Evaluation of the in vitro and in vivo antileishmanial activity of a chloroquinolin derivative against Leishmania species capable of causing tegumentary and visceral leishmaniasis

ABSTRACT Arylimidamides (AIAs) represent a new class of molecules that exhibit potent antileishmanial activity (50% inhibitory concentration [IC50], <1 μM) against both Leishmania donovani axenic amastigotes and intracellular Leishmania, the causative agent for human visceral leishmaniasis (VL). A systematic lead discovery program was employed to characterize in vitro and in vivo antileishmanial activities, pharmacokinetics, mutagenicities, and toxicities of two novel AIAs, DB745 and DB766. They were exceptionally active (IC50 ≤ 0.12 μM) against intracellular L. donovani, Leishmania amazonensis, and Leishmania major and did not exhibit mutagenicity in an Ames screen. DB745 and DB766, given orally, produced a dose-dependent inhibition of liver parasitemia in two efficacy models, L. donovani-infected mice and hamsters. Most notably, DB766 (100 mg/kg of body weight/day for 5 days) reduced liver parasitemia in mice and hamsters by 71% and 89%, respectively. Marked reduction of parasitemia in the spleen (79%) and bone marrow (92%) of hamsters was also observed. Furthermore, these compounds distributed to target tissues (liver and spleen) and had a moderate oral bioavailability (up to 25%), a large volume of distribution, and an elimination half-life ranging from 1 to 2 days in mice. In a repeat-dose toxicity study of mice, there was no indication of liver or kidney toxicity for DB766 from serum chemistries, although mild hepatic cell eosinophilia, hypertrophy, and fatty changes were noted. These results demonstrated that arylimidamides are a promising class of molecules that possess good antileishmanial activity and desirable pharmacokinetics and should be considered for further preclinical development as an oral treatment for VL.

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PREPARATION AND CHARACTERIZATION OF ANDROGRAPHOLIDE NANOPARTICLES FOR VISCERAL LEISHMANIASIS CHEMOTHERAPY: IN VITRO AND IN VIVO EVALUATIONS

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2016v8i12.14773 ◽

2016 ◽

Vol 8 (12) ◽

pp. 102

Author(s):

Pallab Ghosh ◽

Subhasish Mondal ◽

Tanmoy Bera

Keyword(s):

Visceral Leishmaniasis ◽

Leishmania Donovani ◽

Parasite Burden ◽

Plga Nanoparticles ◽

Antileishmanial Activity ◽

Infection Model ◽

Vitamin E Tpgs ◽

Polyethylene Glycol 1000

Objective: To overcome low physiological solubility, poor bioavailability, the short plasma half-life of andrographolide (AG), a delivery system based on poly (D, L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) were developed to increase the efficiency of AG against visceral leishmaniasis (VL). Methods: Andrographolide-PLGA nanoparticles (AGnp) were prepared with Pgp efflux inhibitor vitamin E TPGS (D-α-tocopheryl polyethylene glycol 1000 succinate) by emulsion solvent evaporation method and characterized. Antileishmanial activity was evaluated using in vitro and in vivo VL infection model. Results: The particle size of AGnp was found to be171.4±11.5 nm with an encapsulation efficiency of 81%. The AGnp reduced AG cellular toxicity, retained it's in vitro antileishmanial activity and lead to a reduction (99.9%) of parasite burden in the Leishmania donovani infected spleen and liver. AGnp was more active in infected mice liver at low dose than in spleen. Therapeutic indexes (TI) were 6.9-fold greater in AG and 68-fold in AGnp compared to amphotericin B (AmB) when evaluated in L. donovani infected spleen. Conclusion: Incorporation of AG in PLGA nanoparticles, provided controlled and improved in vivo performance against VL

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Ivermectin presents effective and selective antileishmanial activity in vitro and in vivo against Leishmania infantum and is therapeutic against visceral leishmaniasis

Experimental Parasitology ◽

10.1016/j.exppara.2020.108059 ◽

2021 ◽

Vol 221 ◽

pp. 108059

Author(s):

Thiago A.R. Reis ◽

João A. Oliveira-da-Silva ◽

Grasiele S.V. Tavares ◽

Débora V.C. Mendonça ◽

Camila S. Freitas ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Leishmania Infantum ◽

