Search Results (179)

Background/Objectives: Leishmaniasis is a zoonotic and anthropozoonotic disease with significant public health impact worldwide and is classified as a neglected tropical disease. The search for new affordable treatments, particularly oral and/or topical ones that are easy to administer and have fewer side effects, remains a priority for the scientific community in this field of research. In previous investigations, 3-alkoxy-1-benzyl-5-nitroindazole derivatives showed remarkable in vitro results against Leishmania species, and predictions of absorption, distribution, metabolism, excretion, and toxicity properties, as well as pharmacological scores, of the compounds classified as active were superior to those of amphotericin B, indicating their potential as candidates for in vivo studies. Therefore, the aim of the present study was to evaluate the in vivo antileishmanial activity of the indazole derivatives NV6 and NV16. Methods: The compounds were administered intralesionally at concentrations of 10 and 5 mg/kg in a BALB/c mouse model of cutaneous leishmaniasis caused by Leishmania amazonensis. To evaluate the efficacy of the compounds, indicators such as lesion size, ulcer area, lesion weight, and parasitic load were determined. Amphotericin B was used as a positive control. Results: The compound NV6 showed leishmanicidal activity comparable to that observed with amphotericin B, with a significant reduction in lesion development and parasite load, while NV16 caused a reduction in ulcer area. Conclusions: These results provide strong evidence for the antileishmanial activity of NV6 and support future studies to improve its pharmacokinetic profile, as well as the investigation of combination therapies with other chemotherapeutic agents currently in use. Full article

Leishmaniasis is a significant public health concern, affecting millions and causing substantial mortality, thus urgently requiring more effective and safer treatments. This study explored the potential of 33 novel N-acylhydrazone-derived compounds against Leishmania amazonensis parasites, focusing on their inhibition of the Leishmania arginase enzyme and promastigote growth. Compounds 8 and 18 showed over 90% inhibitory activity against promastigote cultures after 72 h of treatment. Compound 8 showed an IC₅₀ of 10.5 µM (9.4–11.8 µM), while compound 18 exhibited an IC₅₀ of 42.8 µM (41.3–44.4 µM). The antipromastigote effects of these compounds highlight their potential for further new drug design. These findings offer a promising starting point for addressing the pressing need for new therapeutic options against leishmaniasis. In addition, we used web-based tools to predict the compounds’ toxicity and pharmacokinetic parameters. Despite the lack of inhibition against the L. amazonensis arginase enzyme, further investigation into the mechanisms of action of these compounds and in vivo efficacy could contribute to the development of safer and more effective treatments for this neglected tropical disease. Full article

Natural products have long been recognized as invaluable resources in drug discovery. Essential oils have attracted widespread attention due to their broad spectrum of biological activities. Herein, we report the anti-kinetoplastid activity of Aloysia citrodora leaf essential oil through a bioassay-guided fractionation method against the etiological agents of Chagas disease and leishmaniasis. This approach has led to the isolation and structural identification of compound 1 (citral) as the main active constituent, with IC₅₀ values of 8.47 μM against Leishmania amazonensis and 12.90 μM against Trypanosoma cruzi. In addition, eight compounds (2–9) were synthesized and evaluated. Among these, citral 2,4-dinitrophenylhydrazone (9) exhibited the highest anti-kinetoplastid activity, with an IC₅₀ value of 10.62 μM against L. amazonensis, displaying a similar biological profile to citral and the reference drug. Structure–activity relationship studies revealed that the type of Schiff base and acylating agent played a crucial role in the activity. Mechanism of action studies demonstrated that compound 9 directly targets the apoptotic pathway, inducing programmed cell death through selective pathway inhibition. This work underscores the potential of A. citrodora essential oil and its compounds as prospective therapeutic leads against neglected tropical diseases. Full article

