article  PubMed  PubMed Central  Google Scholar 

  13. Spindola KC, Simas NK, Salles TS, de Meneses MD, Sato A, Ferreira D, Romao W, Kuster RM (2014) Anti-Mayaro virus activity of Cassia australis extracts (Fabaceae, Leguminosae). Parasit Vectors 7:537. doi:10.1186/s13071-014-0537-z

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zhao L, Zhang Y, Dai C, Guzi T, Wiswell D, Seghezzi W, Parry D, Fischmann T, Siddiqui MA (2010) Design, synthesis and SAR of thienopyridines as potent CHK1 inhibitors. Bioorg Med Chem Lett 20(24):7216–7221. doi:10.1016/j.bmcl.2010.10.105

    Article  CAS  PubMed  Google Scholar 

  15. Pevet I, Brulé C, Tizot A, Gohier A, Cruzalegui F, Boutin JA, Goldstein S (2011) Synthesis and pharmacological evaluation of thieno[2,3-b]pyridine derivatives as novel c-Src inhibitors. Bioorg Med Chem 19(8):2517–2528. doi:10.1016/j.bmc.2011.03.021

    Article  CAS  PubMed  Google Scholar 

  16. Galal SA, Abd El-All AS, Abdallah MM, El-Diwani HI (2009) Synthesis of potent antitumor and antiviral benzofuran derivatives. Bioorg Med Chem Lett 19(9):2420–2428. doi:10.1016/j.bmcl.2009.03.069

    Article  CAS  PubMed  Google Scholar 

  17. Jakubowski A, Chlopicki S, Olszanecki R, Jawien J, Lomnicka M, Dupin JP, Gryglewski RJ (2005) Endothelial action of thienopyridines and thienopyrimidinones in the isolated guinea pig heart. Prostaglandins Leukot Essent Fatty Acids 72(2):139–145. doi:10.1016/j.plefa.2004.10.011

    Article  CAS  PubMed  Google Scholar 

  18. Karupiah G, Xie QW, Buller RM, Nathan C, Duarte C, MacMicking JD (1993) Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Science 261(5127):1445–1448

    Article  CAS  PubMed  Google Scholar 

  19. Bernardino AMR, Pinheiro LCS, Ferreira VF, Azevedo AR (2004) Synthesis and antiviral activity of new 4-(phenylamino)thieno[2,3-b]pyridine derivatives. Heterocycl Commun 10(6):407–410

    Article  CAS  Google Scholar 

  20. Bernardino AMR, de Azevedo AR, Pinheiro LCS, Borges JC, Carvalho VL, Miranda MD, de Meneses MDF, Nascimento M, Ferreira D, Rebello MA (2007) Synthesis and antiviral activity of new 4-(phenylamino)/4-[(methylpyridin-2-yl) amino]-1-phenyl-1H-pyrazolo [3,4-b]pyridine-4-carboxylic acids derivatives. Med Chem Res 16(7):352–369

    Article  CAS  Google Scholar 

  21. Baer A, Kehn-Hall K (2014) Viral concentration determination through plaque assays: using traditional and novel overlay systems. J Vis Exp 93:e52065. doi:10.3791/52065

    Google Scholar 

  22. Borenfreund E, Puerner JA (1985) Toxicity determined in vitro by morphological alterations and neutral red absorption. Toxicol Lett 24(2–3):119–124

    Article  CAS  PubMed  Google Scholar 

  23. Reed LJ, Muench H (1938) A simple method of estimating fifity per cent endpoints. Am J Epidemiol 27(3):493–497

    Article  Google Scholar 

  24. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227(5259):680–685

    Article  CAS  PubMed  Google Scholar 

  25. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46(1–3):3–26 (pii: S0169-409X(00)00129-0)

    Article  CAS  PubMed  Google Scholar 

  26. Ravichandran R, Manian M (2008) Ribavirin therapy for Chikungunya arthritis. J Infect Dev Ctries 2(2):140–142

    Article  CAS  PubMed  Google Scholar 

  27. Elgizoli M, Dai Y, Kempf C, Koblet H, Michel MR (1989) Semliki Forest virus capsid protein acts as a pleiotropic regulator of host cellular protein synthesis. J Virol 63(7):2921–2928

