Antileishmaniasis Activity Research Articles

Nature-derived Alkaloids as a Promising Bioactive Compound in Drug Discovery to Meet Global Leishmania Needs

Background: Natural products have been important resources for potential drug development. Among the many classes of natural products, alkaloids have the most therapeutic applications. Treatment of leishmaniasis by chemical drugs remains a challenge because of toxic side effects, limited efficacy, and drug resistance. This review focuses to embrace all researches on leishmanicidal alkaloids over a specific range of time, with special consideration the molecular mechanism of action, and structure-related activity. Methods: All publications (in English) from Web of Science, PubMed, Science Direct, Scopus, and Google Scholar from 2000-2021 using a variety of keywords such as natural alkaloids, herbal alkaloids, marine alkaloids along with leishmaniasis were included in the present study. In this summary, the focus is mainly on natural alkaloids of plant, mineral, marine origin, etc., which have empirically demonstrated the antileishmanial effect. Results: Fourteen categories of alkaloids with anti-leishmaniasis activity were extracted from the articles. The highest number of alkaloids belonged to isoquinoline, indole, and quinoline alkaloids (21.78%, 20.67%, and 16.48% respectively). This review indicated that the mentioned alkaloids are able to inhibit the proliferation of parasites, the respiratory chain and protein synthesis, arrest the cell cycle, disrupt the mitochondrial membrane integrity, inhibit leishmanial topoisomerase, induce mitochondrial dysfunction, and changes in the parasite morphology. Discussion: The present study highlighted antileishmanial alkaloids that are active against different species of Leishmania in vitro and some of them are also active in visceral and cutaneous leishmaniasis models. However, more clinical studies are needed to clarify the anti-leishmanial activity of alkaloids against leishmania in detail. Conclusion: Among the reported compounds, two main classes of alkaloids including isoquinoline and indole alkaloids cover a wider range of anti-parasitic compounds, and structure-activity relationships (SAR) studies of these molecular skeletons may be good lead compounds and afford the structural clues to develop novel medicines with more selective therapeutic profiles.

Antileishmanial Activity of Natural Diterpenoids: A Comprehensive Review

Abstract: Infections that occur by protozoa are a chief universal issue for health, with wide endemicity in the involved areas. In the absence of a vaccine, there is an immediate requirement for efficient medications to replace those in common applications. However, their low effectiveness, lengthy treatment regimen, high poisoning, detrimental side effects of drugs and expensive prices require the need for superior medicine; these are all the factors that make leishmaniasis vaccines unavailable in the near future. Therefore, there is an immediate requirement to discover unique antileishmanial drugs with fine power and preferable remedial profile. Even though most of the medications are still derived from medicinal plant origins, the concern in higher plants as the origin of new bioactive natural compounds has been enhanced in recent years. The present study is a review of reports of naturally occurring diterpenoids extracted from plants and exhibiting anti-leishmaniasis activity. This review article refers to 25 plant species, their families, the portion used and the type of extract investigated. It also includes 88 diterpenoids extracted and identified from higher plant species, which are classified into chemically and structurally suitable groups. A number of recent reports and anti-leishmaniasis activities on natural compounds are discussed. This article provides a good overview of the future of leishmaniasis drug discovery.

Evaluation of Antileishmanial Activity of Osteospermum ecklonis Extract of Aerial Parts against Leishmania donovani: in vitro(Conference Paper) #

Abstract
 
 Lack of safe available non-resistant treatment for visceral leishmaniasis (Kala-azar) keeps limiting the complete cure of this disease ,drugs that have toxic side effects or lack of effectiveness have led to disease relapse ,all these factors have lightened the way to the search for imperative drugs from natural resources that have been shown to have antileishmanial activity through literature survey
 . In the present study, the comparative in vitro anti-leishmania activity of various fractions of Osteospermum ecklonis aerial parts fractions have been evaluated. Extracts were prepared through maceration and Soxhlet apparatus using 85% methanol and fractionation was done by separating the active constituents according to the differences in their polarities using petroleum ether and n-butanol respectively. The resultant fractions( petroleum ether as well as n-butanol fractions )were chosen for effective inhibition of Leishmania donovani, The results prove with no doubt that the petroleum ether fraction of the maceration aerial parts in a concentration of 2.5 mg/ml had better antileishmanial activity than other concentrations of tested samples and the result coincided with the anti-leishmaniasis activity of official treatment (pentostam®) ,This finding can be attributed to the terpene nature of the materials used to be existed in such fraction. This observation have paved the road to step in for extended studies in relation to the conventional herbal medicines for better and safe alternatives to available synthetic chemical drugs.

