In vitro and in vivo activity of the chloroaryl-substituted imidazole viniconazole against Trypanosoma cruzi

Chagas disease (CD) is caused by the intracellular protozoan parasite Trypanosoma cruzi and affects more than 10 million people in poor areas of Latin America. There is an urgent need for alternative drugs with better safety, broader efficacy, lower costs and shorter time of administration. Thus the biological activity of viniconazole, a chloroaryl-substituted imidazole was investigated using in vitro and in vivo screening models of T. cruzi infection. Ultrastructural findings demonstrated that the most frequent cellular damage was associated with plasma membrane (blebs and shedding events), Golgi (swelling aspects) and the appearance of large numbers of vacuoles suggesting an autophagic process. Our data demonstrated that although this compound is effective against bloodstream and intracellular forms (16 and 24μ m, respectively) in vitro, it does not present in vivo efficacy. Due to the urgent need for novel agents against T. cruzi, the screening of natural and synthetic products must be further supported with the aim of finding more selective and affordable drugs for C

In Vitro and In Vivo Investigation of the Efficacy of Arylimidamide DB1831 and Its Mesylated Salt Form - DB1965 - against Trypanosoma cruzi Infection

Chagas disease is caused by infection with the intracellular protozoan parasite Trypanosoma cruzi. At present, nifurtimox and benznidazole, both compounds developed empirically over four decades ago, represent the chemotherapeutic arsenal for treating this highly neglected disease. However, both drugs present variable efficacy depending on the geographical area and the occurrence of natural resistance, and are poorly effective against the later chronic stage. As a part of a search for new therapeutic opportunities to treat chagasic patients, pre-clinical studies were performed to characterize the activity of a novel arylimidamide (AIA - DB1831 (hydrochloride salt) and DB1965 (mesylate salt)) against T.cruzi. These AIAs displayed a high trypanocidal effect in vitro against both relevant forms in mammalian hosts, exhibiting a high selectivity index and a very high efficacy (IC50 value/48 h of 5–40 nM) against intracellular parasites. DB1965 shows high activity in vivo in acute experimental models (mouse) of T.cruzi, showing a similar effect to benznidazole (Bz) when compared under a scheme of 10 daily consecutive doses with 12.5 mg/kg. Although no parasitological cure was observed after treating with 20 daily consecutive doses, a combined dosage of DB1965 (5 mg/kg) with Bz (50 mg/kg) resulted in parasitaemia clearance and 100% animal survival. In summary, our present data confirmed that aryimidamides represent promising new chemical entities against T.cruzi in therapeutic schemes using the AIA alone or in combination with other drugs, like benznidazole

In vitro and in vivo activity of the chloroaryl-substituted imidazole viniconazole against Trypanosoma cruzi

SUMMARY Chagas disease (CD) is caused by the intracellular protozoan parasite Trypanosoma cruzi and affects more than 10 million people in poor areas of Latin America. There is an urgent need for alternative drugs with better safety, broader efficacy, lower costs and shorter time of administration. Thus the biological activity of viniconazole, a chloroaryl-substituted imidazole was investigated using in vitro and in vivo screening models of T. cruzi infection. Ultrastructural findings demonstrated that the most frequent cellular damage was associated with plasma membrane (blebs and shedding events), Golgi (swelling aspects) and the appearance of large numbers of vacuoles suggesting an autophagic process. Our data demonstrated that although this compound is effective against bloodstream and intracellular forms (16 and 24 μ m, respectively) in vitro, it does not present in vivo efficacy. Due to the urgent need for novel agents against T. cruzi, the screening of natural and synthetic products must be further supported with the aim of finding more selective and affordable drugs for CD

Activities of Psilostachyin A an Cynaropicrin against Trypanosoma cruzi In Vitro and In Vivo

