scholarly journals Library of Seleno-Compounds as Novel Agents against Leishmania Species

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Álvaro Martín-Montes ◽  
Daniel Plano ◽  
Rubén Martín-Escolano ◽  
Verónica Alcolea ◽  
Marta Díaz ◽  
...  
Keyword(s):  
Parasite Species ◽  
Low Cost ◽  
Leishmania Species ◽  
Leishmania Braziliensis ◽  
Reference Drug ◽  
Content Type ◽  
Product Profile ◽  
Low Toxicity ◽  
Intracellular Amastigote

ABSTRACT The in vitro leishmanicidal activities of a series of 48 recently synthesized selenium derivatives against Leishmania infantum and Leishmania braziliensis parasites were tested using promastigotes and intracellular amastigote forms. The cytotoxicity of the tested compounds for J774.2 macrophage cells was also measured in order to establish their selectivity. Six of the tested compounds (compounds 8, 10, 11, 15, 45, and 48) showed selectivity indexes higher than those of the reference drug, meglumine antimonate (Glucantime), for both Leishmania species; in the case of L. braziliensis, compound 20 was also remarkably selective. Moreover, data on infection rates and amastigote numbers per macrophage showed that compounds 8, 10, 11, 15, 45, and 48 were the most active against both Leishmania species studied. The observed changes in the excretion product profile of parasites treated with these six compounds were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds were potent inhibitors of Fe superoxide dismutase (Fe-SOD) in the two parasite species considered, whereas their impact on human CuZn-SOD was low. The high activity, low toxicity, stability, low cost of the starting materials, and straightforward synthesis make these compounds appropriate molecules for the development of affordable antileishmanicidal agents.

scholarly journals In Vitro and In Vivo Studies of the Trypanocidal Effect of Novel Quinolines

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
A. S. G. Nefertiti ◽  
M. M. Batista ◽  
P. B. Da Silva ◽  
D. G. J. Batista ◽  
C. F. Da Silva ◽  
...  
Keyword(s):  
Parasite Species ◽  
Oral Absorption ◽  
In Vivo Studies ◽  
Cure Rate ◽  
Reference Drug ◽  
Content Type ◽  
African Trypanosomes ◽  
Highly Active

ABSTRACT Therapies for human African trypanosomiasis and Chagas disease, caused by Trypanosoma brucei and Trypanosoma cruzi, respectively, are limited, providing minimal therapeutic options for the millions of individuals living in very poor communities. Here the effects of 10 novel quinolines are evaluated in silico and by phenotypic studies using in vitro and in vivo models. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties revealed that most molecules did not infringe on Lipinski's rules, which is a prediction of good oral absorption. These quinolines showed high probabilities of Caco2 permeability and human intestinal absorption and low probabilities of mutagenicity and of hERG1 inhibition. In vitro screens against bloodstream forms of T. cruzi demonstrated that all quinolines were more active than the reference drug (benznidazole [Bz]), except for DB2171 and DB2192, with five (DB2187, DB2131, DB2186, DB2191, and DB2217) displaying 50% effective concentrations (EC50s) of <3 μM (4-fold lower than that of Bz). Nine quinolines were more effective than Bz (2.7 μM) against amastigotes, showing EC50s ranging from 0.6 to 0.1 μM. All quinolines were also highly active in vitro against African trypanosomes, showing EC50s of ≤0.25 μM. The most potent and highly selective candidates for each parasite species were tested in in vivo models. Results for DB2186 were promising in mice with T. cruzi and T. brucei infections, reaching a 70% reduction of the parasitemia load for T. cruzi, and it cured 2 out of 4 mice infected with T. brucei. DB2217 was also active in vivo and cured all 4 mice (100% cure rate) with T. brucei infection.

scholarly journals Activity of Bisnaphthalimidopropyl Derivatives against Trypanosoma brucei

2016 ◽  
Vol 60 (4) ◽  
pp. 2532-2536 ◽  
Author(s):  
Nuno A. G. Graça ◽  
Luis Gaspar ◽  
David M. Costa ◽  
Inês Loureiro ◽  
Paul Kong Thoo-Lin ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Murine Model ◽  
Single Unit ◽  
Acute Infection ◽  
Parasite Load ◽  
Reference Drug ◽  
Content Type ◽  
Low Toxicity ◽  
Nanomolar Range

