Search Results (679)

Chagas disease, caused by Trypanosoma cruzi, remains a major public health problem in Latin America and an emerging global health concern due to population mobility. Although benznidazole and nifurtimox remain the only approved antiparasitic drugs, their limited efficacy in chronic infection, prolonged treatment regimens, frequent adverse effects, and variable activity across parasite strains highlight the need for new therapeutic strategies. In addition, the pathogenesis of chronic Chagas disease is driven not only by parasite persistence but also by immune-mediated tissue damage, particularly in chronic Chagas cardiomyopathy. In this review, we examine emerging therapeutic approaches that extend beyond conventional trypanocidal chemotherapy, with emphasis on natural products, antimicrobial peptides, and cell-based immunomodulatory strategies. Plant compounds and essential oils have shown antiparasitic activity through mechanisms including oxidative stress induction, membrane disruption, interference with sterol biosynthesis, and mitochondrial dysfunction, while some extracts also modulate host immune responses. Antimicrobial peptides display dual potential by directly damaging parasite membranes and organelles or by reshaping infection-associated inflammatory responses. In parallel, cell-based therapies such as mesenchymal stromal cells, tolerogenic dendritic cells, and bone marrow-derived cells have demonstrated promising cardioprotective and immunoregulatory effects in experimental chronic Chagas disease. Collectively, these approaches support a multitarget therapeutic framework in which parasite-directed and host-directed interventions may complement each other. Further mechanistic studies, standardization, and translational validation will be essential to advance these candidates toward clinically useful therapies for Chagas disease. Full article

Background/Objectives: American trypanosomiasis, caused by Trypanosoma cruzi, remains a major public health challenge due to the limited efficacy and adverse effects associated with current treatments. Octyl gallate (OG), a semi-synthetic derivative of gallic acid, has demonstrated promising biological activities, including antiparasitic effects. Methods: The in vitro trypanocidal activity of OG was evaluated against T. cruzi. Mechanism of action studies included the inhibition of the trypanothione reductase enzyme and flow cytometry assays to measure cell death pathways (propidium iodide uptake). Additionally, the immunomodulatory potential of the compound was investigated by assessing cytokine production and innate immune responses. Results: In this study, the trypanocidal activity of OG against different evolutionary forms of T. cruzi was investigated. Using MTT-based viability assays, OG exhibited significant activity against epimastigotes (IC50 = 5.92 ± 0.47 µM), trypomastigotes (EC50 = 3.20 ± 0.14 µM), and intracellular amastigotes (EC50 = 4.07 ± 0.72 µM). The compound also demonstrated favorable selectivity indices, particularly against trypomastigotes and amastigotes, indicating selective toxicity toward the parasite compared to mammalian host cells. In infected macrophages, OG increased TNF-α and IL-12 production while reducing IL-10 and IL-6 levels, in addition to stimulating reactive oxygen species (ROS) and nitric oxide (NO) production, suggesting an immunomodulatory effect that contributes to parasite control. Molecular docking analyses revealed a favorable interaction between OG and trypanothione reductase (TR), while biochemical assays demonstrated reduced NADPH consumption, indicating interference with TR activity. Ultrastructural analysis revealed severe morphological alterations, including membrane disruption, cytoplasmic disorganization, mitochondrial swelling, and features consistent with apoptosis-like cell death. Conclusions: Collectively, these findings demonstrate that OG exhibits potent and selective trypanocidal activity associated with immunomodulatory effects, ultrastructural damage, and disruption of parasite redox metabolism through TR inhibition, supporting its potential as a candidate for future preclinical studies against Chagas disease. Full article

