First Description of Marinoquinoline Derivatives' Activity against Toxoplasma gondii.

Toxoplasmosis is a globally prevalent zoonotic disease with significant clinical implications, including neurotoxoplasmosis, a leading cause of cerebral lesions in AIDS patients. The current pharmacological treatments for toxoplasmosis face clinical limitations, necessitating the urgent development of new therapeutics. Natural sources have yielded diverse bioactive compounds, serving as the foundation for clinically used derivatives. The exploration of marine bacteria-derived natural products has led to marinoquinolines, which feature a pyrroloquinoline core and demonstrate in vitro and in vivo anti-Plasmodium activity. This study investigates the in vitro anti-Toxoplasma gondii potential of six marinoquinoline derivatives. Additionally, it conducts absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions, and evaluates the in vivo efficacy of one selected compound. The compounds displayed half-maximal effective concentration (EC50) values between 1.31 and 3.78 µM and half-maximal cytotoxic concentration (CC50) values ranging from 4.16 to 30.51 µM, resulting in selectivity indices (SI) from 3.18 to 20.85. MQ-1 exhibiting the highest in vitro SI, significantly reduced tachyzoite numbers in the peritoneum of RH-infected Swiss mice when it was orally administered at 12.5 mg/kg/day for eight consecutive days. Also, MQ-1 significantly reduced the cerebral parasite burden in chronically ME49 infected C57BL/6 mice when it was orally administered at 25 mg/kg/day for 10 consecutive days. These findings underscore the promising anti-T. gondii activity of marinoquinolines and their potential as novel therapeutic agents against this disease.

Anti-Toxoplasma gondii screening of MMV pandemic response box and evaluation of RWJ-67657 efficacy in chronically infected mice.

Toxoplasmosis is a significant public health concern with limited therapeutic options. The medicines for malaria venture (MMV) developed the pandemic response box (PRB) containing 400 drug-like molecules with broad pathogen activity. The aim of this work is to evaluate PRB compounds for their anti-Toxoplasma gondii activity and identify promising candidates for further evaluation. Screening identified 42 selective compounds with half effective concentration (EC50) ranging from 2.4 to 913.1 nm and half cytotoxic concentration (CC50) ranging from 6 µm to >50 µm. Selectivity index (SI) values (CC50/EC50) ranged from 11 to 17 708. Based on its in silico and in vitro profile and its commercial availability, RWJ-67657 was selected for further studies. Molecular docking analysis showed RWJ-67657 is predicted to bind to T. gondii p38 mitogen-activated protein kinase (TgMAPK). Oral administration of RWJ-67657 (20 mg kg day−1/10 days) significantly reduced parasite burden in chronically infected mice compared to mock-treated group (P < 0.01). These findings highlight the PRB as a promising source for anti-T. gondii compounds, with several showing favourable drug properties, including MMV1634492, MMV002731, MMV1634491, MMV1581551, MMV011565, MMV1581558, MMV1578577, MMV233495 and MMV1580482, firstly described here as anti-T. gondii agents. RWJ-67657 emerges as a valuable drug candidate for experimental chronic cerebral toxoplasmosis therapy.

Repurposing the Medicines for Malaria Venture's COVID Box to discover potent inhibitors of Toxoplasma gondii, and in vivo efficacy evaluation of almitrine bismesylate (MMV1804175) in chronically infected mice.

