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 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 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 Intracellular amastigote replication may not be required for successful in vitro selection of miltefosine resistance in Leishmania infantum

2015 ◽  
Vol 114 (7) ◽  
pp. 2561-2565 ◽  
Author(s):  
S. Hendrickx ◽  
A. Mondelaers ◽  
E. Eberhardt ◽  
L. Lachaud ◽  
P. Delputte ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
In Vitro Selection ◽  
Intracellular Amastigote ◽  
Selection Of

scholarly journals Licochalcone a Exhibits Leishmanicidal Activity in vitro and in Experimental Model of Leishmania (Leishmania) Infantum

2020 ◽  
Vol 7 ◽  
Author(s):  
Julia M. Souza ◽  
Érica A. A. de Carvalho ◽  
Ana Carolina B. B. Candido ◽  
Rafael P. de Mendonça ◽  
Maria Fernanda da Silva ◽  
...  
Keyword(s):  
Experimental Model ◽  
Leishmania Infantum ◽  
Parasite Burden ◽  
Negative Control Group ◽  
Negative Control ◽  
Control Group ◽  
Licochalcone A ◽  
Leishmanicidal Activity ◽  
Visceral Leishmaniosis

The efficacy of Licochalcone A (LicoA) and its two analogs were reported against Leishmania (Leishmania) amazonensis and Leishmania (Leishmania) infantum in vitro, and in experimental model of L. (L.) infantum in vitro. Initially, LicoA and its analogs were screened against promastigote forms of L. (L.) amazonensis. LicoA was the most active compound, with IC50 values of 20.26 and 3.88 μM at 24 and 48 h, respectively. Against amastigote forms, the IC50 value of LicoA was 36.84 μM at 48 h. In the next step, the effectivity of LicoA was evaluated in vitro against promastigote and amastigote forms of L. (L.) infantum. Results demonstrated that LicoA exhibited leishmanicidal activity in vitro against promastigote forms with IC50 values of 41.10 and 12.47 μM at 24 and 48 h, respectively; against amastigote forms the IC50 value was 29.58 μM at 48 h. Assessment of cytotoxicity demonstrated that LicoA exhibited moderate mammalian cytotoxicity against peritoneal murine macrophages; the CC50 value was 123.21 μM at 48 h and showed about 30% of hemolytic activity at concentration of 400 μM. L. (L.) infantum-infected hamsters and treated with LicoA at 50 mg/kg for eight consecutive days was able to significantly reduce the parasite burden in both liver and spleen in 43.67 and 39.81%, respectively, when compared with negative control group. These findings suggest that chalcone-type flavonoids can be a promising class of natural products to be considered in the search of new, safe, and effective compounds capable to treat canine visceral leishmaniosis (CVL).

scholarly journals Anti-Trypanosoma cruzieffects of cyclosporin A derivatives: possible role of a P-glycoprotein and parasite cyclophilins

Parasitology ◽  
2007 ◽  
Vol 135 (2) ◽  
pp. 217-228 ◽  
Author(s):  
J. BÚA ◽  
L. E. FICHERA ◽  
A. G. FUCHS ◽  
M. POTENZA ◽  
M. DUBIN ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Mammalian Cells ◽  
Isomerase Activity ◽  
P Glycoprotein ◽  
Demethylase Activity ◽  
Target Molecules ◽  
Intracellular Amastigote

SUMMARYCyclophilins are target molecules for cyclosporin A (CsA), an immunosuppressive antimicrobial drug. We have previously reported thein vitroanti-Trypanosoma cruziactivity of H-7-94 and F-7-62 non-immunosuppressive CsA analogues. In this work, we continue the study of the parasiticidal effect of H-7-94 and F-7-62 CsA analoguesin vitroandin vivoand we analyse 3 new CsA derivatives: MeIle-4-CsA (NIM 811), MeVal-4-CsA (MeVal-4) and D-MeAla-3-EtVal-4-CsA, (EtVal-4). The most efficient anti-T. cruzieffect was observed with H-7-94, F-7-62 and MeVal-4 CsA analogues evidenced as inhibition of epimastigote proliferation, trypomastigote penetration, intracellular amastigote development andin vivo T. cruziinfection. This trypanocidal activity could be due to inhibition of the peptidyl prolylcis-transisomerase activity on theT. cruzirecombinant cyclophilins tested. Furthermore, CsA and F-7-62 derivative inhibited the efflux of rhodamine 123 fromT. cruziepimastigotes, suggesting an interference with a P-glycoprotein activity. Moreover, H-7-94 and F-7-62 CsA analogues were not toxic as shown by cell viability and by aminopyrine-N-demethylase activity on mammalian cells. Our results show that H-7-94, F-7-62 and MeVal-4 CsA analogues expressed the highest inhibiting effects onT. cruzi, being promissory parasiticidal drugs worthy of further studies.

