Assessment of Leishmanicidal and Trypanocidal Activities of Aliphatic Diamine Derivatives

Abstract

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 = 2.6 μm) and L. chagasi (IC50 = 3.0 μm) which showed a selectivity index (SI) >100. N-decyl-1,6-hexanediamine (compound 9) presented an IC50 = 1.6 μm 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 TNFα 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 100 μm. 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.

Polyamine Metabolism for Drug Intervention in Trypanosomatids

“…The first generation of these compounds consisted of symmetrically or nonterminally alkylated polyamine analogs [187]. Substituted polyaminebased derivatives have also been identified, including diamines and imidazole-containing drugs like triclabendazole (comp 10), which showed a multisite mode of action in the parasite [188][189][190] (Figure 9). Several drug screenings have been carried out to identify novel polyamine uptake inhibitors against T. cruzi [190].…”

Differential expression on mitochondrial tryparedoxin peroxidase (mTcTXNPx) in Trypanosoma cruzi after ferrocenyl diamine hydrochlorides treatments

“… 12 , 13 Interestingly, the development of ferroquine, an analogue of chloroquine with an Fc group in the lateral chain, showed particularly good in vitro and in vivo activity against chloroquine-resistant malaria parasite strains. 14 Considering the success of this approach and because alkyl diamines had been recently proposed as leading molecules for the development of new antiparasitic drugs, 15 our team decided to investigate the activity of novel Fc diamine hydrochlorides against T. cruzi and T. brucei. 16 The results revealed that the Fc derivatives were toxic either to T. cruzi and T. brucei , but not toxic to HepG2 cells, a model of mammalian cells.…”