Toxoplasmosis, caused by the obligate intracellular parasite Toxoplasma gondii, affects about one-third of the world's population and can cause severe congenital, neurological and ocular issues. Current treatment options are limited, and there are no human vaccines available to prevent transmission. Drug repurposing has been effective in identifying anti-T. gondii drugs. In this study, the screening of the COVID Box, a compilation of 160 compounds provided by the "Medicines for Malaria Venture" organization, was conducted to explore its potential for repurposing drugs to combat toxoplasmosis. The objective of the present work was to evaluate the compounds' ability to inhibit T. gondii tachyzoite growth, assess their cytotoxicity against human cells, examine their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, and investigate the potential of one candidate drug through an experimental chronic model of toxoplasmosis. Early screening identified 29 compounds that could inhibit T. gondii survival by over 80% while keeping human cell survival up to 50% at a concentration of 1 µM. The Half Effective Concentrations (EC50) of these compounds ranged from 0.04 to 0.92 µM, while the Half Cytotoxic Concentrations (CC50) ranged from 2.48 to over 50 µM. Almitrine was chosen for further evaluation due to its favorable characteristics, including anti-T. gondii activity at nanomolar concentrations, low cytotoxicity, and ADMET properties. Administering almitrine bismesylate (Vectarion®) orally at dose of 25 mg/kg/day for ten consecutive days resulted in a statistically significant (p < 0.001) reduction in parasite burden in the brains of mice chronically infected with T. gondii (ME49 strain). This was determined by quantifying the RNA of living parasites using real-time PCR. The presented results suggest that almitrine may be a promising drug candidate for additional experimental studies on toxoplasmosis and provide further evidence of the potential of the MMV collections as a valuable source of drugs to be repositioned for infectious diseases.

Drug Repurposing Based on Protozoan Proteome: In Vitro Evaluation of In Silico Screened Compounds against Toxoplasma gondii.

Toxoplasma gondii is a protozoan that infects up to a third of the world's population. This parasite can cause serious problems, especially if a woman is infected during pregnancy, when toxoplasmosis can cause miscarriage, or serious complications to the baby, or in an immunocompromised person, when the infection can possibly affect the patient's eyes or brain. To identify potential drug candidates that could counter toxoplasmosis, we selected 13 compounds which were pre-screened in silico based on the proteome of T. gondii to be evaluated in vitro against the parasite in a cell-based assay. Among the selected compounds, three demonstrated in vitro anti-T. gondii activity in the nanomolar range (almitrine, bortezomib, and fludarabine), and ten compounds demonstrated anti-T. gondii activity in the micromolar range (digitoxin, digoxin, doxorubicin, fusidic acid, levofloxacin, lomefloxacin, mycophenolic acid, ribavirin, trimethoprim, and valproic acid). Almitrine demonstrated a Selectivity Index (provided by the ratio between the Half Cytotoxic Concentration against human foreskin fibroblasts and the Half Effective Concentration against T. gondii tachyzoites) that was higher than 47, whilst being considered a lead compound against T. gondii. Almitrine showed interactions with the Na+/K+ ATPase transporter for Homo sapiens and Mus musculus, indicating a possible mechanism of action of this compound.

Repurposing topical triclosan for cutaneous leishmaniasis: Preclinical efficacy in a murine Leishmania (L.) amazonensis model.

Leishmaniasis remains an important neglected tropical infection caused by the protozoan Leishmania and affects 12 million people in 98 countries. The treatment is limited with severe adverse effects. In the search for new therapies, the drug repositioning and combination therapy have been successfully applied to neglected diseases. The aim of the present study was to evaluate the in vitro and in vivo anti-Leishmania (Leishmania) amazonensis potential of triclosan, an approved topical antimicrobial agent used for surgical procedures. in vitro phenotypic studies of drug-treated parasites were performed to evaluate the lethal action of triclosan, accompanied by an isobolographic ex-vivo analysis with the association of triclosan and miltefosine. The results showed that triclosan has activity against L. (L.) amazonensis intracellular amastigotes, with a 50% inhibitory concentration of 16 µM. By using fluorescent probes and transmission electron microscopy, a pore-forming activity of triclosan toward the parasite plasma membrane was demonstrated, leading to depolarization of the mitochondrial membrane potential and reduction of the reactive oxygen species levels in the extracellular promastigotes. The in vitro interaction between triclosan and miltefosine in the combination therapy assay was classified as additive against intracellular amastigotes. Leishmania-infected mice were treated with topical triclosan (1% base cream for 14 consecutive days), and showed 89% reduction in the parasite burden. The obtained results contribute to the investigation of new alternatives for the treatment of cutaneous leishmaniasis and suggest that the coadministration of triclosan and miltefosine should be investigated in animal models.