Enhanced Colloidal Stability of Silver Nanoparticles by Green Synthesis Approach: Characterization and Anti-Leishmaniasis Activity

Silver nanoparticles (AgNPs) are considered an appropriate approach to treat the leishmaniasis in terms of the toxicity and resistance of current anti-leishmanial drugs. This study aimed to prepare stable AgNP and their apoptotic effects on the metabolic activity of Leishmania major. AgNPs were prepared with a green synthesis method using Z. multiflora Boiss ([Formula: see text] extract as a reducing and carboxymethylcellulose (CMC) stabilizer agent. The formation and colloidal stability of AgNPs were shown using ultraviolet-visible absorption spectroscopy during an 80-day period. The average diameter of [Formula: see text] nm and the surface charge of [Formula: see text] mv were obtained for AgNPs. Furthermore, the toxicity and apoptotic values of AgNPs on Leishmania major were evaluated by MTT assay and flow cytometry, compared with [Formula: see text] (meglumine antimoniate) as the current standard medication for leishmaniosis. The results indicated that [Formula: see text] extracts coated AgNPs (Z.M@AgNPs) reached [Formula: see text] at a 100 [Formula: see text]g/mL concentration, while [Formula: see text] reached this point at a concentration of 4000 [Formula: see text]g/mL. The flow cytometry data revealed that the primary mechanism of death in the promastigotes was apoptosis (35.44% for AgNPs and 32.69% for [Formula: see text]). The present findings suggest that Z.M@AgNPs are superior therapeutic agents than [Formula: see text] as the positive control group for leishmaniasis treatment. However, further advanced studies are needed to confirm these results.

Synthesis and characterization of zinc derivatized 3, 5-dihydroxy 4', 7-dimethoxyflavone and its anti leishmaniasis activity against Leishmania donovani.

This study reports the synthesis and characterization of zinc derivatized 3,5-dihydroxy 4', 7- dimethoxyflavone (DHDM-Zn) compound for the development of new antileishmanial agents. The interaction studies of DHDM with zinc were carried out by UV spectra and fluorescence spectra analysis. Characterization of the complex was further accomplished by multi-spectroscopic techniques such as FTIR, Raman, HRMS, NMR, FESEM-EDX. The morphological and topographical studies of synthesized DHDM-Zn were carried out using FESEM with EDX. Further, it was demonstrated that DHDM-Zn exhibited an excellent in vitro antagonistic effect against the promastigote form of L. donovani. In addition, the possible mechanisms of promastigote L. donovani cell death, by involvement of derivatized compound in arrest of the cell cycle in the G1 phase and residual cell count reduction were investigated. Promastigote growth kinetics performed in the presence of the derivatized compound revealed a slow growth rate. The combination of growth kinetics and cell cycle analysis, made it possible to interpret and classify the cause of leishmanial cell death accurately. These results support that zinc derivatized complex (DHDM-Zn) might work as a lead compound for designing and developing a new antileishmanial drug.

Annatto Oil Loaded Nanostructured Lipid Carriers: A Potential New Treatment for Cutaneous Leishmaniasis

