In VitroandIn VivoActivities of Dicationic Diguanidino Compounds against Echinococcus multilocularis Metacestodes

Abstract

c Alveolar echinococcosis (AE) is a disease predominantly affecting the liver, with metacestodes (larvae) of the tapeworm Echinococcus multilocularis proliferating and exhibiting tumor-like infiltrative growth. For many years, chemotherapeutical treatment against alveolar echinococcosis has relied on the benzimidazoles albendazole and mebendazole, which require long treatment durations and exhibit parasitostatic rather than parasiticidal efficacy. Although benzimidazoles have been and still are beneficial for the patients, there is clearly a demand for alternative and more efficient treatment options. Aromatic dications, more precisely a small panel of di-N-aryl-diguanidino compounds, were screened for efficacy against E. multilocularis metacestodes in vitro. Only those with a thiophene core group were active against metacestodes, while furans were not. The most active compound, DB1127, was further investigated in terms of in vivo efficacy in mice experimentally infected with E. multilocularis metacestodes. This diguanidino compound was effective against AE when administered intraperitoneally but not when applied orally. Thus, thiophene-diguanidino derivatives with improved bioavailability when administered orally could lead to treatment options against AE.

Profound Activity of the Anti-cancer Drug Bortezomib against Echinococcus multilocularis Metacestodes Identifies the Proteasome as a Novel Drug Target for Cestodes

“…The complete results of this screening are shown in Table S1 . Seven of these drugs exhibited more than 50% of the activity of DB1127, one of the current lead compounds [15] , [16] and this was also confirmed by macroscopical observations of the vesicles. The 7 active compounds were further evaluated in a concentration series (20, 10, 5, 1, 0.1 µM) ( Figure 1 ).…”

“…Negative controls contained the corresponding amounts of DMSO. As a positive control DB1127 (20 µM) [15] , [16] was applied. PGI measurements were performed as described earlier [10] , with the difference that a 2300 EnSpire multilabel reader (Perkin-Elmer, Turku, Finland) was used for measurement of increase in absorbance at 340 nm.…”

“…A limited number of compounds were found to be active against E. multilocularis metacestodes in vitro, including nitazoxanide and derivatives [10] , [11] , 2-methoxyestradiol [12] , artesunate and semi-synthetic derivatives [13] , mefloquine and enantiomers [14] , [15] , dicationic compounds [15] , [16] , imatinib [17] , ruthenium(II) phosphite complexes [18] , and synthetic amino-ozonides [19] . For two compounds, the di-cationic diguanidino compound DB1127 and mefloquine, profound anti-parasitic activities were also detected in experimentally infected mice [14] , [16] . Unfortunately, the lack of financial incentives and the technical difficulties associated with working with Echinococcus parasites have hampered efforts to develop more effective treatment against AE.…”

In vivo activity of albendazole in combination with thymol against Echinococcus multilocularis

“…Besides benzimidazoles, these include dicationic diguanidino compounds (Küster et al, 2013); the antimalarials dihydroartemisinin and artesunate (Spicher et al, 2008a) and mefloquine (Küster et al, 2011); the cytostatic drugs vincristine, navelbine and methotrexate (Hübner et al, 2010); 2-methoxyestradiol a compound with documented anti-tumor activity (Spicher et al, 2008b), among others. However, none of the compounds investigated has been translated into clinical application.…”

Proceedings of the International Symposium

“…In vivo studies in the mouse model demonstrated the efficacy of oral application of the anti-malarial compound mefloquin, which will be followed up by studies on a range of mefloquine-derivatives that are predicted to have a lower capactiy to cross the bloodbrain barrier. Promising in vivo effects were also obtained with a pentamidine derivative, DB1127, however, only when the drug was applied intraperitoneally (Küster et al, 2013b). In addition, investigations on potential targets of selected drugs in Echinococcus are being carried out in order to explore their potential mechanism of action in the metacestode stage.…”