Leishmanicidal, antiproteolytic, and mutagenic evaluation of alkyltriazoles and alkylphosphocholines

作者：Gontijo Vanessa Silva; Espuri Patricia Ferreira; Alves Rosemeire Brondi; de Camargos Luiz Fernando; dos Santos Fabio Vieira; de Souza Judice Wagner Alves; Marques Marcos Jose; Freitas Rossimiriam Pereira^*

来源：European Journal of Medicinal Chemistry, 2015, 101: 24-33.

DOI：10.1016/j.ejmech.2015.06.005

• Alkyltriazoles
• Antiproteolytic
• Click chemistry
• Heterocycle

A series of 16 simple long-chain alkyltriazoles and two novel alkylphosphocholine derivatives containing an aside 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 mu M, comparable to that of pentamidine (IC50 = 6.62 mu M) and amphotericin B (IC50 = 6.10 mu M), 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.

• 出版日期2015-8-28