Leishmanicidal, antiproteolytic, and mutagenic evaluation of alkyltriazoles and alkylphosphocholines

• Published in: European journal of medicinal chemistry 2015-08, Vol.101, p.24-33
• Main Authors: Gontijo, Vanessa Silva, Espuri, Patrícia Ferreira, Alves, Rosemeire Brondi, de Camargos, Luiz Fernando, Santos, Fábio Vieira dos, de Souza Judice, Wagner Alves, Marques, Marcos José, Freitas, Rossimiriam Pereira
• Format: Article
• Language: English
• Subjects: Alkyltriazoles; Animals; Antiproteolytic; Click chemistry; Dose-Response Relationship, Drug; Heterocycle; Leishmania - drug effects; Macrophages - drug effects; Macrophages - parasitology; Mice; Molecular Structure; Parasitic Sensitivity Tests; Phosphorylcholine - chemistry; Phosphorylcholine - pharmacology; Structure-Activity Relationship; Triazoles - chemistry; Triazoles - pharmacology; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.06.005

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. [Display omitted] •Novel alkylphosphocholine and alkyltriazole compounds were synthesized.•The compounds were tested in vitro against Leishmania amazonensis.•The cytotoxicity and mutagenicity of most active compounds were tested.•The most active compounds were tested as inhibitors of cysteine protease rCPB2.8.•The alkyltriazoles may be a promising template for developing leishmanicidal agents.