scholarly journals Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

2016 ◽  
Vol 60 (6) ◽  
pp. 3802-3812 ◽  
Author(s):  
Ylenia Baquedano ◽  
Verónica Alcolea ◽  
Miguel Ángel Toro ◽  
Killian Jesús Gutiérrez ◽  
Paul Nguewa ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Inhibitory Activity ◽  
Leishmania Infantum ◽  
Trypanothione Reductase ◽  
Content Type ◽  
Bioactive Scaffolds ◽  
Lead Compounds ◽  
Novel Structures ◽  
Micromolar Range

A series of new selenocyanates and diselenides bearing interesting bioactive scaffolds (quinoline, quinoxaline, acridine, chromene, furane, isosazole, etc.) was synthesized, and theirin vitroleishmanicidal activities againstLeishmania infantumamastigotes along with their cytotoxicities in human THP-1 cells were determined. Interestingly, most tested compounds were active in the low micromolar range and led us to identify four lead compounds (1h, 2d, 2e, and 2f) with 50% effective dose (ED50) values ranging from 0.45 to 1.27 μM and selectivity indexes of >25 for all of them, much higher than those observed for the reference drugs. These active derivatives were evaluated against infected macrophages, and in order to gain preliminary knowledge about their possible mechanism of action, the inhibition of trypanothione reductase (TryR) was measured. Among these novel structures, compounds 1h (3,5-dimethyl-4-isoxazolyl selenocyanate) and 2d [3,3′-(diselenodiyldimethanediyl)bis(2-bromothiophene)] exhibited good association between TryR inhibitory activity and antileishmanial potency, pointing to 1h, for its excellent theoretical ADME (absorption, distribution, metabolism, and excretion) properties, as the most promising lead molecule for leishmancidal drug design.

Novel Scaffolds for Leishmania infantum Trypanothione Reductase Inhibitors Derived from Brazilian Natural Products Biodiversity

2021 ◽  
Vol 18 (4) ◽  
pp. 398-418
Author(s):  
Vinícius Guimarães da Paixão ◽  
Samuel Silva da Rocha Pita
Keyword(s):  
Natural Products ◽  
Leishmania Infantum ◽  
In Vitro Assays ◽  
Current Therapy ◽  
Pharmacokinetic Analysis ◽  
Trypanothione Reductase ◽  
Resistant Species ◽  
Reductase Inhibitors ◽  
Thiol Redox

Background: Leishmania infantum causes the most lethal form of Leishmaniasis: Visceral leishmaniasis. Current therapy for this disease is related to the development of drug-resistant species and toxicity. Trypanothione Reductase (LiTR), a validated target for the drug discovery process, is involved with parasites' thiol-redox metabolism. Objective: In this study, through Virtual Screening employing two distinct Natural Products Brazilian databases, we aimed to identify novel inhibitor scaffolds against LiTR. Results: Thus, the “top 10” LiTR-ligand energies have been selected and their interaction profiles into LiTR sites through the AuPosSOM server have been verified. Finally, Pred-hERG, Aggregator Advisor, FAF-DRUGS, pkCSM and DataWarrior were employed and their results allowed us to evaluate, respectively, the cardiotoxicity, aggregation capacity, presence of false-positive compounds (PAINS) and their toxicities. Conclusion: Three molecules that overcame the in silico pharmacokinetic analysis and have a good interaction with LiTR, were chosen to use in vitro assays hoping that our computational results reported here would aid the development of new anti-leishmanial compounds.

scholarly journals Plasmodium falciparum Line-Dependent Association ofIn VitroGrowth-Inhibitory Activity and Risk of Malaria

2012 ◽  
Vol 80 (5) ◽  
pp. 1900-1908 ◽  
Author(s):  
Josea Rono ◽  
Anna Färnert ◽  
Daniel Olsson ◽  
Faith Osier ◽  
Ingegerd Rooth ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Activity ◽  
Content Type ◽  
Phenotypic Differences ◽  
Erythrocyte Invasion ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Control Study