Aspectos da epidemiologia dos acidentes com escorpiões no estado de São Paulo e no município de Jundiaí, Brasil / Aspects of epidemiology of the accidents with scorpions in the State of São Paulo and in the municipality of Jundiaí, Brazil

Realizou-se estudo retrospectivo, quantitativo e descritivo-analítico dos indicadores epidemiológicos obtidos das fichas de investigação de acidentes por animais peçonhentos, notificados no Sistema de Informação de Agravos de Notificação (SINAN), cujos dados foram obtidos por meio do Departamento de Informática do Sistema Único de Saúde do Brasil (DATASUS) pertencente ao Ministério da Saúde. Foram notificados 222.302 casos de acidentes por animais peçonhentos no estado de São Paulo e 1.571 no município de Jundiaí, de 2007 a 2017. Desses, respectivamente 116.705 e 509 notificações corresponderam a acidentes causados por escorpiões. O sexo mais acometido foi o masculino, com 60% dos casos. Em Jundiaí, as faixas etárias de 20-39 e 40-59 respondem por 69% dos acidentes e a escolaridade das vítimas foi ignorada em 69% das notificações. A maioria dos casos evoluiu para cura. Nota-se aumento gradual do número de acidentes por escorpiões no estado e em Jundiaí ao longo dos anos, o que demanda intensificar as medidas de controle e prevenção, para controlar a população desses aracnídeos de risco à saúde humana. Faz-se necessário também, intensificar as ações de educação em saúde, compartilhando informações sobre fatores de risco e divulgando ações preventivas contra acidentes com escorpiões.

Laboratory Diagnosis of Cutaneous and Visceral Leishmaniasis: Current and Future Methods.

Leishmaniasis is a neglected tropical disease with two main clinical forms: cutaneous and visceral leishmaniasis. Diagnosis of leishmaniasis is still a challenge, concerning the detection and correct identification of the species of the parasite, mainly in endemic areas where the absence of appropriate resources is still a problem. Most accessible methods for diagnosis, particularly in these areas, do not include the identification of each one of more than 20 species responsible for the disease. Here, we summarize the main methods used for the detection and identification of leishmaniasis that can be performed by demonstration of the parasite in biological samples from the patient through microscopic examination, by in vitro culture or animal inoculation; by molecular methods through the detection of parasite DNA; or by immunological methods through the detection of parasite antigens that may be present in urine or through the detection of specific antibodies against the parasite. Potential new methods that can be applied for laboratory diagnosis of leishmaniasis are also discussed.

Efficacy of a series of alpha-pyrone derivatives against Leishmania (L.) infantum and Trypanosoma cruzi.

The neglected tropical diseases Chagas disease and leishmaniasis affect together more than 20 million people living mainly in developing countries. The mainstay of treatment is chemotherapy, however the drugs of choice, which include benznidazole and miltefosine, are toxic and have numerous side effects. Safe and effective therapies are urgently needed. Marine alpha-pyrones have been previously identified as scaffolds with potential antiprotozoan activities. In this work, using a phenotypic screen, twenty-seven examples of 3-substituted 4-hydroxy-6-methyl alpha-pyrones were synthesized and their antiparasitic efficacy evaluated against Leishmania (L.) infantum and Trypanosoma cruzi in order to evaluate structure-activity relationships within the series. The mechanism of action and the in vivo efficacy of the most selective compound against T. cruzi were evaluated using different techniques. In vitro data indicated that compounds 8, 15, 25, 26 and 28 presented IC50 values in the range between 13 and 54 µM against L. infantum intracellular amastigotes. Among them, hexanoyl substituted pyrone 8 was the most selective and potent, with a Selectivity Index (SI) > 14. Fifteen of the alpha-pyrones were effective against T. cruzi trypomastigotes, with 3-undecanoyl (11) and 3-tetradecanoyl (12) substituted pyrones being the most potent against trypomastigotes, with IC50 values of 1 and 2 µM, respectively, and SI higher than 70. Using flow cytometry and fluorescent-based assays, pyrone 12 was found to induce hyperpolarization of the mitochondrial membrane potential of T. cruzi, without affecting plasma membrane permeability. An experimental acute phase-murine model, demonstrated that in vivo dosing of 12 (30 mg/kg/day; 5 days), had no efficacy at the first parasitemia onset of T. cruzi, but reduced the second onset by 55% (p < 0.05), suggesting a delayed action in BALB/c mice. Additionally, a histopathology study demonstrated no toxic effects to the treated mice. The finding that several 3-substituted alpha-pyrones have in vitro efficacy against both L. infantum and T. cruzi, and that one analogue exhibited moderate and non-toxic in vivo efficacy against T. cruzi is encouraging, and suggests that this compound class should be explored as long-term treatments in experimental Chagas disease.

