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

Guedes-da-Silva, Francisca Hildemagna; Batista, D. G. J.; Meuser, M. B.; Demarque, Kelly Cristina; Fulco, T O; Araújo, Julianna Siciliano de; Silva, P. B. Da; Silva, C. F. Da; Patrick, Donald A.; Bakunova, Svetlana M.; Bakunov, Stanislav A.; Tidwell, Richard R.; Oliveira, Gabriel Melo de; Britto, Constança; Moreira, Otacílio C.

doi:10.1128/aac.01667-15

Cited by 24 publications

(29 citation statements)

References 37 publications

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“…Other boronic acids, such as NO-03 and NO-13,a lso exhibited good effects, albeit with less potency than NO-12,a nd NO-13 presented better performance than NO-03.T hese resultsi ndicateb oronic acids as effective platformsu pon which new molecules with improved actions against T. cruzi can be designed.A lso, it seems that the mechanism of action is more favored with para-substituted boronic acids with ester-substituted vinyl nitriles. The EC 50 value measured for NO-12 (0.795 mm)i sm ore than 10 times superior to the EC 50 value described for benznidazole [43] and more than four times superior to the EC 50 value of nifurtimox; [44] both drugs are used in the current therapy of Chagas disease. Boronic acid NO-12 exhibitedl ower potency than bortezomib [45] and DDD85646, both strong proteasome inhibitors with trypanocidal activity against T. brucei.…”

Section: Toxicity Assay In Mammalian Primary Cell Linesmentioning

confidence: 72%

Synthesis and Evaluation of the Anticancer and Trypanocidal Activities of Boronic Tyrphostins

et al. 2018

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Molecules containing an (cyanovinyl)arene moiety are known as tyrphostins because of their ability to inhibit proteins from the tyrosine kinase family, an interesting target for the development of anticancer and trypanocidal drugs. In the present work, (E)-(cyanovinyl)benzeneboronic acids were synthesized by Knoevenagel condensations without the use of any catalysts in water through a simple protocol that completely avoided the use of organic solvents in the synthesis and workup process. The in vitro anticancer and trypanocidal activities of the synthesized boronic acids were also evaluated, and it was discovered that the introduction of the boronic acid functionality improved the activity of the boronic tyrphostins. In silico target fishing with the use of a chemogenomic approach suggested that tyrosine-phosphorylation-regulated kinase 1a (DYRK1A) was a potential target for some of the designed compounds.

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Section: Toxicity Assay In Mammalian Primary Cell Linesmentioning

confidence: 72%

Synthesis and Evaluation of the Anticancer and Trypanocidal Activities of Boronic Tyrphostins

et al. 2018

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“…For in vivo studies, a stock solution of the AIA compounds was first prepared in DMSO and then diluted using distilled and sterile water. The final concentration of DMSO never exceeded 10%, which did not provide detectable mice toxicity 18,21. Bz was dissolved in sterilized distilled water supplemented with 3% Tween 80, which did not cause any detectable effect on the mice.…”

Section: Methodsmentioning

confidence: 99%

“…An important structural characteristic of AIAs is that the imino group is linked to the “anilino” nitrogen, while in classical amidines, it is directly attached to an aryl ring 15. Recent findings demonstrated that bis-AIAs are more effective than mono-AIAs and that some of these bis-AIAs are able to reduce the parasitemia in addition to protecting against mortality induced by acute infection with T. cruzi 18–21. In a previous report, our group demonstrated the in vitro efficacy of several bis-AIAs, including DB1867, DB1862 and DB1890B, which exhibited high trypanocidal activity against bloodstream and intracellular forms of T. cruzi superior to that of Bz 22…”

Section: Introductionmentioning

confidence: 99%

Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infection

Silva¹,

Batista²,

Araújo³

et al. 2017

DDDT

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Arylimidamides (AIAs), previously termed as reversed amidines, present a broad spectrum of activity against intracellular microorganisms. In the present study, three novel AIAs were evaluated in a mouse model of Trypanosoma cruzi infection, which is the causative agent of Chagas disease. The bis-AIAs DB1957, DB1959 and DB1890 were chosen based on a previous screening of their scaffolds that revealed a very promising trypanocidal effect at nanomolar range against both the bloodstream trypomastigotes (BTs) and the intracellular forms of the parasite. This study focused on both mesylate salts DB1957 and DB1959 besides the hydrochloride salt DB1890. Our current data validate the high activity of these bis-AIA scaffolds that exhibited EC50 (drug concentration that reduces 50% of the number of the treated parasites) values ranging from 14 to 78 nM and 190 to 1,090 nM against bloodstream and intracellular forms, respectively, also presenting reasonable selectivity indexes and no mutagenicity profile predicted by in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET). Acute toxicity studies using murine models revealed that these AIAs presented only mild toxic effects such as reversible abdominal contractions and ruffled fur. Efficacy assays performed with Swiss mice infected with the Y strain revealed that the administration of DB1957 for 5 consecutive days, with the first dose given at parasitemia onset, reduced the number of BTs at the peak, ranging between 21 and 31% of decrease. DB1957 was able to provide 100% of animal survival, while untreated animals showed 70% of mortality rates. DB1959 and DB1890B did not reduce circulating parasitism but yielded >80% of survival rates.