Biogenic metal nanoparticles are naturally covered with the phytochemical corona, which includes plant-derived metabolites. Emerging evidence suggests that the phytochemical corona, together with the intrinsic properties of the metallic core, contributes significantly to the biological identity, therapeutic behavior, and safety profile of biogenic nanoparticles. In this review, we go beyond the traditional view of plant extracts as reducing and capping agents to the phytochemical corona as a programmable nano–bio interface. Green synthesis from Indian flora has potential that can yield coronas rich in flavonoids, polyphenols, terpenoids, and alkaloids. Each corona composition contributes to different physicochemical properties, such as cellular interactions and downstream effects on reactive oxygen species, endocytic uptake and signaling pathways (p53, AKT, MAPK). When in contact with biological fluids, the corona adsorbs host proteins, giving rise to a hybrid interface that further influences the therapeutic outcome. The corona composition directly contributes to the biological activities of these nanoparticles: for example, anticancer, antimicrobial, antioxidant, and antiparasitic. The corona offers intrinsic targeting, stimuli-responsive release and improved stability for drug delivery. Toxicity and safety assessment shows dose-dependent effects, organ accumulation and long-term concerns for which standardized testing is needed. Translational challenges include: reproducibility, seasonal and geographic phytochemical variation, variability in extraction methods, scalability, shelf life and regulatory ambiguity. Future directions include Artificial intelligence (AI)-driven phytosynthesis, precision nanomedicine, nano–bio interface engineering, multi-omics integration, exploration of endangered Indian flora, and digital twin modeling. This review provides a roadmap for engineering phytochemical coronas as precision nanomedicine platforms by shifting the focus from core to corona and from empirical recipes to predictive design. It positions biogenic nanoparticles not only as eco-friendly alternatives, but as programmable, superior therapeutics for cancer and drug-resistant infections. Full article

Laurinterol, a halogenated sesquiterpene produced by red algae of the genus Laurencia, is one of the most characteristic compounds within the laurane and cyclolaurane families. This review compiles and examines current knowledge on laurinterol, integrating evidence on its occurrence, biosynthesis, biological activities, and structural features. Within a functional and ecological framework, laurinterol is proposed as an archetypal Smart Secondary Metabolite (SSM), a concept that reflects the convergence of structural singularity, high abundance within its biosynthetic context, broad biological activity, multi-target interactions, and ecological or chemotaxonomic relevance. This perspective highlights its role in adaptive processes within producing organisms and associated trophic networks. Laurinterol exhibits a broad bioactivity profile, including antimicrobial, antimycobacterial, cytotoxic, antiparasitic, enzyme inhibitory, antifouling, and insecticidal or repellent effects. Structure–activity relationship (SAR) studies remain limited and are mainly developed in specific models, particularly against Naegleria fowleri. The current intellectual property landscape related to laurinterol, including patent applications, granted patents, and technological development trends, is also examined. Overall, this review positions laurinterol as a structurally distinctive and functionally relevant marine metabolite within chemical ecology and marine natural products research. Full article

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), includes clinically relevant intestinal inflammation; however, the mechanisms associated with tissue injury remain incompletely understood. ArtinM is an immunomodulatory lectin with known effects on innate and adaptive immunity, although its intestinal role during acute T. cruzi infection remains unclear. This study investigated whether ArtinM modulates the intestinal inflammatory response during acute experimental T. cruzi infection. In vivo, BALB/c mice were allocated to Saline control, T. cruzi + Saline, and T. cruzi + ArtinM groups. Intestinal inflammatory infiltrate and tissue concentrations of TNF-α, IFN-γ, IL-12p40, and IL-10 were quantified. Acute infection markedly increased TNF-α, IFN-γ, IL-12p40, and inflammatory infiltrate, whereas ArtinM significantly attenuated these responses. TNF-α, IFN-γ, and IL-12p40 remained associated with group after adjustment for infiltrate, whereas IL-10 reached statistical significance only in the adjusted model and was therefore interpreted cautiously. In parallel, an exploratory analysis of a public murine intestinal scRNA-seq dataset (GSE319934; GSM9529706 and GSM9529707), derived from a chronic infection setting, was performed to provide pathway-level context for inflammatory mediators assessed in vivo. This transcriptomic analysis indicated that related inflammatory, innate immune, chemotactic, and adhesion-associated genes were detectable in intestinal single-cell data from T. cruzi infection. However, because this dataset was not temporally matched to the acute model, it was not interpreted as a phase-matched comparator, mechanistic validation, or temporal extension of the experimental findings. Together, the results support that ArtinM treatment is associated with attenuation of acute intestinal inflammatory outcomes in experimental T. cruzi infection. Because local intestinal parasite burden was not measured, these findings should be interpreted as evidence of inflammatory modulation rather than as direct evidence of local antiparasitic activity. The public scRNA-seq analysis provides only exploratory contextual information for related inflammatory pathways. Full article

