In vitro trypanocidal activity of DB745B and other novel arylimidamides against Trypanosoma cruzi

Silva, Cristiane França da; Junqueira, Angela C. V.; Lima, Marli Maria; Romanha, Álvaro J.; Sales, Policarpo Ademar; Stephens, Chad E.; Som, P.; Boykin, David W.; Soeiro, Maria de Nazaré Correia

doi:10.1093/jac/dkr140

Cited by 14 publications

(27 citation statements)

References 8 publications

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“…AIAs display outstanding in vitro activity against both intracellular Leishmania (8, 22, 27) and intracellular T. cruzi (12,18,19). The high potency of AIAs against these intracellular kinetoplastid parasites could be explained in part by their lower pK a values and higher lipophilicity than those of diamidines (27), which may permit enhanced penetration into intracellular pathogens.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous efforts have identified arylimidamides (AIAs) as compounds with outstanding in vitro antileishmanial (8,22) and anti-T. cruzi (12,18,19) activities. In addition to excellent in vitro antileishmanial potency, the AIA hydrochloride salt 2,5-bis[2-(2-propoxy)-4-(2-pyridylimino)aminophenyl]furan (DB766) displayed good efficacy in both murine and hamster models of VL (27), was as active as Bz in experimental models of T. cruzi infection (3), was not mutagenic in the Ames test, and did not have an effect on the serum chemistry of mice when given orally at a dose of 100 mg/kg/day ϫ 5, although higher dose levels were not tested due to the limited aqueous solubility of DB766 (27).…”

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confidence: 99%

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Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas' Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies

Zhu

Liu

Yang

et al. 2012

Antimicrob Agents Chemother

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Egypt gArylimidamides (AIAs) have shown outstanding in vitro potency against intracellular kinetoplastid parasites, and the AIA 2,5-bis[2-(2-propoxy)-4-(2-pyridylimino)aminophenyl]furan dihydrochloride (DB766) displayed good in vivo efficacy in rodent models of visceral leishmaniasis (VL) and Chagas' disease. In an attempt to further increase the solubility and in vivo antikinetoplastid potential of DB766, the mesylate salt of this compound and that of the closely related AIA 2,5-bis[2-(2-cyclopentyloxy)-4-(2-pyridylimino)aminophenyl]furan hydrochloride (DB1852) were prepared. These two mesylate salts, designated DB1960 and DB1955, respectively, exhibited dose-dependent activity in the murine model of VL, with DB1960 inhibiting liver parasitemia by 51% at an oral dose of 100 mg/kg/day ؋ 5 and DB1955 reducing liver parasitemia by 57% when given by the same dosing regimen. In a murine Trypanosoma cruzi infection model, DB1960 decreased the peak parasitemia levels that occurred at 8 days postinfection by 46% when given orally at 100 mg/kg/day ؋ 5, while DB1955 had no effect on peak parasitemia levels when administered by the same dosing regimen. Distribution studies revealed that these compounds accumulated to micromolar levels in the liver, spleen, and kidneys but to a lesser extent in the heart, brain, and plasma. A 5-day repeat-dose toxicology study with DB1960 and DB1955 was also conducted with female BALB/c mice, with the compounds administered orally at 100, 200, and 500 mg/kg/day. In the high-dose groups, DB1960 caused changes in serum chemistry, with statistically significant increases in serum blood urea nitrogen, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase levels, and a 21% decrease in body weight was observed in this group. These changes were consistent with microscopic findings in the livers and kidneys of the treated animals. The incidences of observed clinical signs (hunched posture, tachypnea, tremors, and ruffled fur) were more frequent in DB1960-treated groups than in those treated with DB1955. However, histopathological examination of tissue samples indicated that both compounds had adverse effects at all dose levels.

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Section: Discussionmentioning

confidence: 99%

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Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas' Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies

Zhu

Liu

Yang

et al. 2012

Antimicrob Agents Chemother

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“…CM were maintained at 37°C under a 5% CO 2 atmosphere, and the medium was replaced every 24 h. Untreated and treated infected CM were then fixed and stained with Giemsa solution, and the mean numbers of infected host cells and parasites per infected cell were scored as reported previously (30). As light microscopy of untreated T. cruzi-infected cell cultures allows the identification of parasites through their typical nuclei and KDNA structures, only intracellular forms that displayed these characteristic cellular elements were considered live/viable parasites (28). Control samples included parasites and infected cell cultures incubated only with vehicle solution (DMSO; final concentration not exceeding 0.6%).…”

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

Silva

Batista

Araújo

et al. 2013

Antimicrob Agents Chemother

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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.A merican trypanosomiasis, also known as Chagas disease (CD), is a neglected disease caused by the intracellular protozoan Trypanosoma cruzi. Despite a large reduction of new acute cases in recent years due to vectorial transmission control policies, other routes of infection, including vertical transmission (mother to fetus) and ingestion of contaminated food and drinks (1), are still a concern. T. cruzi is restricted to Latin America, where about 10 million people are infected and 25 to 90 million are at risk of acquiring the infection (2). According to the Pan American Health Organization (PAHO) and the World Health Organization (WHO), CD causes between 10,000 and 14,000 deaths per year (3). Currently, only two drugs, benznidazole (Bz) and nifurtimox, are available for chagasic patients (4). However, the poor tolerance to and limited efficacy of these drugs, especially in the later stage of the chronic phase, make the search for novel compounds and therapeutic strategies ever more important as a means to offer alternative therapies to patients refractory to both these nitro derivatives (5).Natural products are an excellent source of active compounds. In fact, despite them comprising Ͻ1 percent of known chemical compounds (DNP 2013 [http://dnp.chemnetbase.com/tour/]; Reaxys 2013 [https://www.reaxys.com/documentation/about _query.htm]), they have supplied or inspired more than half of all new drugs introduced to the market in the last 3 dec...

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“…In order to overcome these limitations, novel amidines have been synthesized and phenotypic analysis of novel amidines has been conducted in vivo and in vitro (12,28). Among these, arylimidamides (AIAs) showed considerable biological activity against several intracellular pathogens, including T. cruzi (29), with the bis-AIAs being the most effective of the group (19).…”

Section: Discussionmentioning

confidence: 99%

“…Bz was purchased from the Laboratório Farmacêutico do Estado de Pernambuco (LAFEPE), Brazil. Bz was dissolved in distilled and sterile water supplemented with 3% Tween 80 and does not have any detectable effect on mice (19).…”

Section: Methodsmentioning

confidence: 99%

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

Guedes-da-Silva

Batista

Meuser

et al. 2016

Antimicrob Agents Chemother

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In vitro trypanocidal activity of DB745B and other novel arylimidamides against Trypanosoma cruzi

Abstract: AIAs represent promising new chemical entities against T. cruzi and are also potential trypanocidal agents to prevent transfusion-associated Chagas' disease.

Cited by 14 publications

References 8 publications

Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas' Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies

Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas' Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies

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

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

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