Sarcomphalus joazeiro (Mart.) is a promising candidate for the formulation of new therapies against parasitic infections. This study aimed to quantify the content of phenolic compounds and evaluate the antioxidant, antileishmanial, and cytotoxic potential of ethanolic extracts of the leaves (EELSJ) and bark (EEBSJ) of S. joazeiro. Quantification of phenolic acids (caffeic acid, p-coumaric acid, ferulic acid, cinnamic acid) and flavonoids (naringenin, pinocembrin, and apigenin) was performed by high-performance liquid chromatography with a diode array detector (HPLC-DAD). The extracts were subjected to antioxidant assays, including Fe³⁺ reduction, Fe²⁺ chelation, and inhibition of oxidative degradation of deoxyribose (2-DR). The antileishmanial activity was evaluated against promastigote forms of Leishmania amazonensis, while cytotoxicity was assessed in J774.G8 macrophages. Among the biological effects evaluated, EELSJ showed potent hydroxyl radical (•OH) scavenging activity, with IC₅₀ < 10 µg/mL, which potentially correlates with its phenolic acid and flavonoid content (0.7066 mg/g). In comparison, EEBSJ showed a lower phenolic content (0.197 mg/g) and demonstrated Fe²⁺ chelating activity (IC₅₀ = 14.96 ± 0.0477 µg/mL). EELSJ also exhibited antileishmanial activity against L. amazonensis (IC₅₀ = 246.20 µg/mL), with low cytotoxicity (CC₅₀ = 343.3 µg/mL; SI = 1.39), whereas EEBSJ showed minimal antileishmanial effect and marked cytotoxicity toward J774.G8 macrophages (CC₅₀ = 5.866 µg/mL). The leaves of S. joazeiro stand out as the most promising plant organ for future investigations. Future studies should focus on investigating their action mechanisms in more detail. Full article

Leishmaniasis is a neglected tropical disease caused by Leishmania sp. The therapeutic arsenal is reduced and limited. In this context, acridine derivatives present themselves as promising leishmanicidal compounds. This paper involved synthesizing and evaluating the antileishmanial and immunomodulatory potential of spiro-acridine derivatives. Six spiro-acridine derivatives were obtained through nucleophilic substitution reactions between the acetohydrazide/acetamide intermediates and 9-carbaldehydeacridine, followed by spontaneous cyclization. IR, NMR, and HRMS confirmed the structures. These were analyzed in vitro against L. infantum and L. amazonensis to determine anti-promastigote, anti-amastigote, and cytotoxicity effects. Immunomodulatory activity was evaluated using CBA, DCF-DA, and DAF-FM diacetate. In silico evaluation included molecular docking and dynamics. The spiro-acridines showed a wide range of anti-promastigote activities (IC₅₀ = 0.73–234.95 µM) and non-toxicity to red blood cells. AMTAC-02 and ACMD-03 demonstrated satisfactory anti-amastigote effect (IC₅₀ = 10.47–13.50 µM), low toxicity to macrophages (CC₅₀ = 27.22–569.50 µM), and cytokine and reactive species modulation. Molecular docking proposed cysteine protease B of L. amazonensis as a target, and molecular dynamics analysis highlighted the complex’s stability using RMSD, R_g, SASA, DCCM, PCA, and MM-PBSA (ΔG = −65.225 kJ/mol). Furthermore, QM-MM calculation provided the best energy for ACMD-03 (−199.30 au). Hence, AMTAC-02 and ACMD-03 demonstrated antileishmanial potential, making them promising entities for the development of leishmanicidal drug candidates. Full article

American cutaneous leishmaniasis (ACL), caused by Leishmania (Leishmania) amazonensis and L. (Viannia) braziliensis, presents a wide spectrum of clinical and immunopathological manifestations, ranging from localized cutaneous leishmaniasis (LCL) to severe forms like anergic diffuse cutaneous (ADCL) and mucocutaneous leishmaniasis (MCL). Despite evidence of the immune response’s complexity, the role of inflammasomes in disease severity and parasite persistence remains unclear. We investigated the transcriptomic and immunopathological profiles of inflammasome components in patient lesions across the clinical spectrum. Genes such as NLRP3, AIM2, NLRP12, NLRC4, CASP1, CASP5, GSDMD, and IL1B and all evaluated proteins, showed higher expression in ACL compared to healthy controls. Distinct inflammasome activation patterns were observed: MCL, the hyperreactive form, showed elevated NLRP3, AIM2, and IL-1β, indicating an intensified inflammatory environment. ADCL, the hyporeactive form, displayed increased NLRP12 and NLRC4 expression with reduced GSDMD. Localized forms showed transitional profiles, highlighting ACL’s multifactorial pathogenesis. These findings advance our understanding of inflammasome mechanisms in ACL, identifying potential therapeutic targets to modulate inflammation and improve management. Full article

Caffeic acid phenethyl ester (CAPE) is a polyphenol produced by many plants and is found in red and green propolis. Here, we evaluated the antileishmanial activity of this natural product against Leishmania amazonensis. CAPE exhibited IC₅₀ values of 8.07 µM (95% CI, 6.79–9.62 µM) and 13.51 µM (95% CI, 10.71–17.16 µM) against L. amazonensis promastigotes and intracellular amastigotes, respectively. Additionally, CAPE inhibited L. amazonensis arginase in a non-competitive manner with a K_i value of 1.51 ± 0.04 µM. These results highlight the potential of CAPE as a promising lead compound for developing new therapies against leishmaniasis. Full article