Annatto (Bixa orellana L.) is extensively used as food pigment worldwide. Recently, several studies have found it to have healing and antioxidant properties, as well as effective action against leishmaniasis. Therefore, the purpose of this study was to incorporate the oil obtained from annatto seeds into a nanostructured lipid carrier (NLC) and evaluate its physicochemical properties and biological activity against Leishmania major. Nanoparticles were prepared by the fusion-emulsification and ultrasonication method, with the components Synperonic™ PE (PL) as the surfactant, cetyl palmitate (CP) or myristyl myristate (MM) as solid lipids, annatto oil (AO) (2% and 4%, w/w) as liquid lipid and active ingredient, and ultra-pure water. Physicochemical and biological characterizations were carried out to describe the NLCs, including particle size, polydispersity index (PDI), and zeta potential (ZP) by dynamic light scattering (DLS), encapsulation efficiency (EE%), thermal behavior, X-ray diffraction (XRD), transmission electron microscopy (TEM), Electron Paramagnetic Resonance (EPR), cytotoxicity on BALB/c 3T3 fibroblasts and immortalized human keratinocyte cells, and anti-leishmaniasis activity in vitro. Nanoparticles presented an average diameter of ~200 nm (confirmed by TEM results), a PDI of less than 0.30, ZP between −12.6 and −31.2 mV, and more than 50% of AO encapsulated in NLCs. Thermal analyses demonstrated that the systems were stable at high temperatures with a decrease in crystalline structure due to the presence of AOs (confirmed by XRD). In vitro, the anti-leishmania test displayed good activity in encapsulating AO against L. major. The results indicate that the oily fraction of Bixa orellana L. in NLC systems should be evaluated as a potential therapeutic agent against leishmaniasis.

Biosynthesis of spinel nickel ferrite nanowhiskers and their biomedical applications

Greener methods for the synthesis of various nanostructures with well-organized characteristics and biomedical applicability have demonstrated several advantages, including simplicity, low toxicity, cost-effectiveness, and eco-friendliness. Spinel nickel ferrite (NiFe2O4) nanowhiskers with rod-like structures were synthesized using a simple and green method; these nanostructures were evaluated by X-ray diffraction analysis, transmission electron microscopy, scanning electron microscopy, and X-ray energy diffraction spectroscopy. Additionally, the prepared nanowhiskers could significantly reduce the survival of Leishmania major promastigotes, at a concentration of 500 μg/mL; the survival of promastigotes was reduced to ≃ 26%. According to the results obtained from MTT test (in vitro), it can be proposed that further studies should be conducted to evaluate anti-leishmaniasis activity of these types of nanowhiskers in animal models.

Green Synthesis and Characterization of Carboxymethyl Cellulose Fabricated Silver-Based Nanocomposite for Various Therapeutic Applications.

PurposeThe current study proposed the simple, eco-friendly and cost-effective synthesis of carboxymethyl cellulose (CMC) structured silver-based nanocomposite (CMC-AgNPs) using Syzygium aromaticum buds extract.MethodsThe CMC-AgNPs were characterized by ultraviolet (UV) spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transmission infra-red (FTIR), energy-dispersive X-ray (EDX), and dynamic light scattering (DLS) techniques. The synthesized nanocomposites were evaluated for their bactericidal kinetics, in-vivo anti-inflammatory, anti-leishmaniasis, antioxidant and cytotoxic activities using different in-vitro and in-vivo models.ResultsThe spherical shape nanocomposite of CMC-AgNPs was synthesized with the mean size range of 20–30 nm, and the average pore diameter is 18.2 nm while the mean zeta potential of −31.6 ± 3.64 mV. The highly significant (P < 0.005) antibacterial activity was found against six bacterial strains with the ZIs of 24.6 to 27.9 mm. More drop counts were observed in Gram-negative strains after 10 min exposure with CMC-AgNPs. Significant damage in bacterial cell membrane was also observed in atomic force microscopy (AFM) after treated with CMC-AgNPs. Nanocomposite showed highly significant anti-inflammatory activity in cotton pellet induced granuloma model (Phase I) in rats with the mean inhibitions of 43.13% and 48.68% at the doses of 0.025 and 0.05 mg/kg, respectively, when compared to control. Reduction in rat paw edema (Phase II) was also highly significant (0.025 mg/kg; 42.39%; 0.05 mg/kg, 47.82%). At dose of 0.05 mg/kg, CMC-AgNPs caused highly significant decrease in leukocyte counts (922 ± 83), levels of CRP (8.4 ± 0.73 mg/mL), IL-1 (177.4 ± 21.3 pg/mL), IL-2 (83.7 ± 11.5 pg/mL), IL-6 (83.7 ± 11.5 pg/mL) and TNF-α (18.3 ± 5.3 pg/mL) as compared to control group. CMC-AgNPs produced highly effective anti-leishmaniasis activity with the viable Leishmania major counts decreased up to 36.7% within 24 h, and the IC50 was found to be 28.41 μg/mL. The potent DPPH radical scavenging potential was also observed for CMC-AgNPs with the IC50 value of 112 μg/mL. Furthermore, the cytotoxicity was assessed using HeLa cell lines with the LC50 of 108.2 μg/mL.ConclusionThe current findings demonstrate positive attributes of CMC fabricated AgNPs as a promising antibacterial, anti-inflammatory, anti-leishmaniasis, and antioxidant agent with low cytotoxic potential.