Background: Doramectin (CHC-B1) is an excellent antiparasitic drug produced by feeding cyclohexanecarboxylic acid (CHC) to Streptomycesavermitilis bkd⁻ mutants. AveC, a bifunctional enzyme encoded by aveC (sav_0940), catalyzes the stereospecific spiroketalization and selective dehydration of dihydroxy ketone polyketide intermediates and modulates both the yield and the proportion of avermectin/doramectin in Streptomyces avermitilis. In our previous work, we constructed a strain harboring a synthetic aveC* gene encoding ten amino acid mutations, which produced nearly pure doramectin. However, the doramectin yield achieved only approximately 60% of the total doramectin and CHC-B2 output observed in the parental strain. Methods: To investigate the roles of Ser138 and Ala139 of AveC in the biosynthesis of doramectin and avermectin, site-directed mutagenesis was performed at both sites. The production and proportion of avermectin and doramectin were determined using high-performance liquid chromatography (HPLC). AlphaFold2-based molecular docking simulations were used to interpret the results. Results: Among the tested mutants, S138G, S138T, and A139H exhibited the highest doramectin production, achieving 143.87%, 151.22%, and 153.36% of the control level, respectively. Unfortunately, almost none of the tested mutants showed a positive effect on avermectin production. Molecular docking simulations revealed distinct affinities of these mutants for the dihydroxy ketone polyketide intermediate, both with and without a cyclohexyl group. Notably, all three mutants displayed larger substrate-binding cavity volumes compared with the wild-type enzyme, which likely facilitates doramectin synthesis by effectively accommodating the cyclohexyl moiety. Docking results further indicated that Ser138 and Ala139 are positioned within the binding cavity but probably do not directly participate in the dehydration activity. Conclusions: These findings suggest that optimizing cavity size through residue substitutions can enhance substrate specificity for doramectin production while preserving catalytic functionality. Full article

Flavone–thiazole–aryl hybrid molecules based on 6-aminoflavone and 5-arylidene-4-aminothiazol-2(5H)-ones were synthesized and subjected to physicochemical and biological studies. Microwave-assisted synthesis was performed in two steps. First, an aminolysis reaction of isorhodanine with 6-aminoflavone was carried out to achieve the corresponding hybrid flavone-thiazole 3, which was later subjected to a Knoevenagel condensation with selected aromatic aldehydes, yielding 5-arylidene derivatives 5a–5i. The resulting hybrids were purified and characterized by UV–Vis, NMR, and HR-MS (ESI). In the UV–Vis spectra of all compounds, two characteristic bands were noted. The UV–Vis spectra in DMF of the studied flavone–thiazole–aryl hybrids consist of two major bands with maxima appearing at 280–288 nm, corresponding to band II and 383–399 nm, corresponding to band I, which clearly distinguish them from the large group of modified flavonoids. Among the compounds tested on human bladder cancer 5637 cells, (5Z)-5-[(4-hydroxyphenyl)methylene]-4-[(4-oxo-2-phenyl-chromen-6-yl)amino]thiazol-2-one (5b) exhibited interesting micromolar activity (IC₅₀ 2.37 µM). In addition, four of the tested compounds (3, 5f, 5d, and 5b) presented noteworthy antiplasmodial activity against P. falciparum in the low micromolar range (IC₅₀ 1.90–4.90 µM). The obtained group of flavone–thiazole–aryl hybrid molecules constitutes valuable starting points for further structural optimisation, which could usher in future novel active pharmaceutical ingredients and pave the way for novel therapeutic strategies. Full article