ABSTRACTPlasmodium falciparum's ability to invade erythrocytes is essential for its survival within the human host. Immune mechanisms that impair this ability are therefore expected to contribute to immunity against the parasite. Plasma of humans who are naturally exposed to malaria has been shown to have growth-inhibitory activity (GIA)in vitro. However, the importance of GIA in relation to protection from malaria has been unclear. In a case-control study nested within a longitudinally followed population in Tanzania, plasma samples collected at baseline from 171 individuals (55 cases and 116 age-matched controls) were assayed for GIA using threeP. falciparumlines (3D7, K1, and W2mef) chosen based on their erythrocyte invasion phenotypes. Distribution of GIA differed between the lines, with most samples inhibiting the growth of 3D7 and K1 and enhancing the growth of W2mef. GIA to 3D7 was associated with a reduced risk of malaria within 40 weeks of follow-up (odds ratio, 0.45; 95% confidence interval [CI], 0.21 to 0.96;P= 0.04), whereas GIA to K1 and W2mef was not. These results show that GIA, as well as its association with protection from malaria, is dependent on theP. falciparumline and can be explained by differences in erythrocyte invasion phenotypes between parasite lines. Our study contributes knowledge on the biological importance of growth inhibition and the potential influence ofP. falciparumerythrocyte invasion phenotypic differences on its relationship to protective immunity against malaria.

scholarly journals Skrining Mekanisme Kerja Daun Malaka (Phyllanthus emblica L.) Sebagai Antidiabetes

2018 ◽  
Vol 1 (3) ◽  
pp. 106-110
Author(s):  
Novi Irwan Fauzi ◽  
Seno Aulia Ardiansyah ◽  
Saeful Hidayat
Keyword(s):  
Mechanism Of Action ◽  
Inhibitory Activity ◽  
Leaf Extract ◽  
Test Method ◽  
Diabetic Rat ◽  
Phyllanthus Emblica ◽  
Insulin Sensitizer ◽  
Water Fraction

Daun malaka (Phyllanthus emblica L.) mempunyai potensi digunakan sebagai alternatif obat antidiabetes. Daun malaka menunjukkan efek hipoglikemia pada tikus yang diinduksi aloksan. Namun, mekanisme kerjanya belum diketahui pasti. Penelitian ini dilakukan dalam rangka skrining mekanisme kerja daun malaka sebagai antidiabetes. Skrining mekanisme kerja dilakukan terhadap fraksi air daun malaka melalui uji aktivitas inhibisi enzim α-glukosidase serta α-amilase secara in vitro dan pengujian aktivitas insulin-sensitizer terhadap ekstrak daun malaka dengan metode tes toleransi insulin secara in vivo. Fraksi air daun malaka menunjukkan aktivitas inhibisi terhadap enzim α-glukosidase serta α-amilase dengan nilai IC50 (Inhibitor Concentration 50) pada kedua enzim tersebut berturut-turut adalah 0,87% dan 8,64% b/v. Pada uji aktivitas insulin sensitizer, pemberian ekstrak daun malaka dapat meningkatkan sensitivitas insulin pada tikus diabet dengan kondisi resistensi insulin. Nilai KTTI pada kelompok tikus diabet yang diberi ekstrak daun malaka dosis 100 dan 500 mg/kgbb tikus (74,89 dan 75,57) lebih tinggi dibandingkan kelompok tikus diabet (38,41) dan kadar glukosa darah yang lebih rendah selama interval waktu pengukuran. Daun malaka telah diketahui mampu meningkatkan sekresi insulin dan pada penelitian ini menunjukkan aktivitas inhibisi enzim α-glukosidase serta α-amilase secara in vitro dan menunjukkan aktivitas insulinsensitizer pada tikus diabet dengan kondisi resistensi insulin.   Malaka leaf (Phyllanthus emblica L.) has the potential to be used as an alternative antidiabetic drug. Malacca leaves showed hypoglycemia effect in rat induced by alloxan. However, the mechanism of action is not yet known. This study was conducted to evaluate the mechanism of action of Malaka leaves as antidiabetic. Screening of the mechanism of action was carried out on the water fraction of Malaka leaf  byinhibitory activity examination  on α-glucosidase and α-amylase by in vitro studyand Evaluation of insulin-sensitizer activity of Maaka leaf leaf extract was conducted by invivo  insulin tolerance test method. Malaka leaf water fraction showed inhibitory activity against the α-glucosidase and α-amylase with IC50 values ​​(Inhibitory Concentration 50)  of0.87% and 8.64% b / v on both enzyme, respectively. The evaluation of insulin sensitizer revelead that administration ofMalaka  leaf extract can increase insulin sensitivity in diabetic rat with insulin resistance.KTTI values ​​in diabetic rats given malaka extract  at the dose of 100 and 500 mg / kg BW (74.89 and 75.57) were higher than diabetics rat (38.41) and the extract also decrease blood glucose levels during measurement time intervals . Malaka leafhas been known to increase insulin secretion and the study showedthe  inhibitory activity on α-glucosidase and α-amylase by in vitro study and showed insulinsensitizer activity in diabetic rat with insulin resistance.