Thiolated PVP-Amphotericin B Complexes: An Innovative Approach toward Highly Mucoadhesive Gels for Mucosal Leishmaniasis Treatment.

The aim of this study was to synthesize polymeric excipients that can form mucoadhesive hydrogels containing amphotericin B (AmB) for the treatment of mucosal leishmaniasis. 2-(2-Acryloylaminoethyldisulfanyl)-nicotinic acid (ACENA) was copolymerized with N-vinyl pyrrolidone to obtain thiolated polyvinylpyrrolidone (PVP) that was then complexed with AmB to improve its solubility. The resulting structure of thiolated PVP was evaluated by 1H nuclear magnetic resonance to confirm S-protected thiol groups, and the average molecular mass was determined by size exclusion chromatography. Moreover, variants of thiolated PVP-AmB were studied for the thiol content, amount of complexed AmB, cytotoxicity, mucoadhesive properties, and antileishmaniasis activity. The highest achieved degree of thiolation was 772 ± 24.64 μmol/g, and the amount of complexed AmB was 27.05 ± 0.31 μmol per g of polymer. Thiolated PVP and thiolated PVP-AmB variants (0.5% m/v) showed no cytotoxicity, whereas the equivalent concentration of free AmB reduced Caco-2 cell viability to 70% within 24 h. Thiol-functionalized PVP and PVP-AmB complexes displayed 7.66- and 7.20-fold higher adhesion to the mucosal surface in comparison to unmodified PVP and PVP-AmB, respectively. In addition, variants of thiolated PVP-AmB complexes displayed 100% antileishmaniasis activity in comparison to the 80% killing efficiency of Fungizone, which has been applied in the equivalent AmB concentration of 0.2 μg/mL. Thiol-functionalized PVP proved to be a promising novel excipient for the delivery of AmB providing enhanced solubility and improved mucoadhesive properties which are beneficial for the treatment of mucosal leishmaniasis.

Natural compounds and extracts from Mexican medicinal plants with anti-leishmaniasis activity: An update.

Leishmaniasis is considered as an emerging, uncontrolled disease and is endemic in 98 countries. Annually, about 2 million cases of cutaneous and 500000 cases of visceral-type leishmaniasis are recorded and 60000 persons died from the disease. In Mexico, cutaneous leishmaniasis is known as chiclero's ulcer and is reported in 22 states, it is considered as a health problem. For its treatment, pentavalent antimonial drugs are administered. These drugs cause severe side effects, are costly. Drug-resistant cases have been reported and have been developing for over 70 years. One alternative to the drugs that are currently available is to find active molecules in medicinal plants. Dihydrocorynantheine, corynantheine and corynantheidine are active against Leishmania major, while harmane, pleiocarpin, buchtienin, luteolin and quercetin are active against Leishmania donovani. In Mexico, about 20 medicinal plants have been evaluated against Leishmania mexicana, among which the most active are Tridax procumbens, Lonchocarpus xuul and Pentalinon andrieuxii. From these plants, active compounds with IC50≤30μg/mL or μM have been isolated, such as 3(S)-16,17-didehydrofalcarinol or Oxylipin, cholestra-4,20,24-trien-3-one or pentalinosterol, 24-methylcholest-4-24(28)-dien-3-one, cholest-4-en-3-one, 6,7-dihydroneridie-none, neridienone, cholest-5,20,24-trien-3β-ol, and isocordoin. Today, only pentalinonsterol has been synthesized and assayed in the visceral leishmaniasis experimental model using BALB/c mice infected with Leishmania donovani. Liposome formulation of this compound administered by intravenous route at 2.5mg/kg showed a significant reduction of parasite load in mouse liver and spleen.

