Skip to main content

Advertisement

SpringerLink
Log in

1,2,3-triazenes and 1,2,3-triazoles as antileishmanial, antitrypanosomal, and antiplasmodial agents

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

Abstract

Trypanosomiasis, leishmaniasis, and malaria are tropical diseases that affect poor populations and the commonly-used drugs are toxic and can be subject to drug resistance. There is, therefore, an urgent need to find effective therapeutic agents accessible to these populations that bear the brunt of morbidity and mortality. In vitro activities of seven 1,2,3-triazenes (1a, 1b, 2a, 2b, 3a, 3b, and 4) and five 1,2,3-triazoles (5a, 5b, 6a, 6b, and 7) were evaluated against Trypanosoma brucei gambiense, Leishmania donovani, and Plasmodium falciparum. The 1,2,3-triazenes showed better activities than 1,2,3-triazoles against Leishmania donovani: 2b was the most effective against axenic amastigote forms of Leishmania donovani LV9 (IC50 = 0.89 ± 0.41 μM) and the intramacrophage-amastigote forms (IC50 = 0.99 ± 0.36 μM) with a selectivity index >100. The best trypanocidal activities against Trypanosoma brucei gambiense was observed with the 1,2,3-triazene 3a (IC50 = 3.45 ± 0.09 μM) and the triazole 7, an analog of the cholesterol side chain (IC50 = 3.99 ± 0.23 μM). The most interesting result against Plasmodium falciparum 3D7 strain was obtained with 5b (IC50 = 1.29 ± 0.15 μM) with a selectivity index >77. This study revealed that 1,2,3-triazenes and 1,2,3-triazoles show antiparasitic potential that could lead to a new class of drugs.

Graphical abstract

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

Similar content being viewed by others

References

  1. Mathers CD, Ezzati M, Lopez AD. Measuring the burden of neglected tropical diseases: the global burden of disease framework. PLoS Neglect Trop Dis. 2007;1:e114.

    Article  Google Scholar 

  2. Tabel H, Wei G, Shi M. T cells and immunopathogenesis of experimental African trypanosomiasis. Immunol Rev. 2008;225:128–39.

    Article  Google Scholar 

  3. Barrett MP, Burchmore RJ, Stich A, Lazzari JO, Frasch AC, Cazzulo JJ, et al. The trypanosomiases. Lancet. 2003;362:1469–80.

    Article  Google Scholar 

  4. Steverding D. The development of drugs for treatment of sleeping sickness: a historical review. Parasites Vectors. 2010;3:1–9.

    Article  Google Scholar 

  5. Papageorgiou L, Megalooikonomou V, Vlachakis D. Genetic and structural study of DNA-directed RNA polymerase II of Trypanosoma brucei, towardsthe designing of novel antiparasitic agents. PeerJ 2017;5:e3061.

  6. Komolafe MA, Sanusi AA, Idowu AO, Balogun SA, Olorunmonteni OE, Adebowale AA, et al. Sleep medicine in Africa: past, present, and future. J Clin Sleep Med. 2021;17:1317–21.

    Article  Google Scholar 

  7. Delespaux V, de Koning HP. Drugs and drug resistance in African trypanosomiasis. Drug Resistance Updates. 2007;10:30–50.

    Article  Google Scholar 

  8. P De Koning H. The drugs of sleeping sickness: their mechanisms of action and resistance, and a brief history. Trop Med Infect Dis. 2020;5:14.

    Article  Google Scholar 

  9. Peregrine AS. Chemotherapy and delivery systems: haemoparasites. Vet Parasitol. 1994;54:223–48.

    Article  Google Scholar 

  10. Chappuis F, Sundar S, Hailu A, Ghalib H, Rijal S, Peeling RW, et al. Visceral leishmaniasis: what are the needs for diagnosis, treatment and control? Nat Rev Microbiol. 2007;5:873–82.

