Assessment of Leishmanicidal and Trypanocidal Activities of Aliphatic Diamine Derivatives

作者：Yamanaka Celina N; Giordani Raquel B; Rezende Celso O Jr; Eger Iriane; Kessler Rafael L; Tonini Maiko L; de Moraes Milene H; Araujo Debora P; Zuanazzi Jose A; de Almeida Mauro V; Steindel Mario^*

来源：Chemical Biology & Drug Design, 2013, 82(6): 697-704.

DOI：10.1111/cbdd.12191

• aliphatic diamines
• Leishmania braziliensis
• Leishmania chagasi
• leishmanicidal and trypanocidal activity
• Trypanosoma cruzi

Leishmanicidal and trypanocidal activity of seventeen lipophilic diamines was evaluated in vitro against Leishmania braziliensis, L.chagasi, and Trypanosoma cruzi. Twelve compounds presented anti-Leishmania and six showed anti-T.cruzi amastigote activity. Compound 14 (N-tetradecyl-1,4-butanediamine) was the most active against both L.braziliensis (IC50=2.6m) and L.chagasi (IC50=3.0m) which showed a selectivity index (SI) >100. N-decyl-1,6-hexanediamine (compound 9) presented an IC50=1.6m and SI >187 and was over six times more potent than the reference drug benznidazole against T.cruzi. Treatment of infected or uninfected macrophages with compounds 9 and 14 did not induce significant TNF and NO production. Four compounds (15, 16, 22, and 23) inhibited 78.9%, 77.7%, 83.7%, and 70.1% of rTRLb activity, respectively, and compound 23 inhibited 73.3% of rTRTc activity at 100m. A concentration-dependent effect on mitochondrial membrane depolarization was observed in T.cruzi epimastigotes treated with compound 9, suggesting this mechanism may be involved in the trypanocidal effect. On the contrary, in L.braziliensis promastigotes treated with compound 14, no mitochondrial depolarization was observed. Our results demonstrate that N-decyl-1,6-hexanediamine and N-tetradecyl-1,4-butanediamine are promising molecules for the development of novel leading compounds against T.cruzi and Leishmania spp., particularly given a possible alternative mechanism of action.

• 出版日期2013-12