Arylimidamide DB766, a Potential Chemotherapeutic Candidate for Chagas' Disease Treatment

Abstract

Chagas' disease, a neglected tropical illness for which current therapy is unsatisfactory, is caused by the intracellular parasite Trypanosoma cruzi. The goal of this work is to investigate the in vitro and in vivo effects of the arylimidamide (AIA) DB766 against T. cruzi. This arylimidamide exhibits strong trypanocidal activity and excellent selectivity for bloodstream trypomastigotes and intracellular amastigotes (Y strain), giving IC 50 s (drug concentrations that reduce 50% of the number of the treated parasites) of 60 and 25 nM, respectively. DB766 also exerts striking effects upon different parasite stocks, including those naturally resistant to benznidazole, and displays higher activity in vitro than the reference drugs. By fluorescent and transmission electron microscopy analyses, we found that this AIA localizes in DNA-enriched compartments and induces considerable damage to the mitochondria. DB766 effectively reduces the parasite load in the blood and cardiac tissue and presents efficacy similar to that of benznidazole in mouse models of T. cruzi infection employing the Y and Colombian strains, using oral and intraperitoneal doses of up to 100 mg/kg/day that were given after the establishment of parasite infection. This AIA ameliorates electrocardiographic alterations, reduces hepatic and heart lesions induced by the infection, and provides 90 to 100% protection against mortality, which is similar to that provided by benznidazole. Our data clearly show the trypanocidal efficacy of DB766, suggesting that this AIA may represent a new lead compound candidate to Chagas' disease treatment.

The adaptive potential of a survival artist: characterization of thein vitrointeractions ofToxoplasma gondiitachyzoites with di-cationic compounds in human fibroblast cell cultures

“…0·24 48 0·26 52 0·28 56 0·30 59 0·32 63 0·34 66 0·36 69 0·38 73 0·40 76 0·40 80 0·40 83 0·42 86 0·42 90 0·42 93 0·42 97 0·42 101 0·42 104 0·42 108 0·44 111 0·46 D I S C U S S I O N Although pentamidine was synthesized already in the 1930s, it has remained the only aromatic diamidine that is widely used in the clinic, especially against human stage 1 African trypanosomiasis caused by Trypanosoma brucei gambiense, but also against Pneumocystis pneumonia caused by Pneumocystis jiroveci, and against leishmaniasis, and Candida albicans infections (Werbovetz, 2006). A number of arylimidamides, including DB702, DB750, DB766, DB786, DB811 and DB889 exhibited good in vitro activity against Trypanosoma cruzi, N. caninum, B. besnoiti or L. donovani (Stephens et al 2003;Silva et al 2007a, b;Leepin et al 2008;Cortes et al 2011), and DB766 effectively reduced the parasite burden in the blood and heart of T. cruzi-infected mice at a dose of 100 mg/kg/day given orally and intraperitoneally (Batista et al 2010a). Thus, the goal of this investigation was to study the interactions of T. gondii tachyzoites with DB750, which had shown interesting properties in a previous study (Leepin et al 2008), and possibly identify other compounds with good in vitro activity.…”

“…Since its discovery, pentamidine has been successfully applied to treat African trypanosomiasis, leishmaniasis, and malaria in humans, and the pentamidinederivative diminazene aceturate is commonly used for trypanosome chemotherapy in livestock (Werbovetz, 2006). More recently, novel analogues, known as arylimidamides, with a more favourable pharmacokinetic profile, improved bioavailability and lower host toxicity were shown to be effective against Leishmania donovani and Trypanosoma cruzi in vitro and in vivo (Wang et al 2010;Batista et al 2010a).…”

Anti-parasitic effect of novel amidines against Trypanosoma cruzi: phenotypic and in silico absorption, distribution, metabolism, excretion and toxicity analysis

“…Three of the four diamidines (DB2235, DB2251 and DB2253) are analogues of furamidine and one (DB2232) is an extended bisamidino benzimidazole, which represents another class of highly active diamidines. Lastly, one novel bis-AIA (DB2255) results from a simple modification of the structure of the highly active anti-T. cruzi compound DB766 (Batista et al 2010). In DB2255, the central furan ring of DB766 replaced with a non-aromatic 5-membered imidazolidin-2-one ring.…”

“…The purified parasites were resuspended in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS) as reported previously (Batista et al 2010). Trypomastigotes of Tulahuen strain expressing the Escherichia coli β-galactosidase gene (Buckner et al 1996) were collected from the supernatant of infected cell cultures (L929 culture) as reported .…”

In Vitro and In Vivo Trypanosomicidal Action of Novel Arylimidamides against Trypanosoma cruzi

“…Several ADs and related compounds have been screened for their activities against T. cruzi and have shown promising results, at least in part due to their capacity to alter the kinetoplast DNA molecule (8,9). Arylimidamides (AIAs; formerly called "reversed" amidines, because of the reversed position of the nitrogen and carbon atoms compared to their orientation in classic aromatic amidines) are the most effective amidine analogues tested against T. cruzi in vitro and in vivo (9)(10)(11)(12).…”