ABSTRACTCurrent treatments for African trypanosomiasis are either toxic, costly, difficult to administer, or prone to elicit resistance. This study evaluated the activity of bisnaphthalimidopropyl (BNIP) derivatives againstTrypanosoma brucei. BNIPDiaminobutane (BNIPDabut), the most active of these compounds, showedin vitroinhibition in the single-unit nanomolar range, similar to the activity in the reference drug pentamidine, and presented low toxicity and adequate metabolic stability. Additionally, using a murine model of acute infection and live imaging, a significant decrease in parasite load in BNIPDabut-treated mice was observed. However, cure was not achieved. BNIPDabut constitutes a new scaffold for antitrypanosomal drugs that deserves further consideration.

Imidazole-containing phthalazine derivatives inhibit Fe-SOD performance in Leishmania species and are active in vitro against visceral and mucosal leishmaniasis

Parasitology ◽  
2015 ◽  
Vol 142 (8) ◽  
pp. 1115-1129 ◽  
Author(s):  
M. SÁNCHEZ-MORENO ◽  
F. GÓMEZ-CONTRERAS ◽  
P. NAVARRO ◽  
C. MARÍN ◽  
I. RAMÍREZ-MACÍAS ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Leishmania Donovani ◽  
Cell Damage ◽  
Leishmania Species ◽  
The Other ◽  
Leishmania Braziliensis ◽  
Reference Drug ◽  
Iron Superoxide Dismutase ◽  
Mucosal Leishmaniasis

SUMMARYThe in vitro leishmanicidal activity of a series of imidazole-containing phthalazine derivatives 1–4 was tested on Leishmania infantum, Leishmania braziliensis and Leishmania donovani parasites, and their cytotoxicity on J774·2 macrophage cells was also measured. All compounds tested showed selectivity indexes higher than that of the reference drug glucantime for the three Leishmania species, and the less bulky monoalkylamino substituted derivatives 2 and 4 were clearly more effective than their bisalkylamino substituted counterparts 1 and 3. Both infection rate measures and ultrastructural alterations studies confirmed that 2 and 4 were highly leishmanicidal and induced extensive parasite cell damage. Modifications to the excretion products of parasites treated with 2 and 4 were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds 2 and 4 were potent inhibitors of iron superoxide dismutase enzyme (Fe-SOD) in the three species considered, whereas their impact on human CuZn-SOD was low. Molecular modelling suggests that 2 and 4 could deactivate Fe-SOD due to a sterically favoured enhanced ability to interact with the H-bonding net that supports the antioxidant features of the enzyme.

scholarly journals Leishmanicidal Activity of Isoselenocyanate Derivatives

2018 ◽  
Vol 63 (2) ◽  
pp. e00904-18 ◽  
Author(s):  
Celia Fernández-Rubio ◽  
Esther Larrea ◽  
José Peña Guerrero ◽  
Eduardo Sesma Herrero ◽  
Iñigo Gamboa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Amphotericin B ◽  
Cell Cycle Progression ◽  
Leishmania Major ◽  
Antitumor Agents ◽  
Peritoneal Macrophages ◽  
Reference Drug ◽  
Content Type ◽  
Leishmanicidal Activity

