Leishmanicidal Activity Research Articles

Investigation of Novel Isatinylhydantoin Derivatives as Potential Anti-Kinetoplastid Agents.

Neglected tropical diseases are a group of infectious diseases with a high endemicity in developing countries of Africa, Asia, and the Americas. Treatment for these diseases depends solely on chemotherapy, which is associated with severe side effects, toxicity, and the development of parasitic resistance. This highlights a critical need to develop new and effective drugs to curb these diseases. As a result, a series of novel isatinylhydantoin derivatives were synthesized and evaluated for in vitro anti-kinetoplastid activity against seven human- or animal-infective Trypanosoma and two human-infective Leishmania species. The synthesized derivatives were tested for potential cytotoxicity against human, animal, and parasite host-related cell lines. The isatinylhydantoin hybrid 4 b bearing 5-chloroisatin and p-bromobenzyl moieties, showed strong trypanocidal activity against blood-stage T. congolense parasites; however, the promising in vitro trypanocidal potency of 4 b could not be translated to in vivo treatment efficacy in a preliminary animal study. Compounds 5, 2 b, and 5 b, were the most active against amastigotes of L. donovani, showing higher leishmanicidal activity than the reference drug, amphotericin B. These compounds were identified as early antileishmanicidal leads, and future investigations will focus on confirming their antileishmanial potential through in vivo efficacy evaluation as well as their exact mechanism of action.

Antitrypanosomal and antileishmanial activity of compounds from some Nigerian plants

Ten compounds, six extracts and five fractions obtained from three Nigerian plants were assayed for their in vitro antitrypanosomal and antileishmanial activities. Each plant was extacted with hexane, ethyl acetate, and methanol. Isolated compounds were characterized and identified based on their NMR chemical shifts and comparison to literature reports. The crude extracts, fractions and isolated compounds were tested against the kinetoplastid parasites: bloodstream forms of Trypanosoma brucei Lister 427WT and the derived multi-drug resistant clone B48, and promastigote forms of Leishmania mexicana cas9/T7 and the derived clone cas9ΔNT1. Column chromatography of the extracts using silica gel yielded ten compounds identified as curzerenone, epi-curzerenone, chloranthene F, isofuranodienone, 8(17)-12E-labdadiene-15, 16-dial and 15-hydroxy-8(17),12E-labdadiene-16-al from Siphonochilus aetiopicus, lupeol, linalolic acid and spinasterone from Calliandra portoricensis, and abruquinone B from Abrus precatorius. The assay results showed that the Siphonochilus aetiopicus and Calliandra portoricensis crude extracts, fractions and compounds displayed moderate activity against the Trypanosoma brucei brucei but showed less activity against Leishmania mexicana. Abrus precatorius crude extract, fraction, and isolated compound exhibited only weak trypanocidal and leishmanicidal activities against both kinetoplastid parasites tested. These findings have provided evidence for the use of Siphonochilus aetiopicus and Calliandra portoricensis in traditional medicine relating to parasitic diseases.

Identification of new potential inhibitors of pteridine reductase-1 (PTR1) via biophysical and biochemical mechanism-based approaches: Step towards the treatment of Leishmaniasis

Leishmaniasis is a parasitic disease, which spreads from the bite of an infected Phlebotomine fly to human hosts. The disease is characterized by a number of clinical manifestations, such as ulcerative lesions at the site of sandfly bite (cutaneous form), inflammation of mucosal membranes (mucosal leishmaniasis) or the deadly visceral form. This study was aimed to target pteridine reductase-1 (PTR1), a member of short chain dehydrogenases, which accounts for the reduction of conjugated and unconjugated pterins in Leishmania parasite. The ptr1-pET28a+-tev construct was expressed using BL21 (DE3) cells, followed by two tandem purification steps including affinity and gel permeation chromatography. In the next phase, functional studies of PTR1 were performed via screening of an in-house library of 500 compounds. The biochemical-mechanism based assay of PTR1 identified 11 hits that were also found to be non-cytotoxic against human fibroblast cell line (BJ) (except compound 6), and thus further studied via computational technique and saturation transfer difference-nuclear magnetic resonance (STD-NMR) spectroscopy. These high throughput techniques identified six compounds 2, 4, 5, 7, 9, and 11 as active, which were then assessed via in-vitro assay. Among them, compounds 2, 4, and 7 showed substantial leishmanicidal activity, comparable to the standard drug, miltefosine (IC50 value: 31.8 ± 0.2 μM). These results narrowed down the search to 3 compounds as potential leads, with prominent protein-ligand interaction profiles. Hence, the respective compounds can be further assessed for their therapeutic potential against leishmaniasis.

