Potent and Selective Inhibitors of Trypanosoma cruzi Triosephosphate Isomerase with Concomitant Inhibition of Cruzipain: Inhibition of Parasite Growth through Multitarget Activity.

Triosephosphate isomerase (TIM) is an essential Trypanosoma cruzi enzyme and one of the few validated drug targets for Chagas disease. The known inhibitors of this enzyme behave poorly or have low activity in the parasite. In this work, we used symmetrical diarylideneketones derived from structures with trypanosomicidal activity. We obtained an enzymatic inhibitor with an IC50 value of 86 nm without inhibition effects on the mammalian enzyme. These molecules also affected cruzipain, another essential proteolytic enzyme of the parasite. This dual activity is important to avoid resistance problems. The compounds were studied in vitro against the epimastigote form of the parasite, and nonspecific toxicity to mammalian cells was also evaluated. As a proof of concept, three of the best derivatives were also assayed in vivo. Some of these derivatives showed higher in vitro trypanosomicidal activity than the reference drugs and were effective in protecting infected mice. In addition, these molecules could be obtained by a simple and economic green synthetic route, which is an important feature in the research and development of future drugs for neglected diseases.

Antileishmanial activity of furoquinolines and coumarins from Helietta apiculata.

UNLABELLED: The bark infusion of H. apiculata are used to treat wound healing related to cutaneous leishmaniasis and as anti-inflammatory. AIM OF THE STUDY: To isolate, purify active constituents of H. apiculata stem bark, and evaluate their in vitro and in vivo antileishmanial activities. MATERIALS AND METHODS: Isolation by chromatographic methods and chemical identification of furoquinoline alkaloids and coumarins, then evaluation of the in vitro leishmanicidal activity of these compounds against three strains of Leishmania sp. promastigotes and in vivo against Leishmania amazonensis in Balb/c mice. RESULTS: Furoquinoline alkaloids and coumarins presented a moderate in vitro activity against promastigote forms of Leishmania sp. with IC(50) values in the range between 17 and >50 microg/ml. Balb/c mice infected with Leishmania amazonensis were treated with gamma-fagarine by oral route, or with 3-(1'-dimethylallyl)-decursinol or (-)-heliettin by subscutaneous route for 14 days at 10mg/kg daily. In these conditions, gamma-fagarine, 3-(1'-dimethylallyl)-decursinol and (-)-heliettin showed the same efficacy as the reference drug reducing by 97.4, 95.6 and 98.6% the parasite loads in the lesion, respectively. CONCLUSION: These compounds showed significant efficacy in L. amazonensis infected mice, providing important knowledge to improve its potential role for a future use in the treatment of cutaneous leishmaniasis.

Effects of canthin-6-one alkaloids from Zanthoxylum chiloperone on Trypanosoma cruzi-infected mice.

Canthin-6-one (1), isolated from Zanthoxylum chiloperone (Rutaceae), possesses a broad sprectum of antifungal and leishmanicidal activities. In this study, we have examined the antiparasitic effects of canthin-6-one (1), 5-methoxycanthin-6-one (2), canthin-6-one N-oxide (3), as well as that of the total alkaloids of Zanthoxylum chiloperone stem bark, in Balb/c mice infected either acutely or chronically with Trypanosoma cruzi. The compounds were administered orally or subcutaneously at 5mg/kg/day for 2 weeks, whereas the alkaloidal extract was given at 50mg/kg/day for 2 weeks. The antiparasitic activity was compared with that of benznidazole given at 50mg/kg/day for 2 weeks. In the case of acute infection, parasiteamia was significantly reduced following oral treatment with canthin-6-one (1). Moreover, the total alkaloids of Zanthoxylum chiloperone stem bark led to high levels of parasitological clearance. Seventy days post-infection, the serological response in the acute model was significantly different between oral canthin-6-one (1) and benznidazole-treated mice. Chronic model of the disease showed that both canthin-6-one (1) and the alkaloidal extract at the above dosage induced 80-100% animal survival compared to untreated controls. These results indicate that canthin-6-one (1) exhibits trypanocidal activity in vivo in the mouse model of acute or chronic infection. This is the first demonstration of anti-Trypanosoma cruzi activity for a member of this chemical group (canthinones). Considering the very low toxicity of canthin-6-one (1), our results suggest that long-term oral treatment with this natural product could prove advantageous compared to the current chemotherapy of Chagas disease.

Ocular alterations in patients with cutaneous and mucocutaneous leishmaniasis.

Leishmaniasis is a parasitosis with high prevalence and increasing epidemiologic relevance. Ocular manifestations of visceral leishmaniasis (kala-azar) have been well studied, but less is known about ocular alterations in cutaneous and mucocutaneous leishmaniasis (CL/MCL). Fifty-five patients with CL/MCL and a seronegative control group of 39 were examined ophthalmologically in Paraguay. CL/MCL was diagnosed clinically by detection of the parasite, with serological methods and/or intradermal reaction.