scholarly journals In Vitro Susceptibility to Miltefosine of Leishmania infantum (syn. L. chagasi) Isolates from Different Geographical Areas in Brazil

2021 ◽  
Vol 9 (6) ◽  
pp. 1228
Author(s):  
Caroline Ricce Espada ◽  
Erica V. de Castro Levatti ◽  
Mariana Côrtes Boité ◽  
Dorcas Lamounier ◽  
Jorge Alvar ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Oral Drug ◽  
Efficacy And Safety ◽  
In Vitro Susceptibility ◽  
Intracellular Amastigotes ◽  
Geographic Regions ◽  
Therapeutic Tools ◽  
Cure Rates ◽  
Intracellular Amastigote

Treatment of visceral leishmaniasis in Brazil still relies on meglumine antimoniate, with less than ideal efficacy and safety, making new therapeutic tools an urgent need. The oral drug miltefosine was assayed in a phase II clinical trial in Brazil with cure rates lower than previously demonstrated in India. The present study investigated the susceptibility to miltefosine in 73 Brazilian strains of Leishmania infantum from different geographic regions, using intracellular amastigote and promastigote assays. The EC50 for miltefosine of 13 of these strains evaluated in intracellular amastigotes varied between 1.41 and 4.57 μM. The EC50 of the 73 strains determined in promastigotes varied between 5.89 and 23.7 μM. No correlation between in vitro miltefosine susceptibility and the presence of the miltefosine sensitive locus was detected among the tested strains. The relatively low heterogeneity in miltefosine susceptibility observed for the 73 strains tested in this study suggests the absence of decreased susceptibility to miltefosine in Brazilian L. infantum and does not exclude future clinical evaluation of miltefosine for VL treatment in Brazil.

scholarly journals Identification of Chalcone Derivatives as Inhibitors of Leishmania infantum Arginase and Promising Antileishmanial Agents

2021 ◽  
Vol 8 ◽  
Author(s):  
Andreza R. Garcia ◽  
Danielle M. P. Oliveira ◽  
Jessica B. Jesus ◽  
Alessandra M. T. Souza ◽  
Ana Carolina R. Sodero ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Hydrophobic Interactions ◽  
Docking Studies ◽  
Host Cells ◽  
Polyamine Biosynthesis ◽  
Reference Drug ◽  
Growth And Survival ◽  
Chalcone Derivatives ◽  
Antileishmanial Drug

Arginase catalyzes the hydrolysis of l-arginine into l-ornithine and urea, acting as a key enzyme in the biosynthesis of polyamines. Leishmania growth and survival is dependent on polyamine biosynthesis; therefore, inhibition of Leishmania arginase may be a promising therapeutic strategy. Here, we evaluated a series of thirty-six chalcone derivatives as potential inhibitors of Leishmania infantum arginase (LiARG). In addition, the activity of selected inhibitors against L. infantum parasites was assessed in vitro. Seven compounds exhibited LiARG inhibition above 50% at 100 μM. Among them, compounds LC41, LC39, and LC32 displayed the greatest inhibition values (72.3 ± 0.3%, 71.9 ± 11.6%, and 69.5 ± 7.9%, respectively). Molecular docking studies predicted hydrogen bonds and hydrophobic interactions between the most active chalcones (LC32, LC39, and LC41) and specific residues from LiARG's active site, such as His140, Asn153, His155, and Ala193. Compound LC32 showed the highest activity against L. infantum promastigotes (IC50 of 74.1 ± 10.0 μM), whereas compounds LC39 and LC41 displayed the best results against intracellular amastigotes (IC50 of 55.2 ± 3.8 and 70.4 ± 9.6 μM, respectively). Moreover, compound LC39 showed more selectivity against parasites than host cells (macrophages), with a selectivity index (SI) of 107.1, even greater than that of the reference drug Fungizone®. Computational pharmacokinetic and toxicological evaluations showed high oral bioavailability and low toxicity for the most active compounds. The results presented here support the use of substituted chalcone skeletons as promising LiARG inhibitors and antileishmanial drug candidates.