Molecular docking, network pharmacology, and QSAR modelling studies of benzo[c]phenanthridines - novel antileishmaniasis agents.

Leishmaniasis treatment primarily relies on chemotherapy due to lack of vaccines. However, the low efficacy, parasite resistance, and toxicity associated with existing drugs necessitate the development of effective and safer therapies. Fuchino etal. reported promising leishmanicidal activity in a series of benzo[c]phenanthridines against L. major promastigotes. To progress these compounds towards drug development, it is crucial to understand their molecular targets, mechanisms of action, binding interactions, and structural requirements. In this research, molecular docking, network pharmacology, 2D-QSAR, and 3D-QSAR CoMFA studies were performed on 30 benzo[c]phenanthridines. Docking analysis showed that all molecules had a strong binding affinity to L. major-nucleoside diphosphate kinase (NDPK) compared to the other targets. 10-isopropoxy sanguinarine had the highest binding affinity (-10.6 kcal/mol) and formed ionic and hydrophobic interactions. Network pharmacology analysis of the most active compounds identified serine/threonine-protein kinase Mtor as a potential antileishmaniasis target in humans for benzo[c]phenanthridines. This was confirmed with high-affinity scores > -7.0 kcal/mol for all the compounds docked. GO and KEGG pathway enrichment identified Reg. of fatty acid oxidation (BP), TORC1 complex (CC), RNA polymerase III type 1 promoter sequence-specific DNA binding (MF), and Acute myeloid leukemia (KEGG pathway) to be highly enriched with the hub genes. Both 2D and 3D-QSAR CoMFA models satisfied the internal and external validation tests as follows: 2D-QSAR: R2Train = 0.9040, Q2cv = 0.8648, R2adj = 0.8838, and R2Test = 0.8740; and 3D-QSAR: r2 = 0.998, q2 = 0.526, and SDEP = 0.856. The molecules can be practically evaluated as superior antileishmaniasis agents.

In vitro leishmanicidal activity of Hancornia speciosa latex against Leishmania (Leishmania) amazonensis

BackgroundLeishmaniasis is a neglected tropical disease whose available treatment has limitations. Hancornia speciosa Gomes, a tree native to Brazil, has been studied for its medicinal properties, including antimicrobial and healing properties. However, its effect on parasites of the Leishmania genus still needs to be elucidated. PurposeTo evaluate the leishmanicidal activity for potential therapeutic use of H. speciosa latex and its fractions on Leishmania (Leishmania) amazonensis promastigotes and amastigotes, as well as to analyze its cytotoxic effects on RAW264.7 cells and murine peritoneal macrophages. MethodsThe anti-promastigote activity of latex and its fractions was evaluated by cell viability assays via MTT in L. (L.) amazonensis and monitoring the parasite's growth kinetics by counting under light microscopy. To evaluate anti-amastigote activity, RAW264.7 cells and murine peritoneal macrophages infected with amastigotes were analyzed using microscopy, immunofluorescence, and flow cytometry assays. The cytotoxicity of latex and its fractions was evaluated in these cells via MTT assay. ResultsThe H. speciosa latex and its fractions showed anti-promastigote activities in L. (L.) amazonensis, reducing its proliferation and viability and altering its morphology. These did not interfere with the viability of RAW264.7 cells and peritoneal macrophages. Crude latex and F<10 kDa at 5% reduced the infection of intracellular amastigotes in peritoneal macrophages to 32% and 18% after 24 h of treatment, respectively. Under the same conditions, the F>10 kDa fraction showed 82% of infected cells. The evaluation of the latex composition showed that the F>10 kDa fraction has the highest concentration of carbohydrates, followed by phenolic compounds and proteins. In contrast, the F<10k Da fraction presented fewer phenolic compounds and carbohydrates. ConclusionsThese results indicate that H. speciosa crude latex and F<10 kDa have intense leishmanicidal activity against L. (L.) amazonensis promastigotes and amastigotes internalized by macrophages. Additionally, the lack of cytotoxicity indicates that H. speciosa latex is a strong candidate for new alternative treatments for leishmaniasis.