Leishmaniasis and Chagas disease are parasitic diseases considered to be among the most important neglected diseases, with implications for both developed and developing countries. Currently, there are no effective therapeutic treatments for these diseases due to challenges in drug administration, high toxicity, high costs, and drug resistance. In this study, a series of eleven thymol derivatives were designed, synthesized, and evaluated for their in vitro kinetoplastid activity against Leishmania amazonensis and Trypanosoma cruzi, as well as their cytotoxicity against a murine macrophage cell line. The most active compounds, thymol anysoate (9) and thymol picolinate (10), displayed the highest kinetoplastid activity with IC₅₀ values of 22.87 and 25.16 µM against L. amazonensis and T. cruzi, respectively. Notably, both compounds demonstrated an excellent selectivity index against the mammal cell line. Structure–activity relationship studies revealed that the ester group plays a crucial role in activity. The most promising derivatives, 9 and 10, activate autophagy and apoptosis-like processes in the treated cells. Atomic force microscopy observations showed that derivative 9 induces the formation of cytoplasmic vacuoles, indicating an autophagic process, and drug-likeness analysis revealed that it meets all the pharmacokinetic criteria. Overall, these results highlight derivative 9 as a potential lead compound for the development of new drugs for the treatment of Trypanosomatidae infections and warrants further studies to elucidate the cell death cascade involved. Full article

Background/Objectives: Cutaneous leishmaniasis (CL) is a vector-borne neglected disease that can cause permanent deformities. Current chemotherapy based on injections with toxic drugs or oral miltefosine poses many drawbacks, urging the need for new oral therapies. Here, we proposed to increase the bioavailability of NAT22, an intralesionally but not orally active antileishmanial chalcone, through nanocrystallization to promote its oral use in CL. Methods/Results: NAT22 nanocrystals were produced using a solvent-free green process of dry and wet milling that reduced NAT22 crystal sizes by around 1500-fold to 257 nm (nanoNAT22). Such reduction in size increased water solubility by 15-fold to 4.3 µg/mL and ensured stability in the absence of stabilizers for at least one month. Of note, nanoNAT22 in aqueous medium was more selective for parasites (SI = 35.2) than NAT22 in 1% DMSO (SI = 7.6). Leishmania amazonensis-infected mice treated with oral nanoNAT22 had lesion sizes and parasite loads similar to those achieved with intralesional Glucantime^®, and significantly smaller than NAT22. Conclusions: Together, these results indicate that nanocrystallization is an effective process to render NAT22 chalcone also orally active against CL. Full article

Background: Paullinia cupana Kunth, popularly known as guarana, a native Amazonian shrub cultivated by the Sateré-Mawé ethnic group, has been used in traditional medicine for various purposes, including stimulant and therapeutic actions, due to its chemical composition, which is rich in bioactive compounds. This study explored the reductive potential of guarana with nanobiotechnology and aimed to synthesize silver nanoparticles (AgNPs) using the aqueous extract of leaves collected during the dry and rainy seasons, assessing their biological and catalytic activities. Methods: The AgNPs were synthesized in a water bath at 70 °C for three hours and then characterized using techniques such as UV-Vis spectroscopy, DLS, zeta potential, MET, NTA, and EDX and had their effects on various biological systems assessed in vitro, as well as in catalytic tests aimed at indicating the probable influence of the time when the plant material was collected on the properties of the nanostructures. Results: The AgNPs had an average diameter between 39.33 and 126.2 nm, spherical morphology, absorption bands between 410 and 450 nm, and high colloidal stability over two years. The biological results showed antibacterial activity against all the species tested, as well as remarkable antioxidant action against DPPH and ABTS free radicals, in the same way as the aqueous leaf extracts of P. cupana, in addition to cytotoxic properties against cancerous (A431 and A549) and non-cancerous (HaCaT and HNTMC) cells. The AgNPs were active against promastigote forms of Leishmania (Leishmania) amazonensis while not affecting the viability of macrophages, and from the LC₅₀ and LC₉₀ values, the AgNPs were more effective than the metal salt solution in controlling Aedes aegypti larvae and pupae. We also reported that the catalytic degradation of the organic dyes methylene blue (MB) and methyl orange (MO) by AgNPs was over 90% after 40 or 14 min, respectively. Conclusions: Thus, our results support the potential of seasonal extracts of guarana leaves to produce AgNPs with diverse application possibilities for the health, industrial, and environmental sectors. Full article

