New potent imidazoisoquinolinone derivatives as anti-Trypanosoma cruzi agents: Biological evaluation and structure–activity relationships

Bollini, Mariela; Casal, Juan José; Álvarez, Diego E.; Boiani, Lucı́a; González, Mercedes; Cerecetto, Hugo; Bruno, Ana M.

doi:10.1016/j.bmc.2009.01.011

Cited by 42 publications

(33 citation statements)

References 24 publications

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“…The two compounds showed potent activity when compared to the positive controls pentamidine for L. amazonensis (IC 50 = 6.75 nM) and L. chagasi (IC 50 = 4.0 nM) and benznidazole for T. cruzi (IC 50 = 31.20 μM). The selectivity index (SI), a relevant characteristic for defining hit compounds [18], was calculated for compounds 1 and 2 by dividing their cytotoxic activity against murine macrophages (LC 50 ) by their leishmanicidal and trypanocidal activities (SI = LC 50 /IC 50 ). Macrophages were employed for SI calculation since they are the main host cell for Leishmania and because they were used for the intracellular experiments.…”

Section: Resultsmentioning

confidence: 99%

Antiprotozoal Activity of Quinonemethide Triterpenes from Maytenus ilicifolia (Celastraceae)

et al. 2013

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The present study describes the leishmanicidal and trypanocidal activities of two quinonemethide triterpenes, maytenin (1) and pristimerin (2), isolated from Maytenus ilicifolia root barks (Celastraceae). The compounds were effective against the Trypanosomatidae Leishmania amazonensis and Leishmania chagasi and Trypanosoma cruzi, etiologic agents of leishmaniasis and Chagas’ disease, respectively. The quinonemethide triterpenes 1 and 2 exhibited a marked in vitro leishmanicidal activity against promastigotes and amastigotes with 50% inhibitory concentration (IC50) values of less than 0.88 nM. Both compounds showed IC50 lower than 0.3 nM against Trypanosoma cruzi epimastigotes. The selectivity indexes (SI) based on BALB/c macrophages for L. amazonensis and L. chagasi were 243.65 and 46.61 for (1) and 193.63 and 23.85 for (2) indicating that both compounds presented high selectivity for Leishmania sp. The data here presented suggests that these compounds should be considered in the development of new and more potent drugs for the treatment of leishmaniasis and Chagas’ disease.

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Section: Resultsmentioning

confidence: 99%

Antiprotozoal Activity of Quinonemethide Triterpenes from Maytenus ilicifolia (Celastraceae)

et al. 2013

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“…The compounds assayed (Figure 1) N-phenyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-b]isoquinolin-10-carbothioamide ( C1 ), N-(4-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-b]isoquinolin-10-carbothioamide ( C2 ), N-(4-methylphenyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-b]isoquinolin-10-carbothioamide ( C3 ), and 5-oxo-N-phenyl-1,2,3,5-tetrahydroimidazo[1,2-b]isoquinolin-10-carboxamide ( D ) were synthesized according to Bollini et al [11]. Standard solutions of these compounds were prepared in dimethyl sulphoxide (DMSO), and their final concentrations in the experiments never exceeded 0.5%.…”

Section: Methodsmentioning

confidence: 99%

“…[5, 6], Trypanosoma brucei [7], Plasmodium falciparum [8], and Toxoplasma gondii [9]. Closely related to the tryptanthrin structure (Figure 1( A )), we have synthesized the 2,3-dihydroimidazo[1,2-b]isoquinolin-5(1- H )-one molecule, which is a heterocycle precursor (Figure 1( B )) to then obtain new N-1 or C-10 substituted imidazoquinolinones derivatives, similar to tryptanthrin [10, 11]. Importantly, when a computational analysis was run over, comparing tryptanthrin and the heterocycle precursor structures, which consist in the overlapped structures (HyperChem software, Hypercube.…”

Section: Introductionmentioning

confidence: 99%

“…Inc), a significantly great similarity was found (root-mean-square deviation, RMSD 1.69 × 10 −3 Å; unpublished data). Recalling that thioamide derivatives substituted in C-10 (Figure 1( C )) exhibited the best antichagasic activity on T. cruzi epimastigotes [11], we have therefore selected the compounds of the C series ( C1 , C2 , and C3 , Figure 1), which showed superior activity to that of Nfx, to study their effect in vitro against the different stages of the parasite. D was used as a non-C-10 thioamide substituted imidazoquinolinone derivative (Figure 1( D )).…”

Section: Introductionmentioning

confidence: 99%

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Trypanocidal Activity of Thioamide-Substituted Imidazoquinolinone: Electrochemical Properties and Biological Effects

Frank

Ciccarelli

Bollini

et al. 2013

Evidence-Based Complementary and Alternative Medicine

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Three thioamide-substituted imidazoquinolinone, which possess a heterocyclic center similar to tryptanthrin and are named C1, C2, and C3, were studied regarding (a) their in vitro anti-Trypanosoma cruzi activity, (b) their cytotoxicity and electrochemical behaviour, and (c) their effect on cell viability, redox state, and mitochondrial function. The assayed compounds showed a significant activity against the proliferative forms, but only C1 showed activity on the trypomastigote form (for C1, IC50 epi = 1.49 μM; IC50 amas = 1.74 μM; and IC50 try = 34.89 μM). The presence of an antioxidant compound such as ascorbic acid or dithiotreitol induced a threefold increase in the antiparasitic activity, whereas glutathione had a dual effect depending on its concentration. Our results indicate that these compounds, which exhibited low toxicity to the host cells, can be reduced inside the parasite by means of the pool of low molecular weight thiols, causing oxidative stress and parasite death by apoptosis. The antiparasitic activity of the compounds studied could be explained by a loss of the capacity of the antioxidant defense system of the parasite to keep its intracellular redox state. C1 could be considered a good candidate for in vivo evaluation.

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“…Some of the most relevant examples are the nitroheterocycles 39–41 [82,83,84,85], the N- oxides 42–46 [86,87,88,89,90,91], and some other interesting heterocycles 47–49 [53,92,93,94]. Some of them have passed to the “hit-to-,lead” phase (see below, Section 3) and others, according to their biological behavior, should advance to this stage in the short to medium-term.…”

Section: Medicinal Chemistry In Chagas’ Diseasementioning

confidence: 99%

Synthetic Medicinal Chemistry in Chagas’ Disease: Compounds at The Final Stage of “Hit-To-Lead” Phase

Cerecetto

González

2010

Pharmaceuticals

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Chagas’ disease, or American trypanosomosiasis, has been the most relevant illness produced by protozoa in Latin America. Synthetic medicinal chemistry efforts have provided an extensive number of chemodiverse hits at the “active-to-hit” stage. However, only a more limited number of these have been studied in vivo in models of Chagas’ disease. Herein, we survey some of the cantidates able to surpass the “hit-to-lead” stage discussing their limitations or merit to enter in clinical trials in the short term.

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New potent imidazoisoquinolinone derivatives as anti-Trypanosoma cruzi agents: Biological evaluation and structure–activity relationships

Cited by 42 publications

References 24 publications

Antiprotozoal Activity of Quinonemethide Triterpenes from Maytenus ilicifolia (Celastraceae)

Antiprotozoal Activity of Quinonemethide Triterpenes from Maytenus ilicifolia (Celastraceae)

Trypanocidal Activity of Thioamide-Substituted Imidazoquinolinone: Electrochemical Properties and Biological Effects

Synthetic Medicinal Chemistry in Chagas’ Disease: Compounds at The Final Stage of “Hit-To-Lead” Phase

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