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Patel RK, Burnham AJ, Gebhart NN, Sokoloski KJ, Hardy RW (2013) Role for subgenomic mRNA in host translation inhibition during Sindbis virus infection of mammalian cells. Virology 441(2):171–181. doi:10.1016/j.virol.2013.03.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kanekiyo K, Hayashi K, Takenaka H, Lee JB, Hayashi T (2007) Anti-herpes simplex virus target of an acidic polysaccharide, nostoflan, from the edible blue-green alga Nostoc flagelliforme. Biol Pharm Bull 30(8):1573–1575 (pii: JST.JSTAGE/bpb/30.1573)

    Article  CAS  PubMed  Google Scholar 

  30. Byrnes AP, Griffin DE (1998) Binding of Sindbis virus to cell surface heparan sulfate. J Virol 72(9):7349–7356

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank CAPES, FAPERJ and INBEB/CNPq for their financial support. This work was supported by The National Institute of Structural Biology and Bioimages INBEB/CNPq – Grant no. 57.3767/2008-4) and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ Edital 26/2013 110.034/2014 and FAPERJ APQ1 no.E26/110.370/2012); Raquel Amorim was supported with a Masters scholarship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

Author information

Authors and Affiliations

  1. Departamento de Virologia, Instituto de Microbiologia, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho, 373, Rio de Janeiro, 21941-902, Brazil

    Raquel Amorim, Marcelo Damião Ferreira de Meneses, Claudio Cesar Cirne-Santos, Renata de Mendonça Campos, Moacyr Alcoforado Rebello & Davis Fernandes Ferreira

  2. Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro, Campus Nilópolis, Nilópolis, 26530-060, Brazil

    Julio Cesar Borges

  3. Departamento de Síntese de Fármacos, Instituto de Tecnologia em Fármacos, Farmanguinhos-FIOCRUZ, Rio de Janeiro, 21041-250, Brazil

    Luiz Carlos da Silva Pinheiro

  4. Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho, 373, Rio de Janeiro, 21941-902, Brazil

    Lucio Ayres Caldas

  5. Laboratório de Antibióticos, Bioquímica, Educação e Modelagem Molecular, Universidade Federal Fluminense, Campus Valonguinho, Outeiro de São João Batista s/n°, Niterói, Rio de Janeiro, 24020-150, Brazil

    Marcos Vinícius Palmeira de Mello & Helena Carla Castro

  6. Laboratório de Modelagem Molecular e QSAR, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, CEP 21941-590, Brazil

    Alessandra Mendonça Teles de Souza

  7. Laboratório de Virologia Molecular e Biotecnologia Marinha, Programa, Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Niterói, Brazil

    Izabel Christina Nunes de Palmer Paixão

  8. Centro de Virología Animal (CEVAN), Instituto de Ciencia y Tecnología Dr. César Milstein, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Saladillo 2468, CP: 1440, Buenos Aires, Argentina

    Ingrid E. Bergmann & Viviana Malirat

  9. Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Outeiro de São João Batista, s/n, Centro, Niterói, Rio de Janeiro, 24020-141, Brazil

    Alice Maria Rolim Bernardino

Authors
  1. Raquel Amorim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcelo Damião Ferreira de Meneses
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Julio Cesar Borges
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luiz Carlos da Silva Pinheiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lucio Ayres Caldas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Claudio Cesar Cirne-Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marcos Vinícius Palmeira de Mello
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alessandra Mendonça Teles de Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Helena Carla Castro
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Izabel Christina Nunes de Palmer Paixão
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Renata de Mendonça Campos
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ingrid E. Bergmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Viviana Malirat
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Alice Maria Rolim Bernardino
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Moacyr Alcoforado Rebello
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Davis Fernandes Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Davis Fernandes Ferreira.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Authors’ contributions

RA carried out the cytotoxicity, antiviral, attachment and time of addition assays and drafted the manuscript. JCB and LCSP participated in the analysis of the derivatives chemical characteristics. LAC carried out the electron microscopy assay. MDFM, AMRB, MAR, INCPP and DFF conceived the study, contributed to its design and coordination, and to the drafting of the manuscript. IEB and VM also contributed to the study design and the manuscript review. AMTS and MVPM calculated the structure-activity relationship using the molecular modeling approach. HCC carried out the in silico ADMET evaluation. All authors read and approved the final manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Amorim, R., de Meneses, M.D.F., Borges, J.C. et al. Thieno[2,3-b]pyridine derivatives: a new class of antiviral drugs against Mayaro virus. Arch Virol 162, 1577–1587 (2017). https://doi.org/10.1007/s00705-017-3261-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00705-017-3261-0

Keywords

Search

Navigation