scholarly journals Artemisinin-independent inhibitory activity of Artemisia sp. infusions against different Plasmodium stages including relapse-causing hypnozoites

2021 ◽  
Vol 5 (3) ◽  
pp. e202101237
Author(s):  
Kutub Ashraf ◽  
Shahin Tajeri ◽  
Christophe-Sébastien Arnold ◽  
Nadia Amanzougaghene ◽  
Jean-François Franetich ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Inhibitory Activity ◽  
Parasite Species ◽  
Artemisia Annua ◽  
Combination Therapies ◽  
Lead Compounds ◽  
Low Concentrations ◽  
Inhibitory Activities

Artemisinin-based combination therapies (ACT) are the frontline treatments against malaria worldwide. Recently the use of traditional infusions from Artemisia annua (from which artemisinin is obtained) or Artemisia afra (lacking artemisinin) has been controversially advocated. Such unregulated plant-based remedies are strongly discouraged as they might constitute sub-optimal therapies and promote drug resistance. Here, we conducted the first comparative study of the anti-malarial effects of both plant infusions in vitro against the asexual erythrocytic stages of Plasmodium falciparum and the pre-erythrocytic (i.e., liver) stages of various Plasmodium species. Low concentrations of either infusion accounted for significant inhibitory activities across every parasite species and stage studied. We show that these antiplasmodial effects were essentially artemisinin-independent and were additionally monitored by observations of the parasite apicoplast and mitochondrion. In particular, the infusions significantly incapacitated sporozoites, and for Plasmodium vivax and P. cynomolgi, disrupted the hypnozoites. This provides the first indication that compounds other than 8-aminoquinolines could be effective antimalarials against relapsing parasites. These observations advocate for further screening to uncover urgently needed novel antimalarial lead compounds.

scholarly journals Artemisinin-independent inhibitory activity of Artemisia sp. infusions against different Plasmodium stages including relapse-causing hypnozoites

2021 ◽  
Author(s):  
Kutub Ashraf ◽  
Shahin Tajeri ◽  
Christophe-Sébastien Arnold ◽  
Nadia Amanzougaghene ◽  
Jean-François Franetich ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Inhibitory Activity ◽  
Parasite Species ◽  
Artemisia Annua ◽  
Plasmodium Species ◽  
Combination Therapies ◽  
Lead Compounds ◽  
Low Concentrations ◽  
Inhibitory Activities

Artemisinin-based combination therapies (ACT) are the frontline treatments against malaria worldwide. Recently the use of traditional infusions from Artemisia annua (from which artemisinin is obtained) or A. afra (lacking artemisinin) has been controversially advocated. Such unregulated plant-based remedies are strongly discouraged as they might constitute sub-optimal therapies and promote drug resistance. Here, we conducted the first comparative study of the anti-malarial effects of both plant infusions in vitro against the asexual erythrocytic stages of P. falciparum and the pre-erythrocytic (i. e., liver) stages of various Plasmodium species. Low concentrations of either infusion accounted for significant inhibitory activities across every parasite species and stage studied. We show that these antiplasmodial effects were essentially artemisinin-independent and were additionally monitored by observations of the parasite apicoplast and mitochondrion. In particular, the infusions significantly incapacitated sporozoites, and for P. vivax and P. cynomolgi, disrupted the hypnozoites. This provides the first indication that compounds other than 8- aminoquinolines could be effective antimalarials against relapsing parasites. These observations advocate for further screening to uncover urgently needed novel antimalarial lead compounds.