Efficacy of a series of alpha-pyrone derivatives against Leishmania (L. ) infantum and Trypanosoma cruzi

The neglected tropical diseases Chagas disease and leishmaniasis affect together more than 20 million people living mainly in developing countries. The mainstay of treatment is chemotherapy, however the drugs of choice, which include benznidazole and miltefosine, are toxic and have numerous side effects. Safe and effective therapies are urgently needed. Marine alpha-pyrones have been previously identified as scaffolds with potential antiprotozoan activities. In this work, using a phenotypic screen, twenty-seven examples of 3-substituted 4-hydroxy-6-methyl alpha-pyrones were synthesized and their antiparasitic efficacy evaluated against Leishmania (L.) infantum and Trypanosoma cruzi in order to evaluate structure-activity relationships within the series. The mechanism of action and the in vivo efficacy of the most selective compound against T. cruzi were evaluated using different techniques. In vitro data indicated that compounds 8, 15, 25, 26 and 28 presented IC50 values in the range between 13 and 54 µM against L. infantum intracellular amastigotes. Among them, hexanoyl substituted pyrone 8 was the most selective and potent, with a Selectivity Index (SI) > 14. Fifteen of the alpha-pyrones were effective against T. cruzi trypomastigotes, with 3-undecanoyl (11) and 3-tetradecanoyl (12) substituted pyrones being the most potent against trypomastigotes, with IC50 values of 1 and 2 µM, respectively, and SI higher than 70. Using flow cytometry and fluorescent-based assays, pyrone 12 was found to

As doenças tropicais negligenciadas A doença de Chagas e a leishmaniose afetam juntas mais de 20 milhões de pessoas que vivem principalmente nos países em desenvolvimento. O suporte principal do tratamento é a quimioterapia, no entanto, os medicamentos de escolha, que incluem benznidazol e miltefosina, são tóxicos e têm inúmeros efeitos colaterais. Terapias seguras e eficazes são urgentemente necessárias. As alfa-pironas marinhas foram previamente identificadas como andaimes com potenciais atividades antiprotozoárias. Neste trabalho, usando uma tela fenotípica, sintetizaram-se 27 exemplos de 4-hidroxi-6-metil alfa-pironas 3-substituídas e avaliou-se sua eficácia antiparasitária contra Leishmania (L.) infantum e Trypanosoma cruzi para avaliar a estrutura relações de atividade dentro da série. O mecanismo de ação e a eficácia in vivo do composto mais seletivo contra T. cruzi foram avaliados por diferentes técnicas. Dados in vitro indicaram que os compostos 8, 15, 25, 26 e 28 apresentaram valores de IC50 na faixa entre 13 e 54 µM contra amastigotas intracelulares de L. infantum. Entre elas, a pirona 8 substituída com hexanoílo foi a mais seletiva e potente, com um índice de seletividade (SI)> 14. Quinze das alfa-pironas foram eficazes contra as tripomastigotas de T. cruzi, com 3-undecanoil (11) e 3-tetradecanoil ( 12) pironas substituídas sendo as mais potentes contra tripomastigotas, com valores de IC50 de 1 e 2 µM, respectivamente, e SI superiores a 70. Usando citometria de fluxo e ensaios à base de fluorescência, a pirona 12 foi encontrada para

Investigation of Calcium Channel Blockers as Antiprotozoal Agents and Their Interference in the Metabolism of Leishmania (L.) infantum.