scholarly journals In Vitro Activities of Position 2 Substitution-Bearing 6-Nitro- and 6-Amino-Benzothiazoles and Their Corresponding Anthranilic Acid Derivatives against Leishmania infantum and Trichomonas vaginalis

2002 ◽  
Vol 46 (8) ◽  
pp. 2588-2594 ◽  
Author(s):  
Florence Delmas ◽  
Carole Di Giorgio ◽  
Maxime Robin ◽  
Nadine Azas ◽  
Monique Gasquet ◽  
...  
Keyword(s):  
Benzoic Acid ◽  
Anthranilic Acid ◽  
Leishmania Infantum ◽  
Trichomonas Vaginalis ◽  
No Production ◽  
Protective Mechanisms ◽  
Anthranilic Acid Derivatives ◽  
Intracellular Amastigote ◽  
Amino Benzoic Acid

ABSTRACT 6-Nitro- and 6-amino-benzothiazoles bearing different chains in position 2 and their corresponding anthranilic acid derivatives were investigated for their in vitro antiparasitic properties against parasites of the species Leishmania infantum and Trichomonas vaginalis compared to their toxicity towards human monocytes. Biological investigations established that the antiprotozoal properties depended greatly on the chemical structure of the position 2 substitution-bearing group. Compound C1, 2-[(2-chloro-benzothiazol-6-yl) amino] benzoic acid, demonstrated an interesting antiproliferative activity towards parasites of the species T. vaginalis, while compound C11, 2-({2-[(2-hydroxyethyl) amino]-benzothiazol-6-yl} amino) benzoic acid, exhibited a promising activity against parasites of the species L. infantum in their intracellular amastigote form. Additional experiments established that compound C11, which was poorly toxic against the promastigote and the extracellular amastigote forms of the parasite, could improve host-protective mechanisms against Leishmania by preventing parasite internalization by macrophages and stimulating NO production, by means of a mechanism synergistically enhanced by the presence of gamma interferon.

In vitro leishmanicidal activity of pyrazole-containing polyamine macrocycles which inhibit the Fe-SOD enzyme of Leishmania infantum and Leishmania braziliensis species

Parasitology ◽  
2014 ◽  
Vol 141 (8) ◽  
pp. 1031-1043 ◽  
Author(s):  
P. NAVARRO ◽  
M. SÁNCHEZ-MORENO ◽  
C. MARÍN ◽  
E. GARCÍA-ESPAÑA ◽  
I. RAMÍREZ-MACÍAS ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
Leishmania Infantum ◽  
Potent Inhibitor ◽  
Cell Damage ◽  
Leishmania Braziliensis ◽  
Infection Rates ◽  
Leishmanicidal Activity ◽  
Parasite Cell ◽  
Macrocyclic Polyamines

SUMMARYThe in vitro leishmanicidal activity and cytotoxicity of pyrazole-containing macrocyclic polyamines 1–4 was assayed on Leishmania infantum and Leishmania braziliensis species. Compounds 1–4 were more active and less toxic than glucantime and both infection rates and ultrastructural alterations confirmed that 1 and 2 were highly leishmanicidal and induced extensive parasite cell damage. Modifications in the excretion products of parasites treated with 1–3 were also consistent with substantial cytoplasm alterations. Compound 2 was highlighted as a potent inhibitor of Fe-SOD in both species, whereas its effect on human CuZn-SOD was poor. Molecular modelling suggested that 2 could deactivate Fe-SOD due to a sterically favoured enhanced ability to interact with the H-bonding net that supports the enzyme`s antioxidant features.

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