2. Academic Validation
  3. Leishmanicidal and cytotoxic activity of hederagenin-bistriazolyl derivatives

Leishmanicidal and cytotoxic activity of hederagenin-bistriazolyl derivatives

  • Eur J Med Chem. 2017 Nov 10:140:624-635. doi: 10.1016/j.ejmech.2017.09.045.
Diego Rodríguez-Hernández 1,  Luiz C A Barbosa 2,  Antonio J Demuner 3,  Amalyn Nain-Perez 1,  Sebastião R Ferreira 4,  Ricardo T Fujiwara 5,  Raquel M de Almeida 5,  Lucie Heller 6,  René Csuk 7
Affiliations

Affiliations

  • 1 Department of Chemistry, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil.
  • 2 Department of Chemistry, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil; Department of Chemistry, Universidade Federal de Viçosa, Av. P. H. Rolfs, s/n, CEP 36570-900, Viçosa, MG, Brazil. Electronic address: lcab@ufmg.br.
  • 3 Department of Chemistry, Universidade Federal de Viçosa, Av. P. H. Rolfs, s/n, CEP 36570-900, Viçosa, MG, Brazil.
  • 4 Department of Parasitology, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil; Health Science Center, Universidade Federal de Roraima, Av. Cap. Ene Garcez, CEP 69310-000, Boa Vista, RR, Brazil.
  • 5 Department of Parasitology, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil.
  • 6 Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str.2, D 06120, Halle (Saale), Germany.
  • 7 Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str.2, D 06120, Halle (Saale), Germany. Electronic address: rene.csuk@chemie.uni-halle.de.
PMID: 29024910 DOI: 10.1016/j.ejmech.2017.09.045
Abstract

Aiming to obtain new potent leishmanicidal and cytotoxic compounds from natural sources, the triterpene hederagenin was converted into several new 1,2,3-triazolyl derivatives tethered at C-23 and C-28. For this work hederagenin was isolated from fruits of Sapindus saponaria and reacted with propargyl bromide to afford as a major product bis-propargylic derivative 1 in 74%. Submitting this compound to Huisgen 1,3-dipolar cycloaddition reactions with several azides afforded the derivatives 2-19 with yields in the range of 40-87%. All compounds have been screened for in vitro cytotoxic activity in a panel of five human Cancer cell lines by a SRB assay. The bioassays showed that compound 19 was the most cytotoxic against all human Cancer cell lines with EC50 = 7.4-12.1 μM. Moreover, leishmanicidal activity was evaluated through the in vitro effect in the growth of Leishmania infantum, and derivatives 1, 2, 5 and 17 were highly effective preventing proliferation of intracellular amastigote forms of L. infantum (IC50 = 28.8, 25.9, 5.6 and 7.4 μM, respectively). All these compounds showed a higher selectivity index and low toxicity against two strains of kidney BGM and liver HepG2 cells. Compound 5 has higher selectivity (1780 times) in comparison with the commercial antimony drug and is around 8 times more selective than the most active compound previously reported hederagenin derivative. Such high activity associated with low toxicities make the new bis-traiazolyl derivatives promising candidates for the treatment of leishmaniasis. In addition, hederagenin and some derivatives (2, 5 and 17) showed interaction in the binding site of the Enzyme CYP51Li.

Keywords

CYP51(Li); Cytotoxicity; Hederagenin; Leishmania infantum; Triazol.

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