    Article  Google Scholar 

  11. Sundar S, Chakravarty J. Leishmaniasis: challenges in the control and eradication. Challenges Infect Dis. Springer; 2013. p. 247–64

    Chapter  Google Scholar 

  12. Pearson RD, de Queiroz Sousa A. Clinical spectrum of leishmaniasis. Clin Infect Dis. 1996;22:1–13.

  13. Sundar S, Singh A, Rai M, Prajapati VK, Singh AK, Ostyn B, et al. Efficacy of miltefosine in the treatment of visceral leishmaniasis in India after a decade of use. Clin Infect Dis. 2012;55:543–50.

    Article  Google Scholar 

  14. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison’s principles of internal medicine 18E Vol 2 EB: McGraw Hill Professional; 2012.

  15. Levaique H, Pamlard O, Apel C, Bignon J, Arriola M, Kuhner R, et al. Alkyl-resorcinol derivatives as inhibitors of GDP-mannose pyrophosphorylase with antileishmanial activities. Molecules. 2021;26:1551.

    Article  Google Scholar 

  16. Rosenthal E, Delaunay P, Jeandel P-Y, Haas H, Pomares-Estran C, Marty P. Le traitement de la leishmaniose viscérale en Europe en 2009. Place de l’amphotéricine B liposomale. Méd Maladies Infect. 2009;39:741–4.

    Article  Google Scholar 

  17. Guerrant RL, Walker DH, Weller PF. Tropical infectious diseases: principles, pathogens and practice e-Book: Elsevier Health Sciences; 2011.

  18. Den Boer M, Argaw D, Jannin J, Alvar J. Leishmaniasis impact and treatment access. Clin Microbiol Infect. 2011;17:1471–7.

    Article  Google Scholar 

  19. White Jr AC, Atmar RL, Greenberg SB. Tropical infectious diseases: principles, pathogens, and practice. American College of Physicians; 2000.

  20. Organization WH. Control of the leishmaniases: report of a meeting of the WHO Expert Committee on the Control of Leishmaniases, Geneva, 22–26 March 2010: World Health Organization; 2010.

  21. Croft SL, Coombs GH. Leishmaniasis–current chemotherapy and recent advances in the search for novel drugs. Trends Parasitol. 2003;19:502–8.

    Article  Google Scholar 

  22. Steketee RW, Choi M, Linn A, Florey L, Murphy M, Panjabi R. World Malaria Day 2021: Commemorating 15 years of contribution by the United States President’s Malaria initiative. Am J Trop Med Hyg. 2021;104(6):1955–59 https://doi.org/10.4269/ajtmh.21-0432.

  23. Alonso P, Noor AM. The global fight against malaria is at crossroads. Lancet. 2017;390:2532–4.

    Article  Google Scholar 

  24. Bagavan A, Rahuman AA, Kaushik NK, Sahal D. In vitro antimalarial activity of medicinal plant extracts against Plasmodium falciparum. Parasitol Res. 2011;108:15–22.

    Article  Google Scholar 

  25. Ombaka A. Antibacterial and antifungal activities of novel hydroxytriazenes. J Environ Chem Ecotoxicol. 2012;4:133–6.

    Article  Google Scholar 

  26. Kimball DB, Haley MM. Triazenes: a versatile tool in organic synthesis. Angew Chem Int Ed. 2002;41:3338–51.

    Article  Google Scholar 

  27. Hörner M, Giglio VF, Santos AJRWAD, Westphalen AB, Iglesias BA, Martins PR, et al. Triazenes and antibacterial activity. Rev Brasileira Ciências Farmêuticas. 2008;44:441–9.

    Google Scholar 

  28. Arrhenius K, Brown AS, van der Veen AM. Suitability of different containers for the sampling and storage of biogas and biomethane for the determination of the trace-level impurities–a review. Anal Chim Acta. 2016;902:22–32.

    Article  Google Scholar 

  29. Seck I, Ndoye SF, Ba LA, Fall A, Diop A, Ciss I, et al. Access to a library of 1, 3-disubstituted-1, 2, 3-triazenes and evaluation of their antimicrobial properties. Curr Top Med Chem. 2020;20:713–9.