Antileishmanial Activity

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Successful Therapy of Murine Visceral Leishmaniasis with Astrakurkurone, a Triterpene Isolated from the Mushroom Astraeus hygrometricus, Involves the Induction of Protective Cell-Mediated Immunity and TLR9

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01943-15 ◽

2016 ◽

Vol 60 (5) ◽

pp. 2696-2708 ◽

Cited By ~ 13

Author(s):

Suvadip Mallick ◽

Aritri Dutta ◽

Ankur Chaudhuri ◽

Debasri Mukherjee ◽

Somaditya Dey ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

In Silico ◽

Antileishmanial Activity ◽

Host Cells ◽

Cell Mediated Immunity ◽

Interleukin 17 ◽

Content Type ◽

Tlr9 Agonist

ABSTRACTIn our previous report, we showed that astrakurkurone, a triterpene isolated from the Indian mushroomAstraeus hygrometricus(Pers.) Morgan, induced reactive oxygen species, leading to apoptosis inLeishmania donovanipromastigotes, and also was effective in inhibiting intracellular amastigotes at the 50% inhibitory concentration of 2.5 μg/ml. The aim of the present study is to characterize the associated immunomodulatory potentials and cellular activation provided by astrakurkurone, leading to effective antileishmanial activityin vitroandin vivo. Astrakurkurone-mediated antileishmanial activity was evaluated by real-time PCR and flow cytometry. The involvement of Toll-like receptor 9 (TLR9) was studied byin vitroassay in the presence of a TLR9 agonist and antagonist and byin silicomodeling of a three-dimensional structure of the ectodomain of TLR9 and its interaction with astrakurkurone. Astrakurkurone caused a significant increase in TLR9 expression ofL. donovani-infected macrophages along with the activation of proinflammatory responses. The involvement of TLR9 in astrakurkurone-mediated amastigote killing has been evidenced from the fact that a TLR9 agonist (CpG, ODN 1826) in combination with astrakurkurone enhanced the amastigote killing, while a TLR9 antagonist (bafilomycin A1) alone or in combination with astrakurkurone curbed the amastigote killing, which could be further justified byin silicoevidence of docking between mouse TLR9 and astrakurkurone. Astrakurkurone was found to reduce the parasite burdenin vivoby inducing protective cytokines, gamma interferon and interleukin 17. Moreover, astrakurkurone was nontoxic toward peripheral blood mononuclear cells of immunocompromised patients with visceral leishmaniasis. Astrakurkurone, a nontoxic antileishmanial, enhances the immune efficiency of host cells, leading to parasite clearancein vitroandin vivo.

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An effective in vitro and in vivo antileishmanial activity and mechanism of action of 8-hydroxyquinoline against Leishmania species causing visceral and tegumentary leishmaniasis

Veterinary Parasitology ◽

10.1016/j.vetpar.2016.01.002 ◽

2016 ◽

Vol 217 ◽

pp. 81-88 ◽

Cited By ~ 18

Author(s):

Mariana Costa Duarte ◽

Letícia Martins dos Reis Lage ◽

Daniela Pagliara Lage ◽

Juliana Tonini Mesquita ◽

Beatriz Cristina Silveira Salles ◽

...

Keyword(s):

Mechanism Of Action ◽

Leishmania Species ◽

Antileishmanial Activity ◽

Tegumentary Leishmaniasis

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In vitro and in vivo antileishmanial activity of β-acetyl-digitoxin, a cardenolide of Digitalis lanata potentially useful to treat visceral leishmaniasis

Parasite ◽

10.1051/parasite/2021036 ◽

2021 ◽

Vol 28 ◽

pp. 38

Author(s):

Camila S. Freitas ◽

Daniela P. Lage ◽

João A. Oliveira-da-Silva ◽

Rafaella R. Costa ◽

Débora V.C. Mendonça ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Polymeric Micelles ◽

