scholarly journals Aurones: A Promising Heterocyclic Scaffold for the Development of Potent Antileishmanial Agents

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Marina Roussaki ◽  
Sofia Costa Lima ◽  
Anna-Maria Kypreou ◽  
Panagiotis Kefalas ◽  
Anabela Cordeiro da Silva ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Leishmania Infantum ◽  
Selectivity Index ◽  
Antileishmanial Activity ◽  
Reference Drug ◽  
Antiparasitic Activity ◽  
Methyl Group ◽  
Amastigote Form ◽  
Intracellular Amastigote

A series of (Z)-2-benzylidenebenzofuran-3-(2H)-ones (aurones) bearing a variety of substituents on rings A and B were synthesized and evaluated for their antiparasitic activity against the intracellular amastigote form of Leishmania infantum and their cytotoxicity against human THP1-differentiated macrophages. In general, aurones bearing no substituents on ring A (compounds 4a–4f) exhibit higher toxicity than aurones with 4,6-dimethoxy substitution (compounds 4g–4l). Among the latter, two aurones possessing a 2′-methoxy or a 2′-methyl group (compounds 4i and 4j) exhibit potent antileishmanial activity (IC50=1.3±0.1 μM and IC50=1.6±0.2 μM, resp.), comparable to the activity of the reference drug Amphotericin B, whereas they present significantly lower cytotoxicity than Amphotericin B as deduced by the higher selectivity index.

scholarly journals Surface-Engineered Dendrimeric Nanoconjugates for Macrophage-Targeted Delivery of Amphotericin B: Formulation Development andIn VitroandIn VivoEvaluation

2015 ◽  
Vol 59 (5) ◽  
pp. 2479-2487 ◽  
Author(s):  
Keerti Jain ◽  
Ashwni Kumar Verma ◽  
Prabhat Ranjan Mishra ◽  
Narendra Kumar Jain
Keyword(s):  
Drug Release ◽  
Amphotericin B ◽  
Human Erythrocytes ◽  
Antileishmanial Activity ◽  
Cell Uptake ◽  
Antiparasitic Activity ◽  
Content Type ◽  
Drug Localization

ABSTRACTThe present study aimed to develop an optimized dendrimeric delivery system for amphotericin B (AmB). Fifth-generation (5.0G) poly(propylene imine) (PPI) dendrimers were synthesized, conjugated with mannose, and characterized by use of various analytical techniques, including Fourier transform infrared spectroscopy (FTIR),1H nuclear magnetic resonance (1H-NMR) spectroscopic analysis, and atomic force microscopy (AFM). Mannose-conjugated 5.0G PPI (MPPI) dendrimers were loaded with AmB and evaluated for drug loading efficiency,in vitrodrug release profile, stability, hemolytic toxicity to human erythrocytes, cytotoxicity to and cell uptake by J774A.1 macrophage cells, antiparasitic activity against intracellularLeishmania donovaniamastigotes,in vivopharmacokinetic and biodistribution profiles, drug localization index, toxicity, and antileishmanial activity. AFM showed the nanometric size of the MPPI dendrimers, with a nearly globular architecture. The conjugate showed a good entrapment efficiency for AmB, along with pH-sensitive drug release. Highly significant reductions in toxicity toward human erythrocytes and macrophage cells, without compromising the antiparasitic activity of AmB, were observed. The dendrimeric formulation of AmB showed a significant enhancement of the parasiticidal activity of AmB toward intramacrophagicL. donovaniamastigotes. In thein vitrocell uptake studies, the formulation showed selectivity toward macrophages, with significant intracellular uptake. Further pharmacokinetic and organ distribution studies elucidated the controlled delivery behavior of the formulation. The drug localization index was found to increase significantly in macrophage-rich organs.In vivostudies showed a biocompatible behavior of MPPIA, with negligible toxicity even at higher doses, and promising antileishmanial activity. From the results, we concluded that surface-engineered dendrimers may serve as optimized delivery vehicles for AmB with enhanced activity and low or negligible toxicity.