    Article  Google Scholar 

  30. Insa S, Alioune F, Aicha BL, Fama NS, Seydou K, Abdoulaye D, et al. synthesis, characterization and antimicrobial activities of 1, 4-disubstituted 1, 2, 3-triazole compounds. Curr Top Med Chem. 2020;20:2289–99.

    Article  Google Scholar 

  31. Sanada M, Takagi Y, Ito R, Sekiguchi M. Killing and mutagenic actions of dacarbazine, a chemotherapeutic alkylating agent, on human and mouse cells: effects of Mgmt and Mlh1 mutations. DNA Repair. 2004;3:413–20.

    Article  Google Scholar 

  32. Barceló F, Ortiz-Lombardı́a M, Portugal J. Heterogeneous DNA binding modes of berenil. Biochim Biophys Acta (BBA)-Gene Struct Expr. 2001;1519:175–84.

    Article  Google Scholar 

  33. Katsoulas A, Rachid Z, Brahimi F, McNamee J, Jean-Claude BJ. Engineering 3-alkyltriazenes to block bcr-abl kinase: a novel strategy for the therapy of advanced bcr-abl expressing leukemias. Leuk Res. 2005;29:693–700.

    Article  Google Scholar 

  34. Iglesias BA, Hörner M, Toma HE, Araki K. 5-(1-(4-phenyl)-3-(4-nitrophenyl) triazene)-10, 15, 20-triphenylporphyrin: a new triazene-porphyrin dye and its spectroelectrochemical properties. J Porphyr Phthalocyanines. 2012;16:200–9.

    Article  Google Scholar 

  35. Boechat N, Ferreira VF, Ferreira SB, Ferreira MDLG, da Silva FDC, Bastos MM, et al. Novel 1, 2, 3-triazole derivatives for use against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain. J Med Chem. 2011;54:5988–99.

    Article  Google Scholar 

  36. Costa MS, Boechat N, Rangel EA, Da Silva FdC, De Souza AM, Rodrigues CR. et al. Synthesis, tuberculosis inhibitory activity, and SAR study of N-substituted-phenyl-1, 2, 3-triazole derivatives. Bioorg Med Chem. 2006;14:8644–53.

    Article  Google Scholar 

  37. Nahrwold M, Bogner T, Eissler S, Verma S, Sewald N. “Clicktophycin-52”: a bioactive cryptophycin-52 triazole analogue. Org Lett. 2010;12:1064–7.

    Article  Google Scholar 

  38. Abdel-Wahab BF, Mohamed HA, Awad GE. Synthesis and biological activity of some new 1, 2, 3-triazole hydrazone derivatives. Eur Chem Bull. 2015;4:106–9.

    Google Scholar 

  39. Seck I, Fall A, Lago C, Sene M, Gaye M, Seck M, et al. Synthesis of a cholesterol side-chain triazole analogue via ‘Click’ chemistry. Synthesis 2015;47:2826–30.

    Article  Google Scholar 

  40. Alkhaldi AA, Abdelgawad MA, Youssif BG, El-Gendy AO, De Koning HP. Synthesis, antimicrobial activities and GAPDH docking of novel 1, 2, 3-triazole derivatives. Tropical J Pharm Res. 2019;18:1101–8.

    Article  Google Scholar 

  41. Pocnet C, Dupuis M, Congard A, Jopp D. Personality and its links to quality of life: Mediating effects of emotion regulation and self-efficacy beliefs. Motiv Emot. 2017;41:196–208.

    Article  Google Scholar 

  42. Devender N, Gunjan S, Tripathi R, Tripathi RP. Synthesis and antiplasmodial activity of novel indoleamide derivatives bearing sulfonamide and triazole pharmacophores. Eur J Med Chem. 2017;131:171–84.

    Article  Google Scholar 

  43. Joshi AA, Narkhede SS, Viswanathan C. Design, synthesis and evaluation of 5-substituted amino-2, 4-diamino-8-chloropyrimido-[4, 5-b] quinolines as novel antimalarials. Bioorg Med Chem Lett. 2005;15:73–6.