Antiparasitary potential of Sarcomphalus joazeiro (Mart.) Hauenschild (Rhamnaceae)

Leishmaniasis and American trypanosomiasis are part of a set of diseases characterized by the World Health Organization as neglected diseases caused by infectious and parasitic agents in populations in situations of poverty and poor sanitation. Pharmaceutical industries neglect such diseases, which have limited treatments, mainly due to few drug options and significant toxicity. Therefore, it is essential to search for new substances that have the potential to replace these medications. In this context, this study aimed to evaluate the leishmanicidal and trypanocidal activity of the ethanolic extract of the leaves and bark of Sarcomphalus joazeiro (Mart.) Hauenschild. These extracts were prepared by maceration with cold extraction. When carrying out the susceptibility tests, the extracts were tested in four different concentrations against the epimastigote forms of the CL-B5 parasite strains of Trypanosoma cruzi and promastigote forms of Leishmania braziliensis and Leishmania infantum, both tests were carried out "in vitro" in plates 96-well microdilution system, with nifurtimox and metronidazole as reference medicine. The cytotoxicity assay was performed with mammalian fibroblast lines from the NCTC 929 clone. The results indicate that the ethanolic extract of the bark of the stem of S. joazeiro (EBSJ) presented a more significant antiparasitic effect when compared to the ethanolic extract of the leaves of Sarcomphalus joazeiro (ELSJ) particularly against L. braziliensis and L. infantum. Regarding cytotoxicity, EBSJ and ELSJ presented moderate and low degrees, respectively. Based on the data obtained, further investigations into the properties of the bark extract are necessary, mainly due to its leishmanicidal potential.

Dioclea violacea lectin has potent in vitro leishmanicidal activity against Leishmania infantum via carbohydrate recognition domain

Despite promising advancements in leishmaniasis treatment, existing therapies often face limitations and significant side effects, stimulating the search for novel therapeutic alternatives. In this context, lectins, such as DVL extracted from Dioclea violacea seeds, have emerged as potential candidates due to their diverse biological activities. This study represents the first investigation of the leishmanicidal potential of DVL in vitro against Leishmania infantum. Our results demonstrate that DVL exhibits a leishmanicidal effect (IC50/24 h = 49.37 μg/mL or 2 μM), binding to glycans on L. infantum. Fluorescence assays revealed that DVL can induce the production of reactive oxygen species (ROS) and cause damage to the parasite's membrane. DVL demonstrated a modulating effect when combined with amphotericin B and glucantime, enhancing the activity of these drugs by 40 % and 80 %, respectively. It also showed no cytotoxicity in Raw 264.7 cells and was able to override the toxic effect of amphotericin B on cells and reduce the survival rate of macrophages infected with amastigote forms, as well as their percentage of infection by 31 %. Therefore, DVL shows promise as a treatment for visceral leishmaniasis caused by L. infantum. Our findings provide valuable insights for future therapeutic development targeting leishmania glycans.

