Current and Future Chemotherapy for Chagas Disease

Gaspar, Luís; Moraes, Carolina Borsoi; Freitas‐Junior, Lúcio H.; Ferrari, Stefania; Costantino, Luca; Costi, Maria Paola; Coron, Ross P; Smith, Terence Kenneth; Siqueira-Neto, Jair L.; McKerrow, James H.; Cordeiro-da-Silva, Anabela

doi:10.2174/0929867322666151015120804

Cited by 49 publications

(38 citation statements)

References 49 publications

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“…There is an estimate of 6–7 million people currently infected with T. cruzi , and the cost of treatment for CD remains substantial. Since the discovery of T. cruzi as the etiological agent of CD, a cure has been pursued, but no improvements in chemotherapy have been made regarding safety or effectiveness, despite a half century of intense research (Gaspar et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Moderate Treadmill Exercise Training Improves Cardiovascular and Nitrergic Response and Resistance to Trypanosoma cruzi Infection in Mice

et al. 2017

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There is evidence suggesting that exercise training (ET) acts as a factor toward resistance to Trypanosoma cruzi infection. However, the effects of mean arterial pressure (MAP), heart rate (HR), and nitric oxide (NO) during the acute phase of infection has not been elucidated yet. Swiss mice were randomly assigned into four groups: sedentary control (SC, n = 30), trained control (TC, n = 30), sedentary infected (SI, n = 30), and trained infected (TI, n = 30). ET was performed on the treadmill for 9 weeks. After training, the mice were infected with 5 × 103 trypomastigotes of T. cruzi (Y strain) or PBS. We observed resting bradycardia and improved performance in trained animals compared with sedentary ones. On the 20th day post-infection (DPI), we found a decrease in HR in SI animals compared to TI animals (699.73 ± 42.37 vs. 742.11 ± 25.35 bpm, respectively, P < 0.05). We also observed increased production of NO in cardiac tissue on the 20th DPI in the SI group, normalized in TI group (20.73 ± 2.74 vs. 6.51 ± 1.19 μM, respectively). Plasma pro-inflammatory cytokines (IL-12, TNF-α, IFN-γ,) and MCP-1 were increased in SI animals, but decreased in TI animals. The increase in parasitemia on the 15th and 17th DPI in the SI group was attenuated in the TI group. Our results suggest that previous ET plays a preventive role in resistance to T. cruzi infection, modulating cardiovascular aspects, inflammatory reaction, and NO levels of infected mice.

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Section: Introductionmentioning

confidence: 99%

Moderate Treadmill Exercise Training Improves Cardiovascular and Nitrergic Response and Resistance to Trypanosoma cruzi Infection in Mice

et al. 2017

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“…By contrast, in T. cruzi any perturbation of the furan was detrimental to activity with all analogues greater than 100 µM, the only exception being nitro compound 32 with slightly improved activity (entry 6). For L. major, 5-methyl and 5-nitro substitution was tolerated (entries 2 and 6) but changing the substitution position or adding electron-withdrawing groups gave reduced activity (entries [3][4][5]. The compounds showed generally moderate to no activity against HeLa with nitro compound 32 once again the exception at 0.38 µM.…”

Section: Biological Testingmentioning

confidence: 99%

“…Three such diseases are African sleeping sickness, 4 Chagas disease 5 and Leishmaniasis, 6 spread by the related kinetoplastid parasitic causative agents Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp, respectively. These parasites are present in tropical regions across the world; T. brucei in subSaharan Africa, T. cruzi in South America and increasingly in North America 7 and Leishmania throughout the tropics and sub-tropics.…”

Section: Introductionmentioning

confidence: 99%

Simplifying nature: Towards the design of broad spectrum kinetoplastid inhibitors, inspired by acetogenins

Gould

King

Menzies

et al. 2017

Bioorganic & Medicinal Chemistry

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The need for new treatments for the neglected tropical diseases African sleeping sickness, Chagas disease and Leishmaniasis remains urgent with the diseases widespread in tropical regions, affecting the world's very poorest. We have previously reported bis-tetrahydropyran 1,4-triazole analogues designed as mimics of the annonaceous acetogenin natural product chamuvarinin, which maintained trypanocidal activity. Building upon these studies, we here report related triazole compounds with pendant heterocycles, mimicking the original butenolide of the natural product. Analogues were active against T. brucei, with a nitrofuran compound displaying nanomolar trypanocidal activity. Several analogues also showed strong activity against T. cruzi and L. major. Importantly, select compounds gave excellent selectivity over mammalian cells with a furan-based analogue highly selective while remaining active against all three cell lines, thus representing a potential lead for a new broad spectrum kinetoplastid inhibitor.