A series of substituted pyrrolo[2,3-d]pyrimidines was designed, synthesized, and evaluated in vitro against two protozoan parasites: Plasmodium falciparum and Trypanosoma brucei brucei. Pharmacological studies revealed antiprotozoal activity with IC₅₀ values in the submicromolar to micromolar range. Additionally, the in vitro cytotoxicity of these new compounds was assessed using human HepG2 cells. Among them, the pyrrolopyrimidine derivative 1d emerged as the most potent antimalarial compound, exhibiting a selectivity index (SI) of 600.81 against the P. falciparum chloroquine-resistant W2 strain. For the chloroquine-sensitive 3D7 strain, the most notable selectivity index (SI) was observed for pyrrolo[2,3-d]pyrimidine 1c, with a value of approximately 123. Furthermore, compound 1b demonstrated the most interesting activity against Trypanosoma brucei brucei, with an SI of 39.52, marking it as a promising trypanocidal agent. FRET melting assays confirmed that these nitrogen-containing heterocyclic compounds bind to telomeric G-quadruplexes in P. falciparum and Trypanosoma. However, no clear correlation was found between G-quadruplex binding and antiparasitic activity or selectivity, suggesting that G-quadruplex targeting is unlikely to be the main mechanism underlying cytotoxicity. Full article

Penaeus sp. shells (shrimp) were used to extract chitosan using acid and basic treatments, which were characterized by IR spectroscopy, Raman spectroscopy, potentiometric titration, and elemental analysis. The degrees of deacetylation were determined to be 71.8%, 75.6%, 53.4%, and 68.6%, respectively. Likewise, viscosimetry measurements were carried out, determining an average molecular weight of chitosan 1 of 1521467.919 (g/mol). The obtained chitosan was used as a substrate in condensation reactions with 10 para-substituted benzaldehydes. The products obtained were characterized by IR, Raman, and ¹H-NMR spectroscopy, AE (Elemental Analysis), TGA (Thermogravimetric Analysis), and DSC (Differential Scanning Calorimetry). For the obtained polymers, biological assays of cytotoxicity using RAW macrophage cells and leishmanicidal activity on promastigotes of Leishmania mexicana were performed. The results show that the synthesized products do not present in vitro cytotoxicity, and that 1 (Chitosan) and 3i (Schiff Base) present leishmanicidal activity. Selected derivatives were incorporated into polyvinyl alcohol-based films and evaluated for surface topography and gas permeability. AFM revealed nanometric roughness patterns, while gas exchange studies demonstrated selective CO₂/O₂ permeability, supporting passive modified atmosphere formation in packaged carrots. Mechanical characterization revealed that the incorporation of Schiff base derivatives significantly influences tensile strength and flexibility, with certain films exhibiting enhanced elongation and mechanical performance compared to pure PVA, highlighting their potential for packaging applications. These findings confirm that chemical functionalization enhances the versatility of chitosan, allowing the design of tailored biopolymers. The synthesized derivatives show promising characteristics for the development of biodegradable films with potential applications in food packaging and antiparasitic material development. Full article

Background: Schistosomiasis remains a major neglected tropical disease, with praziquantel (PZQ) as the only widely used treatment, despite its limitations. Parthenolide (PTL), a sesquiterpene lactone, exhibits potent in vitro antischistosomal activity; however, its poor aqueous solubility, low oral bioavailability, and chemical instability may limit its in vivo efficacy. Objective: This study investigated whether nanoencapsulation in nanostructured lipid carriers (NLC) could enable the in vivo antischistosomal activity of PTL. Methods: PTL was isolated from Tanacetum parthenium and incorporated into NLC using hot emulsification followed by ultrasonication. The resulting formulation (NLC-PTL) was physicochemically characterized, and its in vivo antischistosomal efficacy was evaluated in a murine model of Schistosoma mansoni infection. Results: NLC-PTL exhibited nanoscale size, low polydispersity, high encapsulation efficiency, and sustained drug release. In vivo, free PTL showed no significant effect on worm burden, whereas NLC-PTL achieved a marked reduction (77.9%) in adult worms and significantly decreased egg output compared to controls (p < 0.001). Blank NLC had no antiparasitic effect. Conclusions: Nanoencapsulation was associated with in vivo antischistosomal activity of PTL compared to the free compound. These findings suggest that formulation strategies may influence the in vivo performance of lipophilic natural products in schistosomiasis. Full article