Effect of a thiohydantoin salt derived from l-Arginine on Leishmania amazonensis and infected cells: Insights from biological effects to molecular docking interactions

Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania and is responsible for more than 1 million new cases and 70,000 deaths annually worldwide. Treatment has high costs, toxicity, complex and long administration time, several adverse effects, and drug-resistant strains, therefore new therapies are urgently needed. Synthetic compounds have been highlighted in the medicinal chemistry field as a strong option for drug development against different diseases. Organic salts (OS) have multiple biological activities, including activity against protozoa such as Leishmania spp. This study aimed to investigate the in vitro leishmanicidal activity and death mechanisms of a thiohydantoin salt derived from l-arginine (ThS) against Leishmania amazonensis. We observed that ThS treatment inhibited promastigote proliferation, increased ROS production, phosphatidylserine exposure and plasma membrane permeabilization, loss of mitochondrial membrane potential, lipid body accumulation, autophagic vacuole formation, cell cycle alteration, and morphological and ultrastructural changes, showing parasites death. Additionally, ThS presents low cytotoxicity in murine macrophages (J774A.1), human monocytes (THP-1), and sheep erythrocytes. ThS in vitro cell treatment reduced the percentage of infected macrophages and the number of amastigotes per macrophage by increasing ROS production and reducing TNF-α levels. These results highlight the potential of ThS among thiohydantoins, mainly related to the arginine portion, as a leishmanicidal drug for future drug strategies for leishmaniasis treatment. Notably, in silico investigation of key targets from L. amazonensis, revealed that a ThS compound from the l-arginine amino acid strongly interacts with arginase (ARG) and TNF-α converting enzyme (TACE), suggesting its potential as a Leishmania inhibitor.

Bioassay-guided isolation of dehydrocostus lactone from Echinops kebericho as a leishmanicidal drug

Several strains of Leishmania parasite are involved in the occurrence of leishmaniasis infections, which makes its prevention and treatment very challenging. Currently, all forms of leishmaniasis are being treated with chemical drugs, which have limitations and adverse effects. Discovering antileishmanial agents from natural sources can lead to novel drugs against this dreadful disease. The essential oils and nonpolar solvent extracts of the roots of E. kebericho exhibit antileishmanial activity. Thus, the isolation of the leishmanicidal compounds from the roots of E. kebericho through a bioassay-guided technique was carried out in this study. The present finding showed that the essential oil and hexane fraction of crude extract from the roots of E. kebericho possessed significant leishmanicidal activity against L. major and L. tropica. Dehydrocostus lactone (1), one of the major constituents of the essential oil and hexane fraction, was more active than the standard drug miltefosine against L. major and L. tropica promastigotes. The presence of α-methylene, γ-lactone is the responsible moiety of dehydrocostus lactone towards the leishmanicidal activity against the tested Leishmania species. The MTT assay of dehydrocostus lactone showed inactive toxicity against the human cervical carcinoma HeLa cells. In addition, dehydrocostus lactone exhibits a broad spectrum of antibiotic activities. Based on this interesting finding, dehydrocostus lactone was identified as a potential lead for treating infections caused by Leishmania.

Exploring antiviral and antiparasitic activity of gold N-heterocyclic carbenes with thiolate ligands.

Gold(I) N-heterocyclic carbenes have been explored for their therapeutic potential against several diseases. Neglected tropical diseases, including leishmaniasis, Chagas disease, and viral infections, such as zika, mayaro, and chikungunya, urgently require new treatment options. The emergent SARS-CoV-2 also demands significant attention. Gold complexes have shown promise as alternative treatments for these conditions. Previously, gold(I)(1,3-bis(mesityl)imidazole-2-ylidene)Cl (AuIMesCl) demonstrated significant leishmanicidal and anti-Chikungunya virus activities. In this study, we synthesized and fully characterized a series of gold(I)(1,3-bis(mesityl)imidazole-2-ylidene)(SR) complexes, where SR includes thiolate donor species such as 1,3-thiazolidine-2-thione, 1,3-benzothiazole-2-thione, 2-mercaptopyrimidine, and 2-thiouracil. These compounds were stable in solution, and ligand exchange reactions with N-acetyl-L-cysteine indicated that complexes with SR ligands are more labile than those with chloride. Although the reactions are rapid, they reach equilibrium at varying molar ratios depending on the SR ligand. The increased lability of these compounds results in higher cytotoxicity to host cells, such as Vero E6 and bone marrow-differentiated macrophages, compared to AuIMesCl. Despite this, the compounds effectively inhibited viral replication, achieving 95.5% inhibition of Zika virus replication at 2 μM with 96% host cell viability. Although active at low concentrations (∼2 μM) against Leishmania (L.) amazonensis and Trypanosoma cruzi, their high cytotoxicity for macrophages confirmed AuIMesCl as a better candidate with a higher selectivity index. This work correlates the coordination chemistry of pyrimidines and thiazolidines with their in vitro biological activities against significant diseases.

