2. Academic Validation
  3. Leishmanicidal, antiproteolytic, and mutagenic evaluation of alkyltriazoles and alkylphosphocholines

Leishmanicidal, antiproteolytic, and mutagenic evaluation of alkyltriazoles and alkylphosphocholines

  • Eur J Med Chem. 2015 Aug 28:101:24-33. doi: 10.1016/j.ejmech.2015.06.005.
Vanessa Silva Gontijo 1,  Patrícia Ferreira Espuri 2,  Rosemeire Brondi Alves 1,  Luiz Fernando de Camargos 3,  Fábio Vieira Dos Santos 3,  Wagner Alves de Souza Judice 4,  Marcos José Marques 2,  Rossimiriam Pereira Freitas 5
Affiliations

Affiliations

  • 1 Departamento de Química, ICEx, UFMG, Av. Pres, Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil.
  • 2 Laboratório de Biologia Molecular de Microrganismos, Universidade Federal de Alfenas, 37130-000 Alfenas, MG, Brazil.
  • 3 Núcleo de Química Biológica, Laboratório de Biologia Celular e Mutagênese (LaBCeM), Universidade Federal de São João del Rei (UFSJ), Divinópolis, MG 35501-296, Brazil.
  • 4 Centro Interdisciplinar de Investigação Bioquímica, Universidade de Mogi das Cruzes, UMC, Mogi das Cruzes, SP, Brazil.
  • 5 Departamento de Química, ICEx, UFMG, Av. Pres, Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil. Electronic address: rossimiriam@pq.cnpq.br.
PMID: 26112378 DOI: 10.1016/j.ejmech.2015.06.005
Abstract

A series of 16 simple long-chain alkyltriazoles and two novel alkylphosphocholine derivatives containing an azide moiety were evaluated in vitro for their leishmanicidal activity against. Among the 18 compounds tested, the eight most active compounds against promastigote forms were selected for further evaluation against amastigote forms. These compounds were also evaluated for their cytotoxicity against murine macrophages and tested as inhibitors of cysteine protease rCPB2.8, an important target for development of antileishmanial drugs. The mutagenicity of some of these compounds was also evaluated in prokaryotic and eukaryotic cells to assess any genetic effects of the leishmanicidal candidates. The compound 4, an alkylphosphocholine derivative, was found to be the most potent against amastigote forms with an IC50 of 3.81 μM, comparable to that of pentamidine (IC50 = 6.62 μM) and amphotericin B (IC50 = 6.10 μM), two established leishmanicidal drugs. Compound 4 also exhibited the best selectivity index (SI) values of the series, demonstrating low toxicity against macrophages and a cLogP value higher than 5. Among the alkyltriazoles, compounds 13 and 14 were the most active against promastigote and amastigote forms. They were then evaluated for their mutagenicity in vitro; the mutagenicity index (MI) values were lower than 2, suggesting that these compounds are not mutagenic.

Keywords

Alkyltriazoles; Antiproteolytic; Click chemistry; Heterocycle.

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