In vitro and in vivo evaluation of 2-aminoalkanol and 1,2-alkanediamine derivatives against Strongyloides venezuelensis

Abstract

BackgroundStrongyloidiasis is a parasitic disease widely present in tropical and subtropical areas. Strongyloides stercoralis represents the main species that infects human beings. Ivermectin is the current drug of choice; however, issues related with treatment failure in patients with diabetes or infected with T-lymphotropic virus-1 make the identification of new molecules for alternative treatment a priority. In the present study, the activity of sphingosine-related aminoalcohol and diamine were evaluated against Strongyloides venezuelensis third-stage larva (L3) cultures and experimental infections in mice.MethodsThe efficacy of each compound against L3 was assessed using both XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) assay and microscopic observation with concentrations ranging from 1 to 350 μM. Cytotoxicity was evaluated using J774.2 macrophage cell line and XTT assay. Lethal concentration 50 (LC50), selectivity index (SI) and structure-activity relationships were established. The activity compounds 4 (2-(ethylamino) hexadecan-1-ol), 6 (2-(butylamino) hexadecan-1-ol), 17 (tert-butyl N-(1-aminododecan-2-yl) carbamate) and 18 (tert-butyl N-(1-aminohexadecan-2-yl) carbamate) were further assessed against experimental S. venezuelensis infections in CD1 mice measuring reductions in the numbers of parthenogenetic females and egg passed in faeces. Mice were infected with 3,000 L3 and treated with 20 mg/kg/day for five days.ResultsIn the screening study of 15 aminoalcohols [lauryl (n = 9); palmityl (n = 13); stearyl (n = 15) and alcohol derivatives], the presence of a palmitol chain was associated with the highest efficacy against L3 (LC50 31.9–39.1 μM). Alkylation of the 2-amino group with medium size fragments as ethyl or n-butyl showed the best larvicidal activity. The dialkylation did not improve efficacy. Aminoalcohols 4 and 6 showed the highest SI (1.5 and 1.6, respectively). With respect to diamine derivative compounds, a chain size of sixteen carbon atoms (palmitoyl chain, n = 13), and the alkylation of the 2-amino group with medium-sized fragments, were associated with the highest lethal activities. The presence of carbamoyl group in diamines 17 and 18 yielded high SI (1.7 and 1.4, respectively). Infected mice treated with aminoalcohol 6 showed reduction in parthenogenetic females (59 %) and eggs in faeces (51 %).ConclusionsThese results support the potentiality of aminoalcohol and diamine sphingosine-related compounds as suitable prototypes for developing new promising drugs against strongyloidiasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1648-5) contains supplementary material, which is available to authorized users.

Strongyloidiasis Current Status with Emphasis in Diagnosis and Drug Research

“…Currently, few anti- Strongyloides new drug research papers have been published; however, considering the small number, there is a great diversity of protocols used. Parameters evaluated in these papers include larvae survival, determined by parasite movement, and egg hatching ( Table 2 ) [ 16 , 17 , 22 , 24 , 25 ]. A few research groups showed promising in vitro results, as the activity of 2-(butylamino)hexadecan-1-ol, Newbouldia laevis essential oil, and Zanthoxylum zanthoxyloides essential oil against S. ratti and S. venezuelensis or Eryngium foetidum crude extract and Eryngial (trans-2-dodecenal) against S. stercoralis [ 16 , 21 , 22 ] ( Table 3 ).…”

“…On the other hand, in vivo published data (summarized in Table 4 ) do not necessarily support results obtained in vitro. For example, in a study conducted by Legarda-Ceballos et al [ 16 ], out of four compounds with promising in vitro results, only one was capable of reducing mice parasite load in ~60%. Compounds derived from Piper tuberculatum , with known insecticide, trypanocidal, and fungicidal action, and compounds derived from Lippia sidoides , effective against some bacteria and Aedes aegypti larvae, were ineffective against S. venezuelensis in vivo.…”

Evaluation of the Immunomodulatory Effect of the Recombinant 14-3-3 and Major Antigen Proteins of Strongyloides stercoralis against an Infection by S. venezuelensis

“…This strain was maintained by serial passages in Wistar rats routinely infected in the laboratory of Parasitic and Molecular Immunology, CIETUS, University of Salamanca. Rats were subcutaneously infected with third-stage larvae (L3) of S. venezuelensis, as previously described [20]. CD1 female experimental mice and maintenance rats were housed and maintained at the Research and Animal Welfare Service of the University of Salamanca under standard conditions, at a temperature of 24 • C and a humidity-controlled environment with 12 h day-night cycles and provided with water and food ad libitum.…”

Prospecção de produtos sintéticos bioativos no controle da podridão-parda (Monilinia fructicola (Wint.) Honey) do pessegueiro

“…Compostos bioativos obtidos de plantas e seus derivados análogos sintéticos, como chalconas, alcaloides indólicos, aminoalcaloides e diaminas, cujos mecanismos de ação ainda não foram estabelecidos, são atualmente foco de discussões e pesquisas contra patógenos fúngicos de doenças humanas, que utilizam como premissa a potencialidade no controle e baixa toxicidade ao meio ambiente (ABENGÓZAR et al, 2015;LEGARDA-CEBALLOS et al, 2016;OLMO et al, 2016).…”

“…Legarda-Ceballos et al (2016), estudando doenças causadas por parasitas como Strongyloides venezuelensis, encontraram eficácia das diaminas in vitro e in vivo no controle do referido nematoide. Os mesmos autores, em 2015, observaram efeitos semelhantes no controle do protozoário Trypanosoma cruzi, com valores entre 10,8 e 19,2 µM de IC 50 .…”