In Vitro and In Silico Evaluation of the Leishmanicidal and Trypanocidal Activities of Lignan Methylpiperitol Isolated from Persea Fulva.

Neglected Tropical Diseases are a significant concern as they encompass various infections caused by pathogens prevalent in tropical regions. The limited and often highly toxic treatment options for these diseases necessitate the exploration of new therapeutic candidates. In the present study, the lignan methylpiperitol was isolated after several chromatographic steps from Persea fulva L. E. Koop (Lauraceae) and its leishmanicidal and trypanocidal activities were evaluated using in vitro and in silico approaches. The chemical structure of methylpiperitol was defined by NMR and MS spectral data analysis. The antiprotozoal activity of methylpiperitol was determined in vitro and indicated potency against trypomastigote forms of Trypanosoma cruzi (EC50 of 4.5±1.1 mM) and amastigote forms of Leishmania infantum (EC50 of 4.1±0.5 mM), with no mammalian cytotoxicity against NCTC cells (CC50>200 mM). Molecular docking studies were conducted using six T. cruzi and four Leishmania. The results indicate that for the molecular target hypoxanthine phosphoribosyl transferase in T. cruzi and piteridine reductase 1 of L. infatum, the methylpiperitol obtained better results than the crystallographic ligand. Therefore, the lignan methylpiperitol, isolated from P. fulva holds potential for the development of new prototypes for the treatment of Neglected Tropical Diseases, especially leishmaniasis.

In silico studies on leishmanicide activity of limonoids and fatty acids from Carapa guianensis Aubl.

The oil of Carapa guianensis showed leishmanicidal activity, with its activity being related to limonoids, but fatty acids are the major constituents of this oil. The present study evaluated the physicochemical, pharmacokinetic, and toxicity profiles of limonoids and fatty acids already identified in the species. Based on these results, 2 limonoids (methyl angosinlate, 6-OH-methyl angosinlate) and 2 fatty acids (arachidic acid; myristic acid) were selected for the prediction of possible targets and molecular docking. Included in this study were: Gedunin, 6α-acetoxygedunin, Methyl angosenlato, 7-deacetoxy-7-oxogedunin, Andirobin, 6-hydroxy-angolensate methyl, 17β-hydroxyazadiradione, 1,2-dihydro-3β-hydroxy-7-deacetoxy-7-oxogedunin, xyllocensin k, 11beta-Hydroxygedunin, 6α,11-11β-diacetoxygedunin, Oleic Acid, Palmitic Acid, Stearic Acid, Arachidic Acid, Myristic Acid, Palmitoleic Acid, Linoleic Acid, Linolenic Acid, and Beenic Acid. Regarding physicochemical aspects, fatty acids violated LogP, and only limonoid 11 violated Lipinski's rule. A common pharmacokinetic aspect was that all molecules were well absorbed in the intestine and inhibited CYP. All compounds showed toxicity in some model, with fatty acids being mutagenic and carcinogenic, and limonoids not being mutagenic and carcinogenic at least for rats. In in vivo models, fatty acids were less toxic. Molecular dockings were performed on COX-2 steroids (15 and 16) and hypoxia-inducible factor 1 alpha for limonoids (3,6), with this target being essential for the intracellular development of leishmania. Limonoids 3 and 6 appear to be promising as leishmanicidal agents, and fatty acids are promising as wound healers.

