Skip to main content

Advertisement

SpringerLink
Log in

Phenoxyacetohydrazones against Trypanosoma cruzi

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

This article has been updated

Abstract

Herein, we reported the design, synthesis, antitrypanosomal and cytotoxic evaluation of a new phenoxyacetohydrazones series. All derivatives were assayed against bloodstream trypomastigote forms of T. cruzi (Y strain) and intracellular amastigotes using the model of L-929 cells infected with trypomastigotes of the Tulahuen strain. Compound (E)-N′-(3.4-dihydroxybenzylidene)-2-phenoxyacetohydrazide (11) showed activity against trypomastigotes (IC50/24 h = 10.3 µM) equivalent to that of benznidazole and with selectivity index (SI) = 46. Against infected cultures, (E)-N′-((5-nitrofuran-2-yl) methylene)-2-phenoxyacetohydrazide (19) was active at the nanomolar range (IC50/96 h = 40 nM), being about 38-fold more active than the standard drug and with SI equal to 2500. Thus, derivatives 11 and 19 could be considered a good prototypes for the development of new candidates for Chagas disease therapy.

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
Scheme 1
Fig. 2

Similar content being viewed by others

Change history

  • 05 August 2021

    The orcid id of Dr. Camila Capelini has been corrected.

References

  1. Dumonteil E, Herrera C. Ten years of Chagas disease research: looking back to achievements, looking ahead to challenges. PLoS Negl Trop Dis. 2017;11:e0005422.

    Article  Google Scholar 

  2. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis). Accessed 18 Jan 2021.

  3. Conteh L, Engels T, Molyneux DH. Socioeconomic aspects of neglected tropical diseases. Lancet. 2010;375:239–247.

    Article  Google Scholar 

  4. Antinori S, Galimberti L, Bianco R, Grande R, Galli M, Corbellino M. Chagas disease in Europe: a review for the internist in the globalized world. Eur J Intern Med. 2017;43:6–15.

    Article  Google Scholar 

  5. Requena-Méndez A, Aldasoro E, de Lazzari E, Sicuri E, Brown M, Moore DAJ, et al. Prevalence of Chagas disease in Latin-American migrants living in Europe: a systematic review and meta-analysis. PLoS Negl Trop Dis. 2015;9:e0003540.

    Article  Google Scholar 

  6. Coura JR, de Castro SL. A critical review on Chagas disease chemotherapy. Mem Inst Oswaldo Cruz. 2002;97:3–24.

    Article  CAS  Google Scholar 

  7. Patterson S, Wyllie S. Nitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospects. Trends Parasitol. 2014;30:289–298.

    Article  CAS  Google Scholar 

  8. Dias JC, Ramos AN Jr., Gontijo ED, Luquetti A, Shikanai-Yasuda MA, Coura JR, et al. II Consenso Brasileiro em Doença de Chagas, 2015. Epidemiol Serv Saúd. 2016;25:7–86.

    Google Scholar 

  9. Thota S, Rodrigues DA, Pinheiro PSM, Lima LM, Fraga CAM, Barreiro EJ. N-Acylhydrazones as drugs. Bioorg Med Chem Lett. 2017;28:2797–2806.

    Article  Google Scholar 

  10. Ifa D, Rodrigues CR, de Alencastro RB, Fraga CAM, Barreiro EJ. A possible molecular mechanism for the inhibition of cysteine proteases by salicylaldehyde n-acylhydrazones and related compounds. J Mol Struct 2000;505:11–17.

    Article  CAS  Google Scholar 

  11. Serafim RAM, de Oliveira TF, Loureiro APM, Krogh R, Andricopulo AD, Dias LC, et al. Molecular modeling and structure–activity relationships studies of bioisoster hybrids of N-acylhydrazone and furoxan groups on cruzain. Med Chem Res. 2017;26:760–769.

    Article  CAS  Google Scholar 

  12. Vergara S, Carda M, Agut R, Yepes LM, Vélez ID, Robledo SM, et al. Synthesis, antiprotozoal activity and cytotoxicity in U-937 macrophages of triclosan–hydrazone hybrids. Med Chem Res. 2017;26:3262–3273.

    Article  CAS  Google Scholar 

  13. Ferreira RS, Dessoy MA, Pauli I, Souza ML, Krogh R, Sales AIL, et al. Biological evaluation, and structure-activity relationships of potent noncovalent and nonpeptidic cruzain inhibitors as anti-trypanosoma cruzi agents. J Med Chem. 2014;57:2380–2392.

    Article  CAS  Google Scholar 

  14. Carvalho SA, Santa-Rita RM, de Castro SL, Fraga CAM. Synthesis and antitrypanosomal profile of new functionalized 1,3,4-thiadiazole-2-arylhydrazone derivatives, designed as non-mutagenic megazol analogues. Bioorg Med Chem Lett. 2004;14:5967–5970.

    Article  CAS  Google Scholar 

  15. Tait A, Ganzerli S, Di Bella M. Synthesis and free radical scavenging activity of 4-(2H-1,2,4-benzothiadiazine-1, ldioxide-3-yi)-2,6-bis(1,1-dimethylethyl)phenols. Tetrah. 1996;52(38):12587–12596.

    Article  CAS  Google Scholar 

  16. Carvalho SA, Kaiser M, Brun R, da Silva EF, Fraga CAM. Antiprotozoal activity of (E)-cinnamic N-acylhydrazone derivatives. Molecules. 2014;19(12):20374–20381.