Phytochemical screening of the exudate of Aloe otallensis and its effect on Leishmania donovani

Objective: To evaluate the antileishmanial activity of methanolic extract of Aloe otallensis (A. otallensis) on the promastigote stage of Leishmania donovani (L. donovani) as compared to standard drugs and to screen its phytochemical constituents. Methods: Phytochemical screening was done by using the method mentioned by Evans and Trease on methanolic extract of the exudates of Aloe otallensis leaves. The extract was also evaluated for in vitro antileishmanial activity against L. donavani which is found from the Parasitology Unit of Black Lion Hospital. The result was compared to standard drugs of sodium stibogluconate, milfostin and paramomycin. Results: The extract has a good antileishmanial activity with an IC50 of 0.123 0 μg/mL on L. donovani (AM 563). The experimental data showed that relatively it had better activity than paramomycin and milfostin but less activity than sodium stibogluconate. The data analyses were done by GraphPad Prism version 5 software after it was read by ELISA reader at the wave length of 650 nm. The phytochemical screening of the exudates of A. otallensis showed the presence of phenol, alkaloid and saponin. Conclusions: The methanol extract of the exudates of A. otallensis has a good antileishmaniasis activity and this may be attributed to phenol, alkaloid and saponin present in the plant. But it needs further analysis for the conformation of which constituent presents in high concentration to know which one has the strongest effect.

Screening of Aloe otallensis Exudate and Its Effect on Leishmania aethiopica

Background and objectives: The different Aloaceae plant extracts have been tested and found to contain components with anti leishmanial activity. Our study was conducted to assure anti leishmanial activity of the methanol extract of Aloe otallensis on the promastigot stage of Leishmania aethiopica as compared to currently used drugs and also tried to screen its phytochemical constitutes. Methods: Aloe otallensis leaf exudate was extracted by using methanol solvent and phytochemical screening was done using the method mentioned by Trease and Evans as well as the extract was evaluated for in vitro anti leishmanial activity against Leishmania aethiopica which was taken from the Black Lion Specialized Hospital parasitology unit. The result was compared with currently used drug like; Sodium stibogluconate, milfostin and paramomycin. Result: The extract has a good anti leishmanial activity with an IC50 of 0.041 μg/mL on L. aethiopica (LDC/134). The experimental result shows that the extract has better anti leishimanial activity on L. aethiopica than paramomycin and milfostin but less activity than sodium stibogluconate. The data analyses was done by pad graph prison version 5 software after it was read by ELISA reader at the wave length of 650 nm. The phytochemical screening of aloe otallensis exudate showed the presence of phenol, alkaloid and saponin. Conclusion: Aloe otallensis exudate methanol extract was found to have a good anti leishmaniasis activity against L. Aethiopica and this may be attributed to phenol, alkaloid and saponin present in the plant. Even though this is our conclusion it needs further investigations to confirm which constituent(s) is/are responsible for such effect and at how many concentrations.

Plants with anti-Leishmania activity: Integrative review from 2000 to 2011

The search for more effective new drugs to treat Leishmaniasis is undoubtedly relevant. Our objective in this study was to investigate research publications addressing plants with anti-Leishmaniasis activity. An integrative review of the literature from 2000 to 2011 was carried out in the databases such as Latin-American and Caribbean Health Sciences (LILACS), Scientific Electronic Library Online (SciELO), and Medical Literature Analysis and Retrieval System Online (MEDLINE). In the initial search, 150 articles were found, with 25 based in LILACS, 68 in SciELO, and 46 in MEDLINE. From these data, after reading the abstracts that were available online, we excluded 12 from LILACS, 39 from SciELO, and 28 from MEDLINE for presenting article duplications. This left 61 articles to be read; however, only 18 of them answered the research questions and determined the final sample of this review. The results showed that research involving the search for new drugs against Leishmaniasis should be intensified, especially for the amastigote form, and studies with in vivo tests could become a great strategy for successfully finding new treatments for Leishmaniasis. It is believed that it is extremely important and urgent to conduct more trials in search of new effective drugs against Leishmaniasis that possess minimal adverse effects and that are easily accessible to the public.