Leishmaniasis and Chagas disease are neglected parasitic diseases endemic in developing countries; efforts to find new therapies remain a priority. Calcium channel blockers (CCBs) are drugs in clinical use for hypertension and other heart pathologies. Based on previous reports about the antileishmanial activity of dihydropyridine-CCBs, this work aimed to investigate whether the in vitro anti-Leishmania infantum and anti-Trypanosoma cruzi activities of this therapeutic class would be shared by other non-dihydropyridine-CCBs. Except for amrinone, our results demonstrated antiprotozoal activity for fendiline, mibefradil, and lidoflazine, with IC50 values in a range between 2 and 16 µM and Selectivity Index between 4 and 10. Fendiline demonstrated depolarization of mitochondrial membrane potential, with increased reactive oxygen species production in amlodipine and fendiline treated Leishmania, but without plasma membrane disruption. Finally, in vitro combinations of amphotericin B, miltefosine, and pentamidine against L. infantum showed in isobolograms an additive interaction when these drugs were combined with fendiline, resulting in overall mean sum of fractional inhibitory concentrations between 0.99 and 1.10. These data demonstrated that non-dihydropyridine-CCBs present antiprotozoal activity and could be useful candidates for future in vivo efficacy studies against Leishmaniasis and Chagas' disease.

Estudo da atividade Anti-Leishmania e Anti-Trypanosoma Cruzi de bloqueadores de canal de cálcio, furazolidona e buparvaquona: reposicionamento, associações de fármacos e formulações lipossomais / Study of the antileishmanial and Anti-Trypanosoma cruzi activity of calcium channel blockers, furazolidone and buparvaquone: drug repurposing, drug combinations and liposomal formulations

A pesquisa de medicamentos mais eficazes e que atendam aos padrões atuais de segurança é considerada uma prioridade para o tratamento da leishmaniose e doenças de Chagas. Os principais objetivos do presente trabalho foram: avaliar a atividade anti-Leishmania in vitro e in vivo de bloqueadores de canal de cálcio (BCC) e dos fármacos buparvaquona e furazolidona; realizar combinações de BCC com os principais fármacos usados na clínica da leishmaniose visceral (LV); desenvolver formulações lipossomais de buparvaquona, furazolidona e nimodipino e desenvolver um protocolo de PCR em tempo real (qPCR) visando quantificar a carga parasitária de hamsteres infectados com L. (L.) infantum chagasi após tratamento experimental. Buparvaquona, furazolidona e doze dos treze BBC testados (anlodipino, azelnidipino, bepridil, cilnidipino, fendilina, lercanidipino, lidoflazina, mibefradil nicardipino, nifedipino, nimodipino e nitrendipino) apresentaram atividade in vitro contra diferentes espécie de Leishmania e contra Trypanosoma cruzi, com moderada a baixa citotoxicidade contra células de mamíferos. O estudo de QSAR das 1,4-diidropiridinas permitiu a predição de dois análogos com possível atividade antiprotozoária. Anlodipino, bepridil, fendilina e nimodipino não apresentaram redução na carga parasitária de hamteres infectados com...