    Article  Google Scholar 

  17. Xu F, Wang Y, Luo D, Yu G, Wu Y, Dai A, et al. Novel trifluoromethyl pyridine derivatives bearing a 1,3,4-oxadiazole moiety as potential insecticide. Med Chem Drug Disc. 2018;3:2795–2799.

    CAS  Google Scholar 

  18. Kümmerle AE, Schmitt M, Cardozo SVS, Lugnier C, Villa P, Lopes AB, et al. Synthesis, and pharmacological evaluation of N-acylhydrazones and novel conformationally constrained compounds as selective and potent orally active phosphodiesterase-4 inhibitors. J Med Chem. 2012;55:7525–7545.

    Article  Google Scholar 

  19. Capelini C, Câmara VRF, Villar JDF, Barbosa JMC, Salomão K, de Castro SL, et al. Synthesis, antitrypanosomal and antimycobacterial activities of coumarinic N-acylhydrazonic derivatives. Med Chem. 2020;16:1–8.

    Article  Google Scholar 

  20. Carvalho SA. Design and synthesis of new (E)-cinnamic N-acylhydrazones as potent antitrypanosomal agents. Eur J Med Chem. 2012;54:512–521.

    Article  CAS  Google Scholar 

  21. Glidewell C, Low JN, Wardell JL. 2-Nitrobenzaldehyde 2-Iodobenzoylhydrazone. Acta Crystallogr Sect E Struct Rep. Online. 2005;E61:o2438–o2440.

    Article  Google Scholar 

  22. Palla G, Predieri G, Domiano P, Vignali C, Turner W. Conformational behaviour and E/Z isomerization of N-acyl and N-aroylhydrazones. Tetrah. 1986;42:3649–3654.

    Article  CAS  Google Scholar 

  23. Romanha AJ, Castro SL, Soeiro Mde N, Lannes-Vieira J, Ribeiro I, Talvani A, et al. In vitro and in vivo experimental models for drug screening and development for Chagas disease. Mem Inst Oswaldo Cruz. 2010;105:233–238.

    Article  CAS  Google Scholar 

  24. Raja AS, Agarwal AK, Mahajan N, Pandeya SN, Ananthan S. Antibacterial and antitubercular activities of some diphenyl hydrazones and semicarbazones. Indian J Chem B. 2010;49B:1384–1388.

    CAS  Google Scholar 

  25. Niazi S, Javali C, Paramesh M, Shivaraja S. Study of influence of linkers and substitutions on antimicrobial activity of some Schiff bases. Int J Pharm Pharm Sci. 2010;2:100–112.

    Google Scholar 

  26. Kumar PR, Yadav MS, Kumar MMK, Rao TS. Synthesis and antimicrobial activity of some new substituted aryloxy-4-thiazolidinones. J Chem. 2006;3:44–48.

    CAS  Google Scholar 

  27. Salomão K, de Souza EM, Carvalho SA, da Silva EF, Fraga CAM, Barbosa HS, et al. In vitro and in vivo activities of 1,3,4-thiadiazole-2-arylhydrazone derivatives of megazol against Trypanosoma cruzi. Antimicrob Agents Chemother. 2010;54:2023–2031.

    Article  Google Scholar 

  28. Freitas RHCN, Barbosa JMC, Bernardino P, Sueth-Santiago V, et al. CAM. Synthesis and trypanocidal activity of novel pyridinyl-1,3,4-thiadiazole derivatives. Biomed Pharmacother. 2020;127:110162.

    Article  CAS  Google Scholar 

  29. Jardim GAM, Reis WJ, Ribeiro MF, Ottoni FM, Alves RJ, Silva TL, et al. On the investigation of hybrid quinones: synthesis, electrochemical studies and evaluation of trypanocidal activity. RSC Adv. 2015;5:78047–78060.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001. The authors also thank the National Crystallographic Service, Southampton, for the X-ray data collection and the Program for Technological Development of Tools for Health-PDTIS-FIOCRUZ for use of its facilities.

Author information

Authors and Affiliations

  1. Instituto de Tecnologia em Fármacos—Farmanguinhos, Fundação Oswaldo Cruz, 21041-250, Rio de Janeiro, RJ, Brazil

    Camila Capelini, Edson F. da Silva & Samir A. Carvalho

  2. Laboratório de Físico-Química de Materiais, Seção de Engenharia Química, Instituto Militar de Engenharia, Praça General Tibúrcio 80, 22290-270, Rio de Janeiro, Brazil

    Camila Capelini & Kátia R. de Souza

  3. Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, 21040-900, Rio de Janeiro, RJ, Brazil

    Juliana M. C. Barbosa & Kelly Salomão

  4. Instituto René Rachou—Fundação Oswaldo Cruz, 30190002, Belo Horizonte, MG, Brazil

    Policarpo A. Sales Junior & Silvane M. F. Murta

  5. CHEMSOL, 1 Harcourt Road, Aberdeen, AB15 5NY, Scotland

    Solange M. S. V. Wardell

  6. Department of Chemistry, University of Aberdeen, Old Aberdeen, AB24 3UE, Scotland

    James L. Wardell

Authors
  1. Camila Capelini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kátia R. de Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juliana M. C. Barbosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kelly Salomão
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Policarpo A. Sales Junior
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Silvane M. F. Murta
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Solange M. S. V. Wardell
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. James L. Wardell
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Edson F. da Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Samir A. Carvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Samir A. Carvalho.

Ethics declarations

Conflict of interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Capelini, C., de Souza, K.R., Barbosa, J.M.C. et al. Phenoxyacetohydrazones against Trypanosoma cruzi. Med Chem Res 30, 1703–1712 (2021). https://doi.org/10.1007/s00044-021-02768-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-021-02768-9

Search

Navigation