Encapsulation of Citrus sinensis essential oil and R-limonene in lipid nanocarriers: A potential strategy for the treatment of leishmaniasis

Leishmaniases, a group of neglected tropical diseases caused by an intracellular parasite of the genus Leishmania, have significant impacts on global health. Current treatment options are limited due to drug resistance, toxicity, and high cost. This study aimed to develop nanostructured lipid carriers (NLCs) for delivering Citrus sinensis essential oil (CSEO) and its main constituent, R-limonene, against leishmaniasis. The influence of surface-modified NLCs using chitosan was also examined. The NLCs were prepared using a warm microemulsion method, and surface modification with chitosan was achieved through electrostatic interaction. These nanocarriers were characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), transmission electron microscopy, and dynamic light scattering (DLS). In vitro cytotoxicity was assessed in L929 and RAW 264.7 cells, and leishmanicidal activity was evaluated against promastigote and amastigote forms. The NLCs were spherical, with particle sizes ranging from 97.9 nm to 111.3 nm. Chitosan-coated NLCs had a positive surface charge, with zeta potential values ranging from 45.8 mV to 59.0 mV. Exposure of L929 cells to NLCs resulted in over 70 % cell viability. Conversely, surface modification significantly reduced the viability of promastigotes (93 %) compared to free compounds. Moreover, chitosan-coated NLCs presented a better IC50 against the amastigote forms than uncoated NLCs. Taken together, these findings demonstrate the feasibility of using NLCs to overcome the limitations of current leishmaniasis treatments, warranting further research.

Dereplication of 4-Quinolone Alkaloids from Waltheria Indica (Malvaceae) Tissues Using Molecular Network Tools.

Waltheria indica (Malvaceae) is a plant popularly used in folk medicine by traditional African and indigenous communities, and in various countries worldwide, to treat general inflammation. Several biological activities of this plant have been reported, including acetylcholinesterase inhibition and potential anti-human immunodeficiency virus (HIV), antinociceptive, analgesic, antifungal, anticancer, anti-inflammatory, leishmanicidal, trypanocidal, antioxidant, and antibacterial activities. The chemical profile of Waltheria indica was assessed by dereplication analysis using UPLC-MS/MS, and data acquisition was performed using chemoinformatics tools, such as Mass Spectrometry-Data Independent AnaLysis (MS-DIAL) and MS-FINDER softwares. The preprocessed data were sent to the GNPS to build a feature-based molecular network (FBMN). Thirty-three 4-quinolone alkaloids were annotated in the extracts and fractions of stems and roots, whereas 12 were annotated in the extracts and fractions of flowers and leaves. This represents an inaugural chemical investigation study employing UPLC-Q-TOF-MS/MS analysis, along with a molecular network approach, within this species and genus.

A Review of the Leishmanicidal Properties of Lectins.

Lectins are proteins widely distributed among plants, animals and microorganisms that have the ability to recognize and interact with specific carbohydrates. They have varied biological activities, such as the inhibition of the progression of infections caused by fungi, bacteria, viruses and protozoa, which is related to the interaction of these proteins with the carbohydrates present in the cell walls of these microorganisms. Leishmaniasis are a group of endemic infectious diseases caused by protozoa of the genus Leishmania. In vitro and in vivo tests with promastigotes and amastigotes of Leishmania demonstrated that lectins have the ability to interact with glycoconjugates present on the cell surface of the parasite, it prevents their development through various mechanisms of action, such as the production of ROS and alteration of membrane integrity, and can also interact with defense cells present in the human body, thus showing that these molecules can be considered alternative pharmacological targets for the treatment of leishmaniasis. The objective of the present work is to carry out a bibliographic review on lectins with leishmanicidal activity, emphasizing the advances and perspectives of research in this theme. Through the analysis of the selected studies, we were able to conclude that lectins have great potential for inhibiting the development of leishmaniasis. However, there are still few studies on this subject.