Investigation into in vitro anti-leishmanial combinations of calcium channel blockers and current anti-leishmanial drugs

The need for drug combinations to treat visceral leishmaniasis (VL) arose because of resistance to antimonials, the toxicity of current treatments and the length of the course of therapy. Calcium channel blockers (CCBs) have shown anti-leishmanial activity; therefore their use in combination with standard drugs could provide new alternatives for the treatment of VL. In this work, in vitro isobolograms of Leishmania (Leishmania) chagasi using promastigotes or intracellular amastigotes were utilised to identify the interactions between five CCBs and the standard drugs pentamidine, amphotericin B and glucantime. The drug interactions were assessed with a fixed ratio isobologram method and the fractional inhibitory concentrations (FICs), sum of FICs (ΣFICs) and the overall mean ΣFIC were calculated for each combination. Graphical isobologram analysis showed that the combination of nimodipine and glucantime was the most promising in amastigotes with an overall mean ΣFIC value of 0.79. Interactions between CCBs and the anti-leishmanial drugs were classified as indifferent according to the overall mean ΣFIC and the isobologram graphic analysis.

Investigation into in vitro anti-leishmanial combinations of calcium channel blockers and current anti-leishmanial drugs.

The need for drug combinations to treat visceral leishmaniasis (VL) arose because of resistance to antimonials, the toxicity of current treatments and the length of the course of therapy. Calcium channel blockers (CCBs) have shown anti-leishmanial activity; therefore their use in combination with standard drugs could provide new alternatives for the treatment of VL. In this work, in vitro isobolograms of Leishmania (Leishmania) chagasi using promastigotes or intracellular amastigotes were utilised to identify the interactions between five CCBs and the standard drugs pentamidine, amphotericin B and glucantime. The drug interactions were assessed with a fixed ratio isobologram method and the fractional inhibitory concentrations (FICs), sum of FICs (ΣFICs) and the overall mean ΣFIC were calculated for each combination. Graphical isobologram analysis showed that the combination of nimodipine and glucantime was the most promising in amastigotes with an overall mean ΣFIC value of 0.79. Interactions between CCBs and the anti-leishmanial drugs were classified as indifferent according to the overall mean ΣFIC and the isobologram graphic analysis.

Therapeutic evaluation of free and liposome-loaded furazolidone in experimental visceral leishmaniasis.

Drug delivery systems are promising pharmaceutical formulations used to improve the therapeutic index of drugs. In this study, we developed a liposomal formulation of furazolidone that targets Leishmania (Leishmania) chagasi amastigotes in a hamster model. Using laser scanning confocal microscopy, it was demonstrated that the liposomal drug co-localised with L. (L.) chagasi amastigotes within macrophages. Liposomal furazolidone administered intraperitoneally at 0.5mg/kg for 12 consecutive days reduced spleen (74%) and liver (32%) parasite burden at a 100-fold lower dose than the free drug. Free furazolidone (50mg/kg) also effectively reduced spleen (82.5%) and liver (85%) parasites; its in vitro activity against promastigotes and intracellular amastigotes demonstrated a high degree of parasite selectivity. Thus, furazolidone, both in the free and liposome-loaded formulation, is an effective inhibitor of L. (L.) chagasi, representing a possible cost-effective drug candidate for the treatment of visceral leishmaniasis.

Antitrypanosomal activity of a diterpene and lignans isolated from Aristolochia cymbifera.

Bioguided fractionation of extract from the leaves of Aristolochia cymbifera led to the isolation of the furofuran lignans fargesin, epieudesmin, and sesamin; the dibenzylbutyrolactone lignans hinokinin and kusunokinin; and an ENT-labdane diterpene named copalic acid. Our data demonstrated that copalic acid and kusunokinin were the most active compounds against trypomastigotes of Trypanosoma cruzi. Additionally, copalic acid demonstrated the highest parasite selectivity as a result of low toxicity to mammalian cells, despite a considerable hemolytic activity at higher concentrations. Among the isolated compounds, kusunokinin could be considered the most promising candidate, as it displayed significant activity against intracellular amastigotes (IC(50) = 17 µM) and trypomastigotes (IC(50) = 51 µM) without hemolytic activity. Fargesin, hinokinin, epieudesmin, and sesamin were also effective against trypomastigotes, but these compounds were highly toxic to mammalian cells and no parasite selectivity could be identified. The need for novel drugs for American trypanosomiasis is evident, and these secondary metabolites from A. cymbifera represent a useful tool for drug design.