Made available in DSpace on 2015-08-19T13:49:15Z (GMT). No. of bitstreams: 2 license.txt: 1914 bytes, checksum: 7d48279ffeed55da8dfe2f8e81f3b81f (MD5) fabiana_rocha_etal_IOC-2013.pdf: 7997141 bytes, checksum: 4c775f9a5ca87f1b13332fbbeff45911 (MD5) Previous issue date: 2013Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.University of Basel. Department of Pharmaceutical Sciences, Pharmaceutical Biology. Basel, Switzerland.University of Basel. Department of Pharmaceutical Sciences, Pharmaceutical Biology. Basel, Switzerland.University of Basel. Department of Pharmaceutical Sciences, Pharmaceutical Biology. Basel, Switzerland / Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland.University of Basel. Department of Pharmaceutical Sciences, Pharmaceutical Biology. Basel, Switzerland.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland.University of Graz. Institute of Zoology. Graz, Austria.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.In vitro and in vivo activities against Trypanosoma cruzi were evaluated for two sesquiterpene lactones: psilostachyin A and cynaropicrin. Cynaropicrin had previously been shown to potently inhibit African trypanosomes in vivo, and psilostachyin A had been reported to show in vivo effects against T. cruzi, albeit in another test design. In vitro data showed that cynaropicrin was more effective than psilostachyin A. Ultrastructural alterations induced by cynaropicrin included shedding events, detachment of large portions of the plasma membrane, and vesicular bodies and large vacuoles containing membranous structures, suggestive of parasite autophagy. Acute toxicity studies showed that one of two mice died at a cynaropicrin dose of 400 mg/kg of body weight given intraperitoneally (i.p.). Although no major plasma biochemical alterations could be detected, histopathology demonstrated that the liver was the most affected organ in cynaropicrin-treated animals. Although cynaropicrin was as effective as benznidazole against trypomastigotes in vitro, the treatment (once or twice a day) of T. cruzi-infected mice (up to 50 mg/kg/day cynaropicrin) did not suppress parasitemia or protect against mortality induced by the Y and Colombiana strains. Psilostachyin A (0.5 to 50 mg/kg/day given once a day) was not effective in the acute model of T. cruzi infection (Y strain), reaching 100% animal mortality. Our data demonstrate that although it is very promising against African trypanosomes, cynaropicrin does not show efficacy compared to benznidazole in acute mouse models of T. cruzi infection

Biochemical analysis of <i>T.cruz</i>i-infected mice treated or not by DB1965 and Benznidazole.

<p>All assays were run at least two times and the data represent Mean ±SD.</p><p>ALT = alanino Aminotransferase.</p><p>CK = creatine kinase.</p><p>Bz = Benznidazole.</p

Chemical structure of the compounds.

<p>Chemical structure of the compounds.</p

Trypanocidal effect of Arylimidamides and Benznidazole against <i>T. cruzi</i> (Y strain).

<p>The activity of the compounds against bloodstream trypomastigotes (BT) and intracellular parasites was evaluated during their incubation at 37°C and at 4°C for 24 h and 48 h.</p><p>All assays were run at least two times in duplicate.</p><p>IC₅₀ values = Compound concentration that reduces the number of parasites by 50%.</p><p>SI* = selectivity index corresponds to the ratio LC₅₀/IC₅₀ – For BT and intracellular parasites calculated on LC₅₀ values of 24 and 48 h of incubation at 37°C, respectively.</p><p>Bz = Benznidazole.</p

Cure assessment of DB1965 combined or not with benznidazole (Bz) in murine model of acute <i>T. cruzi</i>-infection¹.

1<p>Swiss male mice weight 20 to 24 g inoculated with 10⁴ blood trypomastigotes (Y strain).</p><p>Treatment was initiated at 5° dpi followed by different schemes of treatment (up to 20 consecutive daily doses). All assays were run at least twice.</p>2<p>Intraperitoneal – ip.</p>3<p>per oral – p.o.</p><p>Nd = not done.</p