Capirona macrophylla is a Rubiaceae known as “mulateiro”. Ethnobotanical extracts have been used for skin treatment and in the management of leishmaniasis and malaria. Objectives: The metabolites in aqueous extracts from wood bark, leaves, and stems were identified, and their in silico docking and in vitro cellular efficacy against Leishmania amazonensis and Plasmodium falciparum were evaluated. Methods: The extracts were analyzed by UHPLC/HRMSⁿ using untargeted metabolomics approach with MSDial, MSFinder, and GNPS software for metabolite identification and spectra clustering. The most abundant metabolites underwent molecular docking using AutoDock via PyRx, targeting the dihydroorotate dehydrogenase from Leishmania and P. falciparum, and evaluated through molecular dynamics simulations using Gromacs. In vitro biological assays were conducted on 60 HPLC-fractions against these parasites. Results: Metabolomics analysis identified 5100 metabolites in ESI+ and 2839 in ESI− spectra among the “mulateiro” samples. GNPS clustering highlighted large clusters of quercetin and chlorogenic acid groups. The most abundant metabolites were isofraxidin, scopoletin, 5(S)-5-carboxystrictosidine, loliolide, quercetin, quinic acid, caffeoylquinic acid (and isomers), chlorogenic acid, neochlorogenic acid, tryptophan, N-acetyltryptophan, epicatechin, procyanidin, and kaempferol-3-O-robinoside-7-O-rhamnoside. Molecular docking pointed to 3,4-dicaffeoylquinic acid and kaempferol as promising inhibitors. The in vitro assays yielded four active HPLC-fractions against L. amazonensis with IC50 values ranging from 175.2 μg/mL to 194.8 μg/mL, and fraction G29 showed an IC50 of 119.8 μg/mL against P. falciparum. Conclusions: The ethnobotanical use of “mulateiro” wood bark tea as an antimalarial and antileishmanial agent was confirmed through in vitro assays. We speculate that these activities are attributed to linoleic acids and quinic acids. Full article

Leishmaniasis is a neglected tropical disease caused by protozoan parasites of the genus Leishmania. An estimated 700,000 to 1 million new cases occur annually. Current therapies are limited by high toxicity, cost, prolonged treatment period, and rising resistance in endemic regions. The Asteraceae family has emerged as a promising source of bioactive compounds with proven leishmanicidal activity. In this study, the assessment of the antileishmanial activity of Helianthus tuberosus and Vernonanthura squamulosa extracts, the isolation of the sesquiterpene lactones heliangin and glaucolide A, respectively, and the evaluation of the activity of the compounds were conducted. Dichloromethane extracts of H. tuberosus and V. squamulosa were active on Leishmania amazonensis promastigotes, inhibiting the replication of the parasites in 97.2 ± 3.1% and 89.1 ± 1.1%, respectively, at 100 μg/mL. Heliangin was active against promastigotes of L. amazonensis (IC₅₀ = 9.3 μM) and intracellular amastigotes (IC₅₀ = 0.8 μM), while glaucolide A exhibited moderate activity against promastigotes (IC₅₀ = 46.7 μM) and did not show activity against intracellular amastigotes. Based on these results, heliangin was further evaluated in an animal model of cutaneous leishmaniasis using BALB/c mice infected with L. amazonensis. Heliangin (8 mg/Kg), when administered in combination with Glucantime, significantly reduced lesion progression and parasite load compared to the vehicle-treated group (p < 0.001). These findings show that heliangin is a potential candidate for leishmaniasis treatment, especially in combination with therapeutic drugs. Full article