Furazolidone is a selective in vitro candidate against Leishmania (L.) chagasi: an ultrastructural study.

The current treatment for leishmaniasis is unsatisfactory due to toxic side effects, high cost, and problems with drug resistance. Various approaches have been used to identify novel drug candidates to treat Leishmania sp. parasites including the use of re-purposed drugs. Furazolidone is a nitrofuran derivative with antiprotozoal and antibacterial activity and is used for the treatment of giardiasis. In the present work, we determined the in vitro antileishmanial activity of furazolidone and its ability to induce ultrastructural alterations of parasites. Promastigotes of Leishmania (L.) chagasi, Leishmania (V.) braziliensis, Leishmania (L.) major, and Leishmania (L.) amazonensis were highly susceptible to furazolidone, with IC(50) values ranging between 0.47 and 0.73 microg/mL. Furazolidone was also very effective against L. chagasi intracellular amastigotes, and despite mammalian cytotoxicity, the selectivity index was 8.0 in human monocytes. The drug also had limited toxicity in mice erythrocytes. Furazolidone demonstrated specific activity against Leishmania, a potential consequence of the lack of macrophage nitric oxide activation. As determined by electron transmission microscopy, drug treatment induced severe damage to the parasite mitochondria and nucleus. This older oral drug is an effective agent for the treatment of L. (L.) chagasi in vitro and is a novel candidate for further experimental studies.

Antileishmanial activity and ultrastructural alterations of Leishmania (L.) chagasi treated with the calcium channel blocker nimodipine.

In a search for novel antileishmanial drugs, we investigated the activity of the calcium channel blocker nimodipine against Leishmania spp. and explored the ultrastructural damages of parasites induced by nimodipine after a short period of incubation. Nimodipine was highly effective against promastigotes and intracellular amastigotes of Leishmania (L.) chagasi, with 50% inhibitory concentration values of 81.2 and 21.5 muM, respectively. Nimodipine was about fourfold more effective than the standard pentavalent antimony against amastigotes and showed a Selectivity Index of 4.4 considering its mammalian cells toxicity. Leishmania (L.) amazonensis and Leishmania (L.) major promastigotes were also susceptible to nimodipine in a range concentration between 31 and 128 muM. Ultrastructural studies of L. (L.) chagasi revealed intense mitochondria damage and plasma membrane blebbing, resulting in a leishmanicidal effect as demonstrated by the lack of mitochondrial oxidative metabolism. The amastigote-killing effect suggests other mechanism than macrophage activation, as no upregulation of nitric oxide was seen. This calcium channel blocker is an effective in vitro antileishmanial compound and if adequately studied could be used as a novel drug candidate or as a novel drug lead compound for drug design studies against leishmaniasis.

Antiparasitic activity of biochanin A, an isolated isoflavone from fruits of Cassia fistula (Leguminosae).

The fractionation through bioguided antileishmanial activity of the dichloromethane extract of Cassia fistula fruits (Leguminosae) led to the isolation of the active isoflavone biochanin A, identified by spectroscopic methods. This compound showed 50% effective concentration (EC(50)) value of 18.96 microg/mL against promastigotes of Leishmania (L.) chagasi. The cytotoxicity of this substance against peritoneal macrophages resulted in an EC(50) value of 42.58 microg/mL. Additionally, biochanin A presented an anti-Trypanosoma-cruzi activity, resulting in an EC(50) value of 18.32 microg/mL and a 2.4-fold more effectiveness than benznidazole. These results contribute with novel antiprotozoal compounds for future drug design studies.