Direct Action ◽

Low Cost ◽

Parasite Load ◽

Antileishmanial Activity ◽

Digitalis Lanata ◽

Ifn Γ

Current treatments of visceral leishmaniasis face limitations due to drug side effects and/or high cost, along with the emergence of parasite resistance. Novel and low-cost antileishmanial agents are therefore required. We report herein the antileishmanial activity of β-acetyl-digitoxin (b-AD), a cardenolide isolated from Digitalis lanata leaves, assayed in vitro and in vivo against Leishmania infantum. Results showed direct action of b-AD against parasites, as well as efficacy for the treatment of Leishmania-infected macrophages. In vivo experiments using b-AD-containing Pluronic® F127 polymeric micelles (b-AD/Mic) to treat L. infantum-infected mice showed that this composition reduced the parasite load in distinct organs in more significant levels. It also induced the development of anti-parasite Th1-type immunity, attested by high levels of IFN-γ, IL-12, TNF-α, GM-CSF, nitrite and specific IgG2a antibodies, in addition to low IL-4 and IL-10 contents, along with higher IFN-γ-producing CD4+ and CD8+ T-cell frequency. Furthermore, low toxicity was found in the organs of the treated animals. Comparing the therapeutic effect between the treatments, b-AD/Mic was the most effective in protecting animals against infection, when compared to the other groups including miltefosine used as a drug control. Data found 15 days after treatment were similar to those obtained one day post-therapy. In conclusion, the results obtained suggest that b-AD/Mic is a promising antileishmanial agent and deserves further studies to investigate its potential to treat visceral leishmaniasis.

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Acarbose presents in vitro and in vivo antileishmanial activity against Leishmania infantum and is a promising therapeutic candidate against visceral leishmaniasis

Medical Microbiology and Immunology ◽

10.1007/s00430-021-00707-4 ◽

2021 ◽

Author(s):

Rafaella R. Costa ◽

João A. Oliveira-da-Silva ◽

Thiago A. R. Reis ◽

Grasiele S. V. Tavares ◽

Débora V. C. Mendonça ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Leishmania Infantum ◽

Antileishmanial Activity

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Naphthoquinones and derivatives for chemotherapy: perspectives and limitations of their anti-trypanosomatids activities

Current Pharmaceutical Design ◽

10.2174/1381612826666201109111802 ◽

2020 ◽

Vol 26 ◽

Author(s):

Luíza Dantas-Pereira ◽

Edézio F. Cunha-Junior ◽

Valter V. Andrade-Neto ◽

John F. Bower ◽

Guilherme A. M. Jardim ◽

...

Keyword(s):

Large Scale ◽

Neglected Tropical Diseases ◽

Folk Medicine ◽

Leishmania Species ◽

Parasitic Infections ◽

Mechanistic Analysis ◽

Leishmania Spp ◽

Nanomolar Range

: Chagas disease, Sleeping sickness and Leishmaniasis, caused by trypanosomatids Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively, are considered neglected tropical diseases, and they especially affect impoverished populations in the developing world. The available chemotherapies are very limited and a search for alternatives is still necessary. In folk medicine, natural naphthoquinones have been employed for the treatment of a great variety of illnesses, including parasitic infections. This review is focused on the anti-trypanosomatid activity and mechanistic analysis of naphthoquinones and derivatives. Among all the series of derivatives tested in vitro, naphthoquinone-derived 1,2,3-triazoles were very active on T. cruzi infective forms in blood bank conditions, as well as in amastigotes of Leishmania spp. naphthoquinones containing a CF3 on a phenyl amine ring inhibited T. brucei proliferation in the nanomolar range, and naphthopterocarpanquinones stood out for their activity on a range of Leishmania species. Some of these compounds showed a promising selectivity index (SI) (30 to 1900), supporting further analysis in animal models. Indeed, high toxicity to the host and inactivation by blood components are crucial obstacles to be overcome to use naphthoquinones and/or their derivatives for chemotherapy. Multidisciplinary initiatives embracing medicinal chemistry, bioinformatics, biochemistry, and molecular and cellular biology need to be encouraged to allow the optimization of these compounds. Large scale automated tests are pivotal for the efficiency of the screening step, and subsequent evaluation of both the mechanism of action in vitro and pharmacokinetics in vivo are essential for the development of a novel, specific and safe derivative, minimizing adverse effects.

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In Vivo Antimalarial and In Vitro Antileishmanial Activity of 4- Aminoquinoline Derivatives Hybridized to Isoniazid or Sulfa or Hydrazine Groups

Letters in Drug Design & Discovery ◽

10.2174/1570180813666160927113743 ◽

2017 ◽

Vol 14 (5) ◽

pp. 597-604 ◽

Cited By ~ 3

Author(s):

Roberta Soares ◽

Luciana Antinarelli ◽

Isabela Souza ◽

Fernanda Lopes ◽

...

Keyword(s):

Antileishmanial Activity

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