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“…and Trypanosoma cruzi, respectively, affecting millions of people worldwide (Gaspar et al 2015). The available therapeutic arsenal for the treatment of these diseases is very limited and highly toxic, based on the pentavalent antimonials, amphotericin B, miltefosine and benznidazole (Passero et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Antiprotozoal activity of extracts and isolated triterpenoids of ‘carnauba’ (Copernicia prunifera) wax from Brazil

Almeida

Araújo

Carvalho

et al. 2016

Pharmaceutical Biology

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Context: 'Carnauba' wax is a natural product obtained from the processing of the powder exuded from Copernicia prunifera (Miller) H. E. Moore (Arecaceae). This material is widely used in the Brazilian folk medicine, including the treatment of rheumatism and syphilis. Objective: To investigate the antiprotozoal activity of hexane and EtOH extracts from the 'carnauba' wax as well as from the isolated compounds from the bioactive extracts. Material and methods: Two different samples of 'carnauba' (C. prunifera) waxes -types 1 and 4 -were individually extracted using hexane (EH) and EtOH (EE). Aliquots of hexane (type 1 -EH-1 and EH-4) and EtOH (type 4 -EE-1 and EE-4) extracts were tested against promastigote (2-200 lg/mL in DMSO during 48 h at 24 C) and amastigote (3-150 lg/mL in DMSO during 120 h at 37 C) forms of Leishmania infantum as well as against trypomastigote (3-150 lg/mL in DMSO during 24 h at 37 C) forms of Trypanosoma cruzi. Bioactive extracts EH-1 and EE-4 were subjected to a bioactivity-guided fractionation to afford three dammarane-type triterpenoids (1-3). The in vitro antiprotozoal activities of the obtained compounds were evaluated as described above. Additionally, the cytotoxicity activity of compounds 1-3 against mammalian conjunctive cells (NCTC -2-200 lg/mL in DMSO during 48 h at 37 C) was determined. Results: From the bioactive hexane and EtOH extracts from the 'carnauba' (C. prunifera) wax, were isolated three dammarane-type triterpenoids: (24R Ã )-methyldammar-25-ene-3b,20-diol (carnaubadiol, 1), (24R Ã )-methyldammara-20,25-dien-3-one (2) and (24R Ã )-methyldammara-20,25-dien-3a-ol (3). These compounds were identified based on the analysis of NMR and MS spectroscopic data. Compounds 1-3 were effective against the intracellular amastigotes of L. infantum, with IC 50 values ranging from 8 to 52 lM, while compounds 1 and 3 displayed activity against trypomastigote forms of T. cruzi with IC 50 values of 15 and 35 lM, respectively. The mammalian cytotoxicity assay demonstrated no damage to NCTC conjunctive cells up to 200 lM, except for compound 1, which demonstrated a CC 50 value of 34 lM. Conclusion: Based on the results, it was possible to conclude that the detected antiprotozoal bioactivity of 'carnauba' (C. prunifera) wax extracts could be related to the presence of the natural dammarane triterpenoid derivatives. The results suggested that these compounds could be used as promising scaffolds for drug design studies for leishmaniasis and Chagas disease. ARTICLE HISTORY

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Current and Future Chemotherapy for Chagas Disease

Cited by 49 publications

References 49 publications

Moderate Treadmill Exercise Training Improves Cardiovascular and Nitrergic Response and Resistance to Trypanosoma cruzi Infection in Mice

Moderate Treadmill Exercise Training Improves Cardiovascular and Nitrergic Response and Resistance to Trypanosoma cruzi Infection in Mice

Simplifying nature: Towards the design of broad spectrum kinetoplastid inhibitors, inspired by acetogenins

Antiprotozoal activity of extracts and isolated triterpenoids of ‘carnauba’ (Copernicia prunifera) wax from Brazil

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