A Second Wind for Inorganic APIs: Leishmanicidal and Antileukemic Activity of Hydrated Bismuth Oxide Nanoparticles.

American cutaneous leishmaniasis is a disease caused by protozoa of the genus Leishmania. Currently, meglumine antimoniate is the first-choice treatment for the disease. The limited efficacy and high toxicity of the drug results in the necessity to search for new active principles. Nanotechnology is gaining importance in the field, since it can provide better efficacy and lower toxicity of the drugs. The present study aimed to synthesize, characterize, and evaluate the in vitro leishmanicidal and antileukemic activity of bismuth nanoparticles (BiNPs). Promastigotes and amastigotes of L. (V.) guyanensis and L. (L.) amazonensis were exposed to BiNPs. The efficacy of the nanoparticles was determined by measurement of the parasite viability and the percentage of infected cells, while the cytotoxicity was characterized by the colorimetry. BiNPs did not induce cytotoxicity in murine peritoneal macrophages and showed better efficacy in inhibiting promastigotes (IC50 < 0.46 nM) and amastigotes of L. (L.) amazonensis. This is the first report on the leishmanicidal activity of Bi-based materials against L. (V.) guayanensis. BiNPs demonstrated significant cytotoxic activity against K562 and HL60 cells at all evaluated concentrations. While the nanoparticles also showed some cytotoxicity towards non-cancerous Vero cells, the effect was much lower compared to that on cancer cells. Treatment with BiNPs also had a significant effect on inhibiting and reducing colony formation in HL60 cells. These results indicate that bismuth nanoparticles have the potential for an inhibitory effect on the clonal expansion of cancer cells.

Anti-Leishmania effect of icetexanes from Salvia procurrens

Background and purposeLeishmaniasis is a globally prevalent vector-borne disease caused by parasites of the genus Leishmania. The available chemotherapeutic drugs present problems related to efficacy, emergence of parasite resistance, toxicity and high cost, justifying the search for new drugs. Several classes of compounds have demonstrated activity against Leishmania, including icetexane-type diterpenes, previously isolated from Salvia and other Lamiaceae genera. Thus, in this study, compounds of Salvia procurrens were investigated for their leishmanicidal and immunomodulatory activities. MethodsThe exudate of S. procurrens was obtained by rapidly dipping the aerial parts in dichloromethane. The compounds were isolated by column and centrifugal planar chromatography over silica gel. The effects on L. amazonensis growth, survival, membrane integrity, reactive oxygen species (ROS) generation, mitochondrial membrane potential and cytotoxicity of the compounds towards human erythrocytes, peripheral blood mononuclear cells and macrophages were evaluated. The effects on intracellular amastigote forms, nitric oxide (NO) and TNF-α production were also investigated. ResultsThe exudate from the leaves afforded the novel icetexane 7-hydroxyfruticulin A (1) as well as the known demethylisofruticulin A (2), fruticulin A (3) and demethylfruticulin A (4). The compounds (1–4) were tested against promastigotes of L. amazonensis and showed an effective inhibition of the parasite survival (IC50 = 4.08–16.26 μM). In addition, they also induced mitochondrial ROS production, plasma membrane permeability and mitochondrial dysfunction in treated parasites, and presented low cytotoxicity against macrophages. Furthermore, all diterpenes tested reduced the number of parasites inside macrophages, by mechanisms involving TNF-α, NO and ROS. ConclusionThe results suggest the potential of 7-hydroxyfruticulin A (1) as well as the known demethylisofruticulin A (2),fruticulin A (3) and demethylfruticulin A (4) as candidates for use in further studies on the design of anti-leishmanial drugs.

