Anthelmintic effects of alkylated diamines and amino alcohols against Schistosoma mansoni

Abstract

Polyamines are substances involved in many aspects of cell growth, division, and differentiation. Because of the metabolic differences between host cells and parasite cells, polyamine metabolism has been considered as a potential target for the chemotherapy of parasitic diseases. The aim of this work was to evaluate the schistosomicidal activity of different N-alkylated diamines (3a-3h), amino alcohols (4a-4d), and glycosylated amino alcohols (10a-10d). Compounds were prepared by synthetic methods and submitted to in vitro evaluation against adult worms of Schistosoma mansoni. At 100 μM, 3b, 3e, and 3h as well as 4a, 4b, 4d, 10a, 10b, and 10d resulted in 100% mortality of adult schistosomes. Compound 3d (12.5 to 100 μM) caused the death of 100% of both male and female adult schistosomes, while 3f (12.5 to 100 μM) resulted in 100% mortality of only male adult worms, whereas no mortality in female worms was observed. Compounds 3d and 3f were also able to reduce viability and decrease production of developed eggs in comparison with the negative control group. Diamines 3d and 3f may represent useful lead compounds for further optimization in order to develop new schistosomicidal agents.

Scheme 1

Synthesis of N-alkylated and N,N′-dialkylated diamines: (a) MsCl, CH₂Cl₂, Py, 0°C to room temperature; (b) diamine, EtOH reflux.

Scheme 2

Synthesis of N-alkylated amino alcohols.

Scheme 3

Synthesis of N-alkylated amino alcohols.

Figure 1

In vitro effects of active diamines 3d and 3f on the viability of the S. mansoni adult worms. Pairs of adult worms were treated with samples in different concentrations for 72 h, and the viability was measured by using the MTT assay at 550 nm. RPMI 1640 medium and 0.4% DMSO in RPMI 1640 medium were used as negative controls. Praziquantel (PZQ, 10 μM) was used as positive control group. The viability was expressed as mean of the absorbance values from four experiments. ***P < 0.001.

Figure 2

In vitro active diamines 3d and 3f on egg development (quantitative analysis of the development phenotype). After treatment, the eggs were microscopically examined and scored as developed or undeveloped based on the presence or absence of the miracidium. Data are presented as the mean of developed eggs from four separate experiments. *P < 0.05, ***P < 0.001.

Scheme 4

Preparation of D-galactose derivatives. Reagents and conditions: (a) acetone, H₂SO₄, ZnCl₂ (58%); (b) NaOH 40%, TBAB, Epichlorohydrin, THF (94%); (c) CH₃(CH₂)_nCH₂NHCH₂CH₂OH, EtOH, TBAB, rt (51–61%).