scholarly journals Evaluation of 4-Amino 2-Anilinoquinazolines against Plasmodium and Other Apicomplexan Parasites In Vitro and in a P. falciparum Humanized NOD-scid IL2Rγnull Mouse Model of Malaria

2018 ◽  
Vol 63 (3) ◽  
Author(s):  
Paul R. Gilson ◽  
William Nguyen ◽  
William A. Poole ◽  
Jose E. Teixeira ◽  
Jennifer K. Thompson ◽  
...  
Keyword(s):  
Mouse Model ◽  
Babesia Bovis ◽  
Parasite Line ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Content Type ◽  
Apicomplexan Parasites ◽  
Micromolar Range

ABSTRACT A series of 4-amino 2-anilinoquinazolines optimized for activity against the most lethal malaria parasite of humans, Plasmodium falciparum, was evaluated for activity against other human Plasmodium parasites and related apicomplexans that infect humans and animals. Four of the most promising compounds from the 4-amino 2-anilinoquinazoline series were equally as effective against the asexual blood stages of the zoonotic P. knowlesi, suggesting that they could also be effective against the closely related P. vivax, another important human pathogen. The 2-anilinoquinazoline compounds were also potent against an array of P. falciparum parasites resistant to clinically available antimalarial compounds, although slightly less so than against the drug-sensitive 3D7 parasite line. The apicomplexan parasites Toxoplasma gondii, Babesia bovis, and Cryptosporidium parvum were less sensitive to the 2-anilinoquinazoline series with a 50% effective concentration generally in the low micromolar range, suggesting that the yet to be discovered target of these compounds is absent or highly divergent in non-Plasmodium parasites. The 2-anilinoquinazoline compounds act as rapidly as chloroquine in vitro and when tested in rodents displayed a half-life that contributed to the compound’s capacity to clear P. falciparum blood stages in a humanized mouse model. At a dose of 50 mg/kg of body weight, adverse effects to the humanized mice were noted, and evaluation against a panel of experimental high-risk off targets indicated some potential off-target activity. Further optimization of the 2-anilinoquinazoline antimalarial class will concentrate on improving in vivo efficacy and addressing adverse risk.

scholarly journals Synthesis and evaluation of N-alkynylaminosteroids as potential CYP450 17A1 inhibitors

2019 ◽  
Vol 65 (4) ◽  
pp. 324-330 ◽  
Author(s):  
J.U. Panada ◽  
Y.V. Faletrov ◽  
N.S. Frolova ◽  
V.M. Shkumatov
Keyword(s):  
Enzymatic Activity ◽  
Inhibitory Activity ◽  
Optimal Number ◽  
Side Chain ◽  
Micromolar Range

Four isomeric dehydroepiandrosterone- and pregnenolone-based N-alkynylaminosteroids were synthesized and tested in vitro for inhibition of heterologously expressed CYP17A1. The highest inhibitory activity was observed when the optimal number of side chain atoms was met. The conjugate based on pregnenolone containing an N-propynyl moiety was found to interefere with enzymatic activity most effectively and consistently in the micromolar range.

scholarly journals Toll-Like Receptor 9 Signaling in Dendritic Cells Regulates Neutrophil Recruitment to Inflammatory Foci following Leishmania infantum Infection

2015 ◽  
Vol 83 (12) ◽  
pp. 4604-4616 ◽  
Author(s):  
Laís Sacramento ◽  
Silvia C. Trevelin ◽  
Manuela S. Nascimento ◽  
Djalma S. Lima-Jùnior ◽  
Diego L. Costa ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Critical Role ◽  
Costimulatory Molecule ◽  
Protozoan Parasite ◽  
Neutrophil Recruitment ◽  
Content Type ◽  
Target Organs ◽  
Myd88 Signaling