ABSTRACTConventional chemotherapy against leishmaniasis includes agents exhibiting considerable toxicity. In addition, reports of drug resistance are not uncommon. Thus, safe and effective therapies are urgently needed. Isoselenocyanate compounds have recently been identified with potential antitumor activity. It is well known that some antitumor agents demonstrate effects againstLeishmania. In this study, thein vitroleishmanicidal activities of several organo-selenium and organo-sulfur compounds were tested againstLeishmania majorandLeishmania amazonensisparasites, using promastigotes and intracellular amastigote forms. The cytotoxicity of these agents was measured in murine peritoneal macrophages and their selectivity indexes were calculated. One of the tested compounds, the isoselenocyanate derivative NISC-6, showed selectivity indexes 2- and 10-fold higher than those of the reference drug amphotericin B when evaluated inL. amazonensisandL. major, respectively. The American strain (L. amazonensis) was less sensitive to NISC-6 thanL. major, showing a trend similar to that observed previously for amphotericin B. In addition, we also observed that NISC-6 significantly reduced the number of amastigotes per infected macrophage. On the other hand, we showed that NISC-6 decreases expression levels ofLeishmaniagenes involved in the cell cycle, such astopoisomerase-2(TOP-2),PCNA, andMCM4, therefore contributing to its leishmanicidal activity. The effect of this compound on cell cycle progression was confirmed by flow cytometry. We observed a significant increase of cells in the G1phase and a dramatic reduction of cells in the S phase compared to untreated cells. Altogether, our data suggest that the isoselenocyanate NISC-6 may be a promising candidate for new drug development against leishmaniasis.

scholarly journals Fenbendazole Controls In Vitro Growth, Virulence Potential, and Animal Infection in the Cryptococcus Model

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Haroldo C. de Oliveira ◽  
Luna S. Joffe ◽  
Karina S. Simon ◽  
Rafael F. Castelli ◽  
Flavia C. G. Reis ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Mammalian Cells ◽  
Fungal Pathogens ◽  
Therapeutic Potential ◽  
Low Cost ◽  
Macrophage Infection ◽  
Content Type ◽  
Virulence Potential ◽  
Cryptococcal Disease

ABSTRACT The human diseases caused by the fungal pathogens Cryptococcus neoformans and Cryptococcus gattii are associated with high indices of mortality and toxic and/or cost-prohibitive therapeutic protocols. The need for affordable antifungals to combat cryptococcal disease is unquestionable. Previous studies suggested benzimidazoles as promising anticryptococcal agents combining low cost and high antifungal efficacy, but their therapeutic potential has not been demonstrated so far. In this study, we investigated the antifungal potential of fenbendazole, the most effective anticryptococcal benzimidazole. Fenbendazole was inhibitory against 17 different isolates of C. neoformans and C. gattii at a low concentration. The mechanism of anticryptococcal activity of fenbendazole involved microtubule disorganization, as previously described for human parasites. In combination with fenbendazole, the concentrations of the standard antifungal amphotericin B required to control cryptococcal growth were lower than those required when this antifungal was used alone. Fenbendazole was not toxic to mammalian cells. During macrophage infection, the anticryptococcal effects of fenbendazole included inhibition of intracellular proliferation rates and reduced phagocytic escape through vomocytosis. Fenbendazole deeply affected the cryptococcal capsule. In a mouse model of cryptococcosis, the efficacy of fenbendazole to control animal mortality was similar to that observed for amphotericin B. These results indicate that fenbendazole is a promising candidate for the future development of an efficient and affordable therapeutic tool to combat cryptococcosis.

scholarly journals In vitro antileishmanial activity and iron superoxide dismutase inhibition of arylamine Mannich base derivatives

Parasitology ◽  
2017 ◽  
Vol 144 (13) ◽  
pp. 1783-1790 ◽  
Author(s):  
ALVARO MARTIN-MONTES ◽  
MERY SANTIVAÑEZ-VELIZ ◽  
ELSA MORENO-VIGURI ◽  
RUBÉN MARTÍN-ESCOLANO ◽  
CARMEN JIMÉNEZ-MONTES ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Leishmania Donovani ◽  
Mannich Base ◽  
Neglected Diseases ◽  
Leishmania Braziliensis ◽  
Reference Drug ◽  
Iron Superoxide Dismutase ◽  
Therapeutic Tools