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“…These results are particularly promising because both aspects, the establishment of the mammalian host infection and the release of trypomastigote forms, are required for the maintenance of the chronic phase of the disease. Nonetheless, in vivo studies will be necessary to validate the antiparasitic effect of MB17 (42,43). This possibility should be carefully evaluated because similar compounds were effective (alone or in combination with other drugs) while other amidine derivatives showed high toxicity in animal models (43).…”

Section: Discussionmentioning

confidence: 99%

“…Nonetheless, in vivo studies will be necessary to validate the antiparasitic effect of MB17 (42,43). This possibility should be carefully evaluated because similar compounds were effective (alone or in combination with other drugs) while other amidine derivatives showed high toxicity in animal models (43).…”

Section: Discussionmentioning

confidence: 99%

An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells

Girard

Crispim

Stolić

et al. 2016

Antimicrob Agents Chemother

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dTrypanosoma cruzi is the etiological agent of Chagas disease, affecting approximately 10 million people in the Americas and with some 40 million people at risk. The objective of this study was to evaluate the anti-T. cruzi activity of three new diamidines that have a 3,4-ethylenedioxy extension of the thiophene core, designated MB17, MB19, and MB38. All three diamidines exhibited dose-dependent inhibition of epimastigote replication. The mechanisms of action of these diamidines were investigated. Unlike MB17 and MB19, MB38 exhibited a significant increase in the number of annexin-propidium iodide double-labeled cells compared to levels in control parasites. As MB17 had shown a lower 50% inhibitory concentration (IC 50 ) against epimastigote growth, the mechanism of action of this drug was studied in more detail. MB17 triggered a decrease in the intracellular ATP levels. As a consequence, MB17 affected the genomic DNA and kinetoplast DNA (kDNA) and impaired the parasite cell cycle. Moreover, MB17 caused DNA fragmentation, with a more severe effect on kDNA than on nuclear DNA, resulting in dyskinetoplastic cells. MB17 was tested for toxicity and effectiveness for the treatment of infected CHO-K 1 cells, exhibiting a 50% cytotoxic concentration (CC 50 ) of 13.47 ؎ 0.37 M and an IC 50 of 0.14 ؎ 0.12 M against trypomastigote release. MB17 also diminished the infection index by 60% at 0.5 M. In conclusion, despite belonging to the same family, these diamidines have different efficiencies. To summarize, MB17 was the most potent of these diamidines against epimastigotes, producing DNA damage preferentially in kDNA, impairing the parasite cell cycle, and decreasing the infection index and trypomastigote release from infected mammalian host cells, with a high selectivity index (SI) (<90). These data suggest that MB17 could be an interesting lead compound against T. cruzi. A merican trypanosomiasis, or Chagas disease, affects approximately 10 million people, with 40 million people at risk of acquiring the infection. Chagas disease is endemic to South and Central America and the southern states of the United States. Currently, it is also spreading in Europe and the rest of North America due to the immigration of infected people, as well as through transmission of the disease by transfusions, transplants, and congenital mechanisms (1, 2). The disease is caused by the protozoan Trypanosoma cruzi, which shares some distinctive features with other trypanosomes, such as the presence of a flagellum and of a kinetoplast, a complex structure bearing the mitochondrial genome. In this case, the mitochondrial genomic DNA is referred to as kinetoplast DNA, or kDNA. It consists of a great number of relaxed circular DNA molecules interlocked with each other to form a catenated DNA network (3). T. cruzi has a complex life cycle, which occurs within invertebrate and vertebrate hosts (4-6). Chagas disease presents two clinical phases, the acute phase, which appears shortly after infection and is characterized by an evident parasitemia and ...

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

Cited by 24 publications

References 37 publications

Synthesis and Evaluation of the Anticancer and Trypanocidal Activities of Boronic Tyrphostins

Synthesis and Evaluation of the Anticancer and Trypanocidal Activities of Boronic Tyrphostins

Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of <em>Trypanosoma cruzi</em> infection

An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells

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