    Article  Google Scholar 

  44. Jagu E, Pomel S, Diez-Martinez A, Rascol E, Pethe S, Loiseau PM, et al. Synthesis and antikinetoplastid evaluation of bis (benzyl) spermidine derivatives. Eur J Med Chem. 2018;150:655–66.

    Article  Google Scholar 

  45. El Ghozlani M, Bouissane L, Berkani M, Mojahidi S, Allam A, Menendez C, et al. Synthesis and biological evaluation against Leishmania donovani of novel hybrid molecules containing indazole-based 2-pyrone scaffolds. MedChemComm. 2019;10:120–7.

    Article  Google Scholar 

  46. Balaraman K, Vieira NC, Moussa F, Vacus J, Cojean S, Pomel S, et al. In vitro and in vivo antileishmanial properties of a 2-n-propylquinoline hydroxypropyl β-cyclodextrin formulation and pharmacokinetics via intravenous route. Biomed Pharmacother. 2015;76:127–33.

    Article  Google Scholar 

  47. Trager W, Jensen JB. Human malaria parasites in continuous culture. Science 1976;193:673–5.

    Article  Google Scholar 

  48. Lambros C, Vanderberg JP. Synchronization of Plasmodium falciparum erythrocytic stages in culture. J Parasitol. 1979;65:418–20.

  49. Ortiz S, Vásquez-Ocmín PG, Cojean S, Bouzidi C, Michel S, Figadere B, et al. Correlation study on methoxylation pattern of flavonoids and their heme-targeted antiplasmodial activity. Bioorg Chem. 2020;104:104243.

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the FIRST (Fonds impulsion pour la Recherche Scientifique et Technique) of the Senegalese Government and the Xunta de Galicia, Spain: (ED431C2017/70) and CITACA Strategic Partnership (ED431E 2018/07) for providing financial assistance for this study.

Author information

Authors and Affiliations

  1. Laboratoire de Chimie Organique et Thérapeutique, Faculté de Médecine, de Pharmacie et d’Odontologie de l’Université Cheikh Anta Diop de Dakar, BP 5005, Dakar-Fann, Sénégal

    Insa Seck, Ismaïla Ciss, Adama Diédhiou, Mamadou Baldé, Seydou Ka, Samba F. Ndoye & Matar Seck

  2. Laboratoire de Chimie de Coordination Organique (LCCO), Département de Chimie, Faculté des Sciences et Techniques, Université Cheikh Anta Diop de Dakar, Dakar, Sénégal

    Insa Seck & Samba F. Ndoye

  3. Université Amadou Mahtar MBOW. BP 45927 Dakar Nafa VDN, Sénégal, Dakar-Fann, Sénégal

    Lalla A. Ba

  4. BioCIS, Université Paris-Saclay, CNRS 8076, 92290, Châtenay-Malabry, France

    Bruno Figadère, Blandine Seon-Meniel, Sandrine Cojean, Sébastien Pomel & Philippe M. Loiseau

  5. Departamento de Química Orgánica, Facultad de Química and Instituto de Investigación Biomedica (IBI), University of Vigo, Campus Lagoas de Marcosende, 36310, Vigo, Spain

    Generosa Gomez & Yagamare Fall

Authors
  1. Insa Seck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ismaïla Ciss
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adama Diédhiou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mamadou Baldé
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seydou Ka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lalla A. Ba
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Samba F. Ndoye
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bruno Figadère
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Blandine Seon-Meniel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Generosa Gomez
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sandrine Cojean
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sébastien Pomel
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Philippe M. Loiseau
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yagamare Fall
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Matar Seck
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Insa Seck or Matar Seck.

Ethics declarations

Conflict of interest

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.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Seck, I., Ciss, I., Diédhiou, A. et al. 1,2,3-triazenes and 1,2,3-triazoles as antileishmanial, antitrypanosomal, and antiplasmodial agents. Med Chem Res 32, 158–164 (2023). https://doi.org/10.1007/s00044-022-02994-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-022-02994-9

Keywords

Search

Navigation