SUMMARYLeishmaniasis is one of the world's most neglected diseases, and it has a worldwide prevalence of 12 million. There are no effective human vaccines for its prevention, and treatment is hampered by outdated drugs. Therefore, research aiming at the development of new therapeutic tools to fight leishmaniasis remains a crucial goal today. With this purpose in mind, we present 20 arylaminoketone derivatives with a very interesting in vitro and in vivo efficacy against Trypanosoma cruzi that have now been studied against promastigote and amastigote forms of Leishmania infantum, Leishmania donovani and Leishmania braziliensis strains. Six out of the 20 Mannich base-type derivatives showed Selectivity Index between 39 and 2337 times higher in the amastigote form than the reference drug glucantime. These six derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at an IC25 dose. In addition, these derivatives were substantially more active against the three Leishmania species tested than glucantime. The mechanism of action of these compounds has been studied, showing a greater alteration in glucose catabolism and leading to greater levels of iron superoxide dismutase inhibition. These molecules could be potential candidates for leishmaniasis chemotherapy.

scholarly journals Nitrotriazole-Based Compounds as Antichagasic Agents in a Long-Treatment In Vivo Assay

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Maria V. Papadopoulou ◽  
William D. Bloomer ◽  
Howard S. Rosenzweig ◽  
Ana Lia Mazzeti ◽  
Karolina Ribeiro Gonçalves ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Adverse Effects ◽  
Myocardial Inflammation ◽  
Reference Drug ◽  
Content Type ◽  
Number Of Treatment ◽  
Better Than

ABSTRACT 3-Nitrotriazole-based compounds belonging to various chemical subclasses were found to be very effective against Chagas disease both in vitro and in vivo after a short administration schedule. In this study, five compounds with specific characteristics were selected to be administered for longer periods of time to mice infected with the virulent Trypanosoma cruzi Y strain to further evaluate their effectiveness as antichagasic agents and whether or not potential adverse effects occur. Benznidazole was included for comparison purposes. Complete parasitemia depletion, weight gain, 100% survival, and a lack of myocardial inflammation were observed with four of the compounds and benznidazole administered intraperitoneally at 15 or 20 mg/kg of body weight/day for 40 days. There was a significant reduction in the number of treatment days (number of doses) necessary to induce parasitemia suppression with all four compounds compared to that required with benznidazole. Partial cures were obtained with only one compound tested at 15 mg/kg/day and on the schedule mentioned above but not with benznidazole. Taken together, our data suggest that these compounds demonstrate potent trypanocidal activity comparable to or better than that of the reference drug, benznidazole, when they are administered at the same dose and on the same schedule.

scholarly journals Leishmanicidal Activity of Nine Novel Flavonoids fromDelphinium staphisagria

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Inmaculada Ramírez-Macías ◽  
Clotilde Marín ◽  
Jesús G. Díaz ◽  
María José Rosales ◽  
Ramón Gutiérrez-Sánchez ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Mammalian Cells ◽  
Mechanisms Of Action ◽  
Reference Drug ◽  
Ultrastructural Alteration ◽  
Leishmanicidal Activity ◽  
Design And Methods ◽  
Electronic Microscope ◽  
Intracellular Amastigote

Objectives. To evaluate thein vitroleishmanicidal activity of nine flavonoid derivatives fromDelphinium staphisagriaagainstL. infantumandL. braziliensis.Design and Methods. Thein vitroactivity of compounds1–9was assayed on extracellular promastigote and axenic amastigote forms and on intracellular amastigote forms of the parasites. Infectivity and cytotoxicity tests were carried on J774.2 macrophage cells using Glucantime as the reference drug. The mechanisms of action were analysed performing metabolite excretion and transmission electronic microscope ultrastructural alteration studies.Results. Nine flavonoids showed leishmanicidal activity against promastigote as well as amastigote forms ofLeishmania infantumandL. braziliensis. These compounds were nontoxic to mammalian cells and were effective at similar concentrations up to or lower than that of the reference drug (Glucantime). The results showed that2″-acetylpetiolaroside (compound8) was clearly the most active.Conclusion. This study has demonstrated that flavonoid derivatives are active againstL. infantumandL. braziliensis.

scholarly journals Knockdown of Host Antioxidant Defense Genes Enhances the Effect of Glucantime on Intracellular Leishmania braziliensis in Human Macrophages