Background/Objectives: Neglected tropical diseases (NTDs), such as leishmaniasis, remain a global health challenge due to limited therapeutic options and rising drug resistance. In this study, we developed an advanced nanogel formulation incorporating curcumin (CUR) and Pectis brevipedunculata essential oil (EOPb) within an F127/Carbopol 974P matrix to enhance bioavailability and therapeutic efficacy against Leishmania (Leishmania) amazonensis (LLa) promastigotes. Methods: The chemical profile of EOPb was determined through GC-MS and NMR analyses, confirming the presence of key bioactive monoterpenes such as neral, geranial, $\alpha$-pinene, and limonene. The nanogel formulation (nGPC) was optimized to ensure thermosensitivity, and stability, exhibiting a sol–gel transition at physiological temperatures. Rheological analysis revealed that nGPC exhibited Newtonian behavior at 5 °C, transitioning to shear-thinning and thixotropic characteristics at 25 and 32 °C, respectively. This behavior facilitates its application and controlled drug release, making it ideal for topical formulations. Dynamic light scattering (DLS) analysis demonstrated that nGPC maintained a stable nanoscale structure with hydrodynamic radius below 300 nm, while Fourier-transform infrared spectroscopy (FTIR) confirmed strong molecular interactions between EOPb, CUR, and the polymer matrix. Biological assays demonstrated that nGPC significantly enhanced anti-promastigote activity compared to free CUR and OEPb. Results: At the highest tested concentration (50 μg/mL EOPb and 17.5 μg/mL CUR) nGPC induced over 88% mortality in LLa promastigotes across 24, 48, and 72 h, indicating sustained efficacy. Even at lower concentrations, nGPC retained dose-dependent activity, suggesting a synergistic effect between CUR and EOPb. These findings highlight the potential of nGPC as an innovative nanocarrier for daylight photodynamic therapy (dPDT) in the treatment of leishmaniasis. Future studies will investigate the underlying mechanisms of this synergism and explore the potential application of photodynamic therapy (PDT) to further enhance therapeutic outcomes. Full article

Leishmania amazonensis, a cause of cutaneous leishmaniasis in Brazil, is a neglected disease with toxic and inconsistently effective treatments. The parasite’s survival depends on managing oxidative stress, making redox-regulating enzymes potential therapeutic targets. Geopropolis, a resinous product from native stingless bees, shows promising antiparasitic effects. This study aims to evaluate the anti-L. amazonensis activity of geopropolis produced by Melipona bicolor, M. marginara, M. mondury, and M. quadrifasciata (two samples), targeting enzymes responsible for the parasite’s redox balance. Ethanol extracts of geopropolis produced by each bee (BCRL, MRGT, MNDY, MNDA(1), and MNDA(2), respectively) were analyzed for total phenolics and flavonoids. Promastigotes and axenic amastigotes were treated with various extract concentrations, and parasite viability was assessed using the resazurin reduction method. Cytotoxicity was tested on peritoneal macrophages, RAW 264.7, VERO cell lines (MTT assay), and erythrocytes (hemolysis assay). Additionally, mitochondrial dehydrogenase activity, reactive oxygen species (ROS) production, the inhibition of recombinant arginase, and autophagic activity were also evaluated in treated parasites. MRGT showed the highest levels of phenolics (762 mg GAE/g) and flavonoids (345 mg QE/g). MDRY was more effective against promastigote and axenic amastigote forms (IC₅₀ = 168 and 19.7 µg/mL, respectively). MRGT showed lower cytotoxicity against RAW 264.7 and VERO (CC₅₀ = 654 µg/mL and 981 µg/mL, respectively). Erythrocytes exhibited reduced sensitivity to MNDA(2) (HC₅₀ = 710 µg/mL). The activity of dehydrogenases and LiARG was reduced by treating the parasites with the extracts following the induction of ROS and autophagic activity. These results highlight geopropolis extracts as a source of substances with anti-L. amazonensis activity capable of inducing oxidative stress on the parasite. Full article

Leishmaniasis, a complex disease caused by protozoal parasites of the genus Leishmania, presents various clinical forms, particularly a cutaneous clinical form. Treatment is typically performed with pentavalent antimonial and amphotericin B, both of which have severe side effects that hinder patient compliance. This emphasizes the need for the development of new, effective, and safe treatments. In this study, the leishmanicidal activity of the methanolic extract, an alkaloid-enriched fraction and dicentrine, the main alkaloid of the leaves of Ocotea puberula (Lauraceae), a native Brazilian plant traditionally used by the indigenous population to treat skin affections, was investigated in vitro. Additionally, an in vivo study evaluated the efficacy of a topical cream containing 0.5% dicentrine. The in vitro studies demonstrated high activity and selectivity of methanolic extract, alkaloid-enriched fraction, and dicentrine against the promastigote and amastigote forms of Leishmania (Leishmnia) amazonensis and Leishmania (Viannia) braziliensis. The leishmanicidal effect of dicentrine was related to the modulation of macrophage microbicidal activity. A cream containing 0.5% dicentrine showed high stability and, in permeation studies, dicentrine was retained in a skin-mimicking artificial membrane. This cream effectively inhibited the progression of the skin lesion in BALB/c mice infected with L. (L.) amazonensis, together with a reduced parasite number. Thus, dicentrine offers a promising alternative to the treatment of skin leishmaniasis. Full article