Estudo da atividade anti-leishmania de compostos de invertebrados marinhos brasileiros

Doenças parasitárias causadas por protozoários afetam grandes populações marginais ao processo econômico globalizado, e desta forma, não são consideradas como mercados potenciais para o desenvolvimento de drogas. A leishmaniose visceral é uma doença progressiva e fatal, sendo endêmica em 65 países e atualmente incluída entre as seis endemias mais importantes segundo a OMS. O tratamento dá-se pela administração de medicamentos com elevada toxicidade como os antimoniais pentavalentes, anfotericina B e pentamidina, demonstrando um restrito arsenal terapêutico, muitas vezes superado por relatos de resistência. Produtos naturais são importante fonte de novos compostos antiparasitários. Compostos bioativos de invertebrados marinhos vêm contribuindo para uma extensa pesquisa na área farmacêutica, porém quase inexistente em protozoários. O presente trabalho teve como objetivo a avaliação da atividade in vitro de cnidários marinhos da costa brasileira em Leishmania (L.) chagasi. Foi realizada uma triagem dos extratos metanólicos de oito espécies de invertebrados marinhos do Filo Cnidaria (espécies Aiptasia pallida, Carijoa riisei, Heterogorgia uatumani, Leptogorgia punicea, Macrorhynchia philippina, Palythoa caribaeorum, Physalia physalis e Zoanthus sociatus), coletados na região de São Sebastião/SP, com o objetivo de selecionar aqueles com atividade anti-Leishmania. Os extratos foram submetidos a testes in vitro com promastigotas de L. (L.) chagasi e a citotoxicidade avaliada em macrófagos peritoneais de camundongos BALB/c. A viabilidade celular foi determinada utilizando o método do MTT. As espécies C. riisei, H. uatumani, L. punicea e M. philippina apresentaram atividade anti-Leishmania, mostrando valores de CE50 (Concentração Efetiva 50%) entre 2.8 e 93.3 μg/mL. As espécies L. punicea e M. philippina foram fracionadas por meio de diferentes técnicas cromatográficas, visando ao isolamento...

Estudo da atividade anti-leishmania de compostos de invertebrados marinhos brasileiros / Pharmacology study of bioactive compounds of marine invertebrates in leishmaniasis

Doenças parasitárias causadas por protozoários afetam grandes populações marginais ao processo econômico globalizado, e desta forma, não são consideradas como mercados potenciais para o desenvolvimento de drogas. A leishmaniose visceral é uma doença progressiva e fatal, sendo endêmica em 65 países e atualmente incluída entre as seis endemias mais importantes segundo a OMS. O tratamento dá-se pela administração de medicamentos com elevada toxicidade como os antimoniais pentavalentes, anfotericina B e pentamidina, demonstrando um restrito arsenal terapêutico, muitas vezes superado por relatos de resistência. Produtos naturais são importante fonte de novos compostos antiparasitários. Compostos bioativos de invertebrados marinhos vêm contribuindo para uma extensa pesquisa na área farmacêutica, porém quase inexistente em protozoários. O presente trabalho teve como objetivo a avaliação da atividade in vitro de cnidários marinhos da costa brasileira em Leishmania (L.) chagasi. Foi realizada uma triagem dos extratos metanólicos de oito espécies de invertebrados marinhos do Filo Cnidaria (espécies Aiptasia pallida, Carijoa riisei, Heterogorgia uatumani, Leptogorgia punicea, Macrorhynchia philippina, Palythoa caribaeorum, Physalia physalis e Zoanthus sociatus), coletados na região de São Sebastião/SP, com o objetivo de selecionar aqueles com atividade anti-Leishmania. Os extratos foram submetidos a testes in vitro com promastigotas de L. (L.) chagasi e a citotoxicidade avaliada em macrófagos peritoneais de camundongos BALB/c. A viabilidade celular foi determinada utilizando o método do MTT. As espécies C. riisei, H. uatumani, L. punicea e M. philippina apresentaram atividade anti-Leishmania, mostrando valores de CE50 (Concentração Efetiva 50%) entre 2.8 e 93.3 μg/mL. As espécies L. punicea e M. philippina foram fracionadas por meio de diferentes técnicas cromatográficas, visando ao isolamento do composto efetivo contra L. (L.) chagasi...