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 Synthesis and Evaluation of Antileishmanial and Cytotoxic Activity of Benzothiopyrane Derivatives

2019 ◽  
Author(s):  
Cristian Ortiz ◽  
Fernando Echeverri ◽  
Sara Robledo ◽  
Daniela Lanari ◽  
Massimo Curini ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Hydroxy Group ◽  
Selectivity Index ◽  
Antileishmanial Activity ◽  
Antiparasitic Activity ◽  
Intracellular Amastigotes ◽  
Ongoing Effort ◽  
Sar Analysis

As a part of our ongoing effort in the search for promising antileishmanial agents based on the thiochroman scaffold, we prepared a series of substituted 2H-thiochromenes. Thirty-three compounds were evaluated against intracellular amastigotes forms of L. (V) panamensis. Twelve compounds were active with EC50 values lower than 40 μM, and among those three compounds displayed the highest antileishmanial activity with EC50 values below 10 uM. Cytotoxicity was determined against human U-937 macrophages; thus, compounds having electrophilic alkenes (α,β-unsaturated carbonyl, or nitriles) displayed the highest antileishmanial activity but also moderate to high cytotoxicities. Based on SAR analysis, compounds 8d and 10, which differ only in the hydroxy group at C4, were selected as the most promising compounds in this library because good antiparasitic activity and Selectivity Index.

scholarly journals Inhibition of Leishmania mexicana Growth by the Tuberculosis Drug SQ109

2016 ◽  
Vol 60 (10) ◽  
pp. 6386-6389 ◽  
Author(s):  
Verónica García-García ◽  
Eric Oldfield ◽  
Gustavo Benaim
Keyword(s):  
Inhibitory Concentration ◽  
Selectivity Index ◽  
Leishmania Mexicana ◽  
Content Type ◽  
Amastigote Form ◽  
Intracellular Amastigote

ABSTRACTWe report that the tuberculosis drug SQ109 [N-adamantan-2-yl-N′-((E)-3,7-dimethyl-octa-2,6-dienyl)-ethane-1,2-diamine] has potent activity against the intracellular amastigote form ofLeishmania mexicana(50% inhibitory concentration [IC50], ∼11 nM), with a good selectivity index (>500). It is also active against promastigotes (IC50, ∼500 nM) and acts as a protonophore uncoupler, in addition to disrupting Ca2+homeostasis by releasing organelle Ca2+into the cytoplasm, and as such, it is an interesting new leishmaniasis drug hit candidate.

scholarly journals Antileishmanial Activity of Amphotericin B-loaded-PLGA Nanoparticles: An Overview

Materials ◽  
2018 ◽  
Vol 11 (7) ◽  
pp. 1167 ◽  
Author(s):  
Ernesto Palma ◽  
Antonella Pasqua ◽  
Agnese Gagliardi ◽  
Domenico Britti ◽  
Massimo Fresta ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Plga Nanoparticles ◽  
Antileishmanial Activity

scholarly journals In vivo antileishmanial activity and histopathological evaluation in Leishmania infantum infected hamsters after treatment with a furoxan derivative

2017 ◽  
Vol 95 ◽  
pp. 536-547 ◽  
Author(s):  
Letícia de Almeida ◽  
Thaís Gaban Passalacqua ◽  
Luiz Antonio Dutra ◽  
Jéssica N. Varonez da Fonseca ◽  
Rhayanne F. Queiroz Nascimento ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Antileishmanial Activity ◽  
Histopathological Evaluation

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 Identification of Leucinostatins from Ophiocordyceps sp. as Antiparasitic Agents Against Trypanosoma cruzi

2021 ◽  
Author(s):  
Jean A. Bernatchez ◽  
Yun-Seo Kil ◽  
Elany Barbosa da Silva ◽  
Diane Thomas ◽  
Laura-Isobel McCall ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Parasitic Infection ◽  
Antiparasitic Activity ◽  
Gastrointestinal Pathology ◽  
Phenotypic Screen ◽  
Benthic Environment ◽  
Intracellular Amastigote ◽  
Kinetoplastid Parasite

Safe and effective treatments for Chagas disease, a potentially fatal parasitic infection associated with cardiac and gastrointestinal pathology and caused by the kinetoplastid parasite Trypanosoma cruzi, have yet to be developed. Benznidazole and nifurtimox, which are currently the only available drugs against T. cruzi, are associated with severe adverse effects and questionable efficacy in the late stage of the disease. Natural products have proven to be a rich source of new chemotypes for other infectious agents. We utilized a microscopy-based high-throughput phenotypic screen to identify inhibitors of T. cruzi from a library of natural product samples obtained from fungi procured through a Citizen Science Soil Collection Program (https://whatsinyourbackyard.org/), and the Great Lakes (USA) benthic environment. We identified five leucinostatins (A, B, F, NPDG C and NPDG D) as potent inhibitors of the intracellular amastigote form of T. cruzi. Leucinostatin B also showed in vivo efficacy in a mouse model of Chagas disease. Given prior reports that leucinostatins A and B have antiparasitic activity against the related kinetoplastid T. brucei, our findings suggest a potential cross-trypanocidal compound class and provide a platform for further chemical derivatization of a potent chemical scaffold against T. cruzi.

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