In Vitro
 and
 In Vivo
 Studies of the Biological Activity of Novel Arylimidamides against Trypanosoma cruzi

Araújo, Julianna Siciliano de; Silva, C. F. Da; Batista, D. G. J.; Silva, P. B. Da; Meuser, M. B.; Aiub, Cláudia Alessandra Fortes; Silva, M. F. V. da; Araújo-Lima, Carlos Fernando; Banerjee, Mohua; Farahat, Abdelbasset A.; Stephens, Chad E.; Kumar, Arvind; Boykin, David W.; Soeiro, M. N. C.

doi:10.1128/aac.01403-13

Cited by 13 publications

(20 citation statements)

References 27 publications

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“…Among the diamidines studied, arylimidamides have been shown to be highly effective against T. cruzi and several different species of Leishmania, as well as other intracellular pathogens (13,16). In this study, 10 amidino molecules were tested in vitro following a well-established work flow and methodology, resulting in the determination of the EC 50 , IC 50 , and selectivity index (SI) (24).…”

Section: Discussionmentioning

confidence: 99%

“…The time-kill assay was performed according to a standardized protocol, in which compound activity was evaluated at two time points: after 2 h of treatment, in order to test the ability of compounds to show rapid action against the parasite, and at 24 h of incubation as the endpoint, since more prolonged incubation times affect BT integrity (8,13). In addition, evaluation at the early time point (2 h) allows a head-to-head comparison of the test compounds with other fastacting amidines already assayed by our group and others using protocols similar to those described here (16). The monoamidines (DB2261, DB2262, DB2266, DB2268, and DB2269) with tethered potential intercalation units gave EC 50 s of between 2.14 and 3.37 M against Y strain BT.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a new class of diamidines, arylimidamides, has been found to be effective against several pathogens, including T. cruzi. The excellent trypanocidal activity of this new class of amidines in vitro and in vivo encourages further exploration of the amidine family of compounds (14)(15)(16).…”

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confidence: 99%

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Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi

Simões-Silva

Nefertiti

Araújo

et al. 2016

Antimicrob Agents Chemother

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The current treatment of Chagas disease (CD), based on nifurtimox and benznidazole (Bz), is unsatisfactory. In this context, we performed the phenotypic in vitro screening of novel mono-and diamidines and drug interaction assays with selected compounds. Ten novel amidines were tested for their activities against bloodstream trypomastigote (BT) and amastigote forms of Trypanosoma cruzi (Y and Tulahuen strains) and their toxicities for mammalian host cells (L929 cells and cardiac cells). Seven of 10 molecules were more active than Bz against BT, with the most active compound being the diamidine DB2267 (50% effective concentration [EC 50 ] ‫؍‬ 0.23 M; selectivity index ‫؍‬ 417), which was 28-fold more active and about 3 times more selective than the standard drug. Five of the six monoamidines were also more active than Bz. The combination of DB2267 and DB2236 in fixed-ratio proportions showed an additive effect (sum of fractional inhibitory concentrations < 4) on BT. Interestingly, when intracellular forms were exposed to DB2267, its activity was dependent on the parasite strain, being effective (EC 50 ‫؍‬ 0.87 ؎ 0.05 M) against a discrete typing unit (DTU) II strain (strain Y) but not against a representative DTU VI strain (strain Tulahuen) even when different vehicles (␤-cyclodextrin and dimethyl sulfoxide) were used. The intrinsic fluorescence of several diamidines allowed their uptake to be studied. Testing of the uptake of DB2236 (inactive) and DB2267 (active) by amastigotes of the Y strain showed that the two compounds were localized intracellularly in different compartments: DB2236 in the cytoplasm and DB2267 in the nucleus. Our present data encourage further studies regarding the activities of amidines and provide information which will help with the identification of novel agents for the treatment of CD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi

Simões-Silva

Nefertiti

Araújo

et al. 2016

Antimicrob Agents Chemother

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“…AIAs have extraordinary biological action toward different trypanosomatids, both in vitro13–16 and in vivo 17–19. 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.…”

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

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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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“…The anti-parasitic action of Pt has been known since 1937 (King et al 1937) and in the ensuing years many analogues and derivatives have been synthetized and screened against parasitic organisms. Several of these molecules have demonstrated a wide spectrum of activity against human and veterinary pathogens such as leishmaniasis, human African trypanosomes and T. cruzi (De Souza et al 2004;Soeiro et al 2008Soeiro et al , 2013De Araújo et al 2014). Among novel amidine molecules, the arylimidamides (AIAs) have shown very promising profiles and potent activity against intracellular parasites like Neospora caninum, Leishmania sp and T. cruzi (Soeiro et al 2013).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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S U M M A R YNew more selective and potent drugs are urgently need to treat Chagas disease (CD). Among the many synthetic compounds evaluated against Trypanosoma cruzi, aromatic amidines (AAs) and especially arylimidamides (AIAs) have potent activity against this parasite. Presently, the effect of four mono-amidines (DB2228, DB2229, DB2292 and DB2294), four diamidines (DB2232, DB2235, DB2251 and DB2253) and one AIA (DB2255) was screened in vitro against different forms (bloodstream trypomastigotes -BT and intracellular forms) and strains from discrete typing unit (DTU) I and VI of T. cruzi and their cytotoxic profile on mammalian host cells. Except for DB2253, all molecules were as active as benznidazole (Bz), resulting in 50% of reduction in the number of alive BT, with EC 50 ranging from 2·7 to 10·1 µM after 24 h of incubation. DB2255 was also the most potent against amastigotes (Tulahuen strain) showing similar activity to that of Bz (3 µM). In silico absorption, distribution, metabolism, excretion and toxicity analysis demonstrated probability of human intestinal adsorption, while mutagenicity and inhibition of hERG1 were not predicted, besides giving acceptable predicted volumes of distribution. Our findings contribute for better knowledge regarding the biological effect of this class of aromatic molecules against T. cruzi aiming to identify novel promising agent for CD therapy.

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In Vitro and In Vivo Studies of the Biological Activity of Novel Arylimidamides against Trypanosoma cruzi

Cited by 13 publications

References 27 publications

Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi

Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi

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

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

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