Paromomycin loaded solid lipid nanoparticles: Characterization of production parameters

Paromomycin has been shown to have anti-leishmaniasis activity; however, its clinical use is restricted to some content owing to its poor skin penetration. To identify innovative methods of dermal administration of paromomycin and controlling the release delivery system, paromomycin was loaded into the solid lipid media as nanoparticles. Type of the method; microemulsion or solvent diffusion, the type of lipid; cetyl palmitate or stearic acid, were comparatively investigated on the average diameter, size distribution and entrapment efficiency of the lipid nanoparticles to maximize entrapment efficiency, reduce the particle size and its distribution. Three quantitative factors, paromomycin content, weight fraction of Tween 80 and drug to lipid ratio, were also investigated at two levels for Solid Lipid Nanoparticles (SLNs) formulation in a fractional factorial design. The results indicated that microemulsion was the most efficient method and stearic acid was the preferred lipid for SLNs formulation. The average size of the particles was reduced to 299.08 nm and the entrapment efficiency was enhanced from immediate release to 24 h.

Mannosylated liposomes bearing Amphotericin B for effective management of visceral Leishmaniasis

The cationic and mannosylated liposomes were prepared using the cast film method and compared for their antileishmaniasis activity. The surface of the Amphotericin B (Amp B)-bearing cationic multilamellar liposomes was covalently coupled with p-aminophenyl-α-D-mannoside using glutaraldehyde as a coupling agent, which was confirmed by agglutination of the vesicles with concanavalin A. The prepared liposomes were characterized for shape, size, percent drug entrapment, vesicle count, zeta potential, and in vitro drug release. Vesicle sizes of cationic and mannosylated liposomes were found to be 2.32 ± 0.23 and 2.69 ± 0.13 µm, respectively. Zeta potential of cationic liposomes was higher (30.38 ± 0.3 mV), as compared to mannosylated liposomes (17.7 ± 0.8 mV). Percentage drug release from cationic and mannose-coupled liposomes was found to be 45.7% ± 3.1 and 41.9% ± 2.8, respectively, after 24 hours. The in vivo antileishmanial activity was performed on Leishmania donovani–infected golden hamster, and results revealed that Amp B solution was reduced by 42.5 ± 1.8% in the parasite load, whereas the placebo cationic liposomes and drug-containing cationic liposomes showed a reduced parasite load (i.e., 28.1 ± 1.5 and 61.2 ± 3.2%, respectively). The mannose-coupled liposomes showed a maximum reduction in parasite load (i.e., 78.8 ± 3.9%). The biodistribution study clearly showed the higher uptake of mannosylated liposomes in the liver and spleen and hence the active targeting to the reticular endothelial system, which, in turn, would provide a direct attack of the drug to the site where the pathogen resides, rendering the other organs free and safe from the toxic manifestations of the drug.

Antileishmanial, Antimicrobial and Antifungal Activities of Some New Aryl Azomethines

A series of eighteen azomethines has been synthesized by the reaction of appropriate primary aromatic amines with aryl and/or heteroaryl carboxaldehydes. The synthesized azomethines have been evaluated for their in vitro antileishmanial, antibacterial and antifungal activities. The results revealed some antifungal activity of most of the synthesized compounds, whereas the antileishmaniasis activity results highlighted that all synthesized azomethines inhibited parasite growth and most of them showed highly potent action towards Leishmania major promastigotes. No remarkable bactericidal activities were observed.

Synthesis and anti-leishmaniasis activity of 5-substituted 2-furyl-1,3-dioxans

Synthesis and anti-leishmaniasis activity of 5-substituted 2-furyl-1,3-dioxans