Leishmania infantumis a protozoan parasite that causes visceral leishmaniasis (VL). This infection triggers dendritic cell (DC) activation through the recognition of microbial products by Toll-like receptors (TLRs). Among the TLRs, TLR9 is required for DC activation by differentLeishmaniaspecies. We demonstrated that TLR9 is upregulatedin vitroandin vivoduring infection. We show that C57BL/6 mice deficient in TLR9 expression (TLR9−/−mice) are more susceptible to infection and display higher parasite numbers in the spleen and liver. The increased susceptibility of TLR9−/−mice was due to the impaired recruitment of neutrophils to the infection foci associated with reduced levels of neutrophil chemoattractants released by DCs in the target organs. Moreover, both Th1 and Th17 cells were also committed in TLR9−/−mice. TLR9-dependent neutrophil recruitment is mediated via the MyD88 signaling pathway but is TIR domain-containing adapter-inducing interferon beta (TRIF) independent. Furthermore,L. infantumfailed to activate both plasmacytoid and myeloid DCs from TLR9−/−mice, which presented reduced surface costimulatory molecule expression and chemokine release. Interestingly, neutrophil chemotaxis was affected bothin vitroandin vivowhen DCs were derived from TLR9−/−mice. Our results suggest that TLR9 plays a critical role in neutrophil recruitment during the protective response againstL. infantuminfection that could be associated with DC activation.

scholarly journals Snapshot Profiling of the Antileishmanial Potency of Lead Compounds and Drug Candidates against Intracellular Leishmania donovani Amastigotes, with a Focus on Human-Derived Host Cells

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Markela Koniordou ◽  
Stephen Patterson ◽  
Susan Wyllie ◽  
Karin Seifert
Keyword(s):  
Host Cell ◽  
Leishmania Donovani ◽  
Host Cells ◽  
Content Type ◽  
Human Macrophages ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Intracellular Amastigotes ◽  
Peritoneal Exudate Macrophages

ABSTRACT This study characterized the in vitro potencies of antileishmanial agents against intracellular Leishmania donovani amastigotes in primary human macrophages, obtained with or without CD14-positive monocyte enrichment, phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells, and mouse peritoneal exudate macrophages (PEMs). Host cell-dependent potency was confirmed for pentavalent and trivalent antimony. Fexinidazole was inactive against intracellular amastigotes across the host cell panel. Fexinidazole sulfone, (R)-PA-824, (S)-PA-824, and VL-2098 displayed similar potency in all of the host cells tested.

scholarly journals Footprinting of Inhibitor Interactions ofIn SilicoIdentified Inhibitors of Trypanothione Reductase ofLeishmaniaParasite

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Santhosh K. Venkatesan ◽  
Vikash Kumar Dubey
Keyword(s):  
Virtual Screening ◽  
Leishmania Infantum ◽  
Trypanothione Reductase ◽  
Inhibition Kinetics ◽  
Screening Process ◽  
Protein Ligand Interactions ◽  
Enzymatic Reduction ◽  
Ligand Interactions ◽  
First Time

Structure-based virtual screening of NCI Diversity set II compounds was performed to indentify novel inhibitor scaffolds of trypanothione reductase (TR) fromLeishmania infantum. The top 50 ranked hits were clustered using the AuPoSOM tool. Majority of the top-ranked compounds were Tricyclic. Clustering of hits yielded four major clusters each comprising varying number of subclusters differing in their mode of binding and orientation in the active site. Moreover, for the first time, we report selected alkaloids and dibenzothiazepines as inhibitors ofLeishmania infantumTR. The mode of binding observed among the clusters also potentiates the probablein vitroinhibition kinetics and aids in defining key interaction which might contribute to the inhibition of enzymatic reduction of T[S] 2. The method provides scope for automation and integration into the virtual screening process employing docking softwares, for clustering the small molecule inhibitors based upon protein-ligand interactions.

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