Potent antileishmanial activity of chitosan against Iranian strain of Leishmania major (MRHO/IR/75/ER): In vitro and in vivo assay

ABSTRACT Our study represents the first report demonstrating the antileishmanial activity of nicotinamide (NAm), a form of vitamin B3. A 5 mM concentration of NAm significantly inhibited the intracellular growth of Leishmania amastigotes and the NAD-dependent deacetylase activity carried by parasites overexpressing Leishmania major SIR2 (LmSIR2). However, the transgenic parasites were as susceptible as the wild-type parasites to NAm-induced cell growth arrest. Therefore, we conclude that NAm inhibits leishmanial growth and that overexpression of LmSIR2 does not overcome this inhibition. The mechanism of the inhibition is not defined but may include other in vivo targets. NAm may thus represent a new antileishmanial agent which could potentially be used in combination with other drugs during therapy.

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Antileishmanial Activity of Date (Phoenix dactylifera L) Fruit and Pit Extracts In Vitro

Journal of Evidence-Based Complementary & Alternative Medicine ◽

10.1177/2156587216651031 ◽

2016 ◽

Vol 21 (4) ◽

pp. NP98-NP102 ◽

Cited By ~ 6

Author(s):

Sedighe Albakhit ◽

Shahram Khademvatan ◽

Monir Doudi ◽

Masoud Foroutan-Rad

Keyword(s):

Leishmania Major ◽

Morphological Changes ◽

Public Health Problem ◽

Phoenix Dactylifera ◽

Antileishmanial Activity ◽

Major Public Health Problem ◽

Methanolic Extracts ◽

Phoenix Dactylifera L

Leishmaniasis is considered as a major public health problem worldwide. Current drugs in treatment of leishmaniasis have some limitations; thus, the current study was aimed to assess the methanolic extracts of pit and fruit of Phoenix dactylifera against Leishmania major promastigotes. L major promastigotes were cultured in RPMI 1640 and incubated at 25°C ± 1°C for 24, 48, and 72 hours. For obtaining the IC50 (half maximal inhibitory concentration) value, MTT assay was employed. Furthermore, promastigotes were examined in terms of morphology under light microscope. About 48 hours after treatment, IC50s were estimated 23 μg/mL and 500 mg/mL for methanolic extracts of pit and fruit of P dactylifera, respectively. Both extracts exhibited a dose and time-dependent antileishmanial activity against L major parasites. Also, some visible morphological changes were seen. This finding revealed both date fruit and pit, are effective against L major promastigotes. Further studies should be designed in future based on apoptosis induction in vitro and in vivo.

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Novel Arylimidamides for Treatment of Visceral Leishmaniasis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00250-10 ◽

2010 ◽

Vol 54 (6) ◽

pp. 2507-2516 ◽

Cited By ~ 44

Author(s):

Michael Zhuo Wang ◽

Xiaohua Zhu ◽

Anuradha Srivastava ◽

Qiang Liu ◽

J. Mark Sweat ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Leishmania Donovani ◽

Leishmania Major ◽

Oral Treatment ◽

Antileishmanial Activity ◽

Repeat Dose ◽

Lead Discovery ◽

Preclinical Development

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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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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Efficacy of biogenic selenium nanoparticles against Leishmania major: In vitro and in vivo studies

Journal of Trace Elements in Medicine and Biology ◽

10.1016/j.jtemb.2012.11.002 ◽

2013 ◽

Vol 27 (3) ◽

pp. 203-207 ◽

Cited By ~ 57

Author(s):

Nasibeh Beheshti ◽

Saied Soflaei ◽

Mojtaba Shakibaie ◽

Mohammad Hossein Yazdi ◽

Fatemeh Ghaffarifar ◽

...

Keyword(s):

Leishmania Major ◽

Selenium Nanoparticles ◽

In Vivo Studies ◽

Biogenic Selenium Nanoparticles

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04213-14 ◽

2015 ◽

Vol 59 (5) ◽

pp. 2479-2487 ◽

Cited By ~ 40

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.

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Characterization and selective inhibition of myristoyl-CoA:protein N-myristoyltransferase from Trypanosoma brucei and Leishmania major

Biochemical Journal ◽

10.1042/bj20051886 ◽

2006 ◽

Vol 396 (2) ◽

pp. 277-285 ◽

Cited By ~ 46

Author(s):

Chrysoula Panethymitaki ◽

Paul W. Bowyer ◽

Helen P. Price ◽

Robin J. Leatherbarrow ◽

Katherine A. Brown ◽

...

Keyword(s):

Trypanosoma Brucei ◽

Leishmania Major ◽

Homo Sapiens ◽

Selective Inhibition ◽

Fungal Species ◽

Chemotherapeutic Agents ◽

Human Pathogens ◽

Ic50 Values

The eukaryotic enzyme NMT (myristoyl-CoA:protein N-myristoyltransferase) has been characterized in a range of species from Saccharomyces cerevisiae to Homo sapiens. NMT is essential for viability in a number of human pathogens, including the fungi Candida albicans and Cryptococcus neoformans, and the parasitic protozoa Leishmania major and Trypanosoma brucei. We have purified the Leishmania and T. brucei NMTs as active recombinant proteins and carried out kinetic analyses with their essential fatty acid donor, myristoyl-CoA and specific peptide substrates. A number of inhibitory compounds that target NMT in fungal species have been tested against the parasite enzymes in vitro and against live parasites in vivo. Two of these compounds inhibit TbNMT with IC50 values of <1 μM and are also active against mammalian parasite stages, with ED50 (the effective dose that allows 50% cell growth) values of 16–66 μM and low toxicity to murine macrophages. These results suggest that targeting NMT could be a valid approach for the development of chemotherapeutic agents against infectious diseases including African sleeping sickness and Nagana.

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