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Jair Téllez ◽  
Ibeth Romero ◽  
Maurilio José Soares ◽  
Mario Steindel ◽  
Alvaro José Romanha
Keyword(s):  
Protein Expression ◽  
Antioxidant Defense ◽  
Expression Patterns ◽  
Public Health Problem ◽  
Control Group ◽  
Glutathione Synthetase ◽  
Leishmania Braziliensis ◽  
Major Public Health Problem ◽  
Content Type

ABSTRACT Leishmaniasis is a neglected tropical disease that affects millions of people worldwide and represents a major public health problem. Information on protein expression patterns and functional roles within the context of Leishmania-infected human monocyte-derived macrophages (MDMs) under drug treatment conditions is essential for understanding the role of these cells in leishmaniasis treatment. We analyzed functional changes in the expression of human MDM genes and proteins during in vitro infection by Leishmania braziliensis and treatment with Glucantime (SbV), using quantitative PCR (qPCR) arrays, Western blotting, confocal microscopy, and small interfering RNA (siRNA) human gene inhibition assays. Comparison of the results from gene transcription and protein expression analyses revealed that glutathione S-transferase π1 (GSTP1), glutamate-cysteine ligase modifier subunit (GCLM), glutathione reductase (GSR), glutathione synthetase (GSS), thioredoxin (TRX), and ATP-binding cassette, subfamily B, member 5 (ABCB5), were strongly upregulated at both the mRNA and protein levels in human MDMs that were infected and treated, compared to the control group. Subcellular localization studies showed a primarily phagolysosomal location for the ABCB5 transporter, indicating that this protein may be involved in the transport of SbV. By inducing a decrease in L. braziliensis intracellular survival in THP-1 macrophages, siRNA silencing of GSTP1, GSS, and ABCB5 resulted in an increased leishmanicidal effect of SbV exposure in vitro. Our results suggest that human MDMs infected with L. braziliensis and treated with SbV express increased levels of genes participating in antioxidant defense, whereas our functional analyses provide evidence for the involvement of human MDMs in drug detoxification. Therefore, we conclude that GSS, GSTP1, and ABCB5 proteins represent potential targets for enhancing the leishmanicidal activity of Glucantime.

scholarly journals Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways

2016 ◽  
Vol 60 (11) ◽  
pp. 6635-6649 ◽  
Author(s):  
Erik L. Allman ◽  
Heather J. Painter ◽  
Jasmeet Samra ◽  
Manuela Carrasquilla ◽  
Manuel Llinás
Keyword(s):  
High Performance ◽  
Parasite Species ◽  
Metabolic Effects ◽  
Content Type ◽  
Lead Compounds ◽  
Metabolomic Profiling ◽  
Metabolic Disruption ◽  
Malaria Box ◽  
Selection Of

ABSTRACTThe threat of widespread drug resistance to frontline antimalarials has renewed the urgency for identifying inexpensive chemotherapeutic compounds that are effective againstPlasmodium falciparum, the parasite species responsible for the greatest number of malaria-related deaths worldwide. To aid in the fight against malaria, a recent extensive screening campaign has generated thousands of lead compounds with low micromolar activity against blood stage parasites. A subset of these leads has been compiled by the Medicines for Malaria Venture (MMV) into a collection of structurally diverse compounds known as the MMV Malaria Box. Currently, little is known regarding the activity of these Malaria Box compounds on parasite metabolism during intraerythrocytic development, and a majority of the targets for these drugs have yet to be defined. Here we interrogated thein vitrometabolic effects of 189 drugs (including 169 of the drug-like compounds from the Malaria Box) using ultra-high-performance liquid chromatography–mass spectrometry (UHPLC-MS). The resulting metabolic fingerprints provide information on the parasite biochemical pathways affected by pharmacologic intervention and offer a critical blueprint for selecting and advancing lead compounds as next-generation antimalarial drugs. Our results reveal several major classes of metabolic disruption, which allow us to predict the mode of action (MoA) for many of the Malaria Box compounds. We anticipate that future combination therapies will be greatly informed by these results, allowing for the selection of appropriate drug combinations that simultaneously target multiple metabolic pathways, with the aim of eliminating malaria and forestalling the expansion of drug-resistant parasites in the field.

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