Addressing Toxicity Concerns: State-of-the-Art Synthesis Methods and Emerging Multifaceted Applications of Silver Nanoparticles

Abstract: Silver nanoparticles (AgNPs), typically ranging in size from 10 to 1000 nm, are synthesize through physical, chemical, or biological methods. The biological approach, which often uses plant extracts, microbes, or fungi, is recommended for its eco-friendliness and lower dangers, while physical and chemical procedures can be costly and potentially dangerous. AgNPs are widely used in treatments and diagnostics in the medical field. Their exceptional antibacterial, antifungal, antiviral, anticancer, antiangiogenic, leishmanicidal, anti-inflammatory, antidiabetic, antioxidant, and anthelmintic action are just a few of their special qualities. However, AgNPs do have certain disadvantages due to worries about their nanotoxicity. This thorough study covers a wide range of AgNP topics, including their synthesis, properties, factors affecting particle size, and modes of action. Additionally, it covers their uses in the medical field, any potential toxicity issues, and the difficulties associated with their application.

Synthesis, characterization, and biological activity of novel 1,2,4-triazole moieties: Antileishmanial, antimicrobial effects, and molecular docking studies

In this study; new 1,2,4-triazole derivatives, (E)-4-(((3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)imino)methyl)phenyl 4-methoxybenzoate (3a), (E)-4-(((3-benzyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)imino)methyl)phenyl 4-methoxybenzoate (3b) and (E)-4-(((3-(4-fluorobenzyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)imino)methyl)phenyl 4‑methoxy benzoate methoxy benzoate (3c) were synthesized and characterized by FTIR and NMR (1H- and 13C-) spectroscopic methods. Structural and spectral parameters were calculated by DFT/B3LYP/6–311++G(d,p) methods. The newly synthesized compounds 3a–3c were evaluated for their antimicrobial activities against eight pathogenic microorganisms. Standard commercial drugs ampicillin and fluconazole were used as references for bacteria and yeast, respectively. The leishmanicidal activity of three different synthesized compounds against Leishmania infantum promastigotes was investigated using the microdilution method. In addition, the study attempted to investigate the interactions crucial for the antileishmanial activity of compound 3b by molecular docking analysis targeting trypanothione reductase (TRe).

Nanostructured Lipid Carriers for oral treatment of leishmaniasis: Design and preclinical evaluation

Pentavalent antimonials are the primary treatment for leishmaniasis due to their proven efficacy and cost-effectiveness. However, they present poor oral absorption, parenteral administration, and serious adverse effects due to prolonged use. Nanostructured Lipid Carriers (NLC) offer a promising solution, providing prolonged release, enhanced intestinal permeability, and oral bioavailability. This study aimed to address these issues by developing Nanostructured Lipid Carrier loaded with meglumine antimoniate (NLC-MA) for oral leishmaniasis treatment. We used design of experiments (DoE) for optimization. The chosen NLC-MA was characterized assessing size, polydispersity index (PdI), zeta potential (ZP), entrapment efficiency (EE), pH, and by analytical techniques such as DSC, FTIR, XRD, and TEM. Stability under simulated gastrointestinal conditions, in vitro release kinetics, cytotoxicity in RAW 264.7 macrophages, and leishmanicidal activity were assessed. NLC-MA presented 41.13 nm, PdI 0.227, ZP −27.9 mV, EE of 62.43%, and pH 5.23. Characterization techniques confirmed drug incorporation and nanoparticles with reduced crystallinity. TEM images showed spherical morphology. NLC remained stable in gastrointestinal pH and under refrigeration storage, while lyophilized formulations retained their initial properties. MA release from NLC followed the Peppas-Sahlin model, an anomalous transport mechanism. Importantly, MA showed no cytotoxicity in macrophages, but the NLCs exhibited cytotoxicity beyond 50 µg/mL. NLC-MA displayed improved efficacy against Leishmania infantum. Overall, these results highlight the potential of utilizing a lipid nanocarrier incorporating meglumine antimoniate as an innovative drug delivery platform for oral treatment against leishmaniasis.