Background/Objectives: Cryptosporidium parvum (C. parvum), a waterborne intestinal parasite, causes severe, persistent infections in immunocompromised hosts and has been linked to the onset of ileocecal adenocarcinoma. However, the molecular pathways linking chronic infection to carcinogenesis remain unclear. Nitazoxanide (NTZ), the only FDA-approved drug for this infection, shows limited efficacy. In contrast, azithromycin (AZM) possesses both antiparasitic and anticancer activity, though conclusive evidence supporting its effectiveness against cryptosporidiosis is still lacking. This study aimed to investigate the therapeutic potential of AZM against chronic cryptosporidiosis and its associated tumorigenic sequelae. Methods: Immunosuppressed mice were infected with C. parvum and treated with NTZ or AZM. Parasite burden was assessed by quantifying fecal oocyst shedding. Ileocecal tissues were analyzed for histopathology, inflammation (IL-6 and TNF-α), autophagy markers (LC3II, Beclin-1, and Atg7), PI3K/AKT signaling, and apoptotic markers (Bcl2, Bax, cleaved caspase-3, DR4, and DR5) using ELISA, real-time PCR, and Western blot. Results: Chronic C. parvum infection induced Vienna 4.4 adenocarcinoma, activated autophagy and PI3K/AKT signaling, and suppressed intrinsic and TRAIL-mediated apoptosis. AZM significantly reduced the parasitic load by 87%, outperforming NTZ (62%). It also restored epithelial integrity, attenuated inflammation, and counteracted pro-tumorigenic effects by inhibiting autophagy, downregulating the PI3K/AKT pathway, and stimulating apoptosis. Conclusions: AZM counteracted parasite-driven tumorigenic mechanisms by disrupting survival pathways and promoting apoptosis in infected and transformed cells. These findings provide evidence that AZM exerts dual antiparasitic effects and counteracts pro-tumorigenic signaling in chronic cryptosporidiosis, highlighting its potential as a therapeutic agent to prevent infection-associated ileocecal carcinogenesis. Full article

Resistance formation and considerable toxicities limit the application of currently available antiparasitic drugs. Thus, new drug candidates are required. Piperlongumine-based cinnamides are promising antiparasitic compounds. In this study, new synthetic cinnamide derivatives with variable halogen substituents (F, Cl, and Br) were prepared and analyzed. They were tested for activity against Toxoplasma gondii and Leishmania major parasites. Considerable activities against T. gondii parasites were observed for certain chloro- and bromo-substituted cinnamides (IC₅₀ = 1.88–2.72 µM), while activities against L. major were less pronounced. Structure–activity relationships were investigated, which revealed notable relations of anti-toxoplasmal activity with the nature of the applied halogen substituents and a preference for chloro- and bromo-substituents in active compounds. In contrast to piperlongumine, the new active compounds have no methoxy substituents anymore and appear to be suitable for advanced antiparasitic studies. Successful docking of selected derivatives into the colchicine binding site of tubulin provided a strong hint at a possible mode of action for these cinnamides (S-scores of −6.075 and −5.993 kcal/mol). In addition, considerable drug-like properties were determined by ADME-T calculations. Thus, in conclusion, new halo-substituted cinnamides with promising activity against Toxoplasma gondii were identified. The selectivity for Toxoplasma parasites can lead to better drugs for the therapy of toxoplasmosis. Full article

Background/Objectives: Jatrophone is a bioactive diterpenoid with reported antitrypanosomal activity; however, its development as a lead compound is limited by pronounced cytotoxicity toward mammalian cells. This study aimed to explore the structural modification of jatrophone through triazole functionalization to modulate its antiparasitic activity and improve selectivity against Trypanosoma cruzi. Methods: A series of mono- and bis-triazole jatrophone derivatives was semi-synthesized via Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) from a stereoselectively prepared diazido intermediate. Jatrophone, its azido precursor, and the synthesized triazole derivatives were evaluated in vitro against T. cruzi epimastigotes and intracellular amastigotes. Cytotoxicity toward mammalian host cells was assessed in parallel to determine selectivity indices. Results: Jatrophone exhibited potent activity against epimastigotes but showed poor selectivity due to significant mammalian cell toxicity. Introduction of azide and triazole functionalities altered the biological profile of the parent scaffold, leading to derivatives with reduced cytotoxicity and improved selectivity in extracellular assays. Among the evaluated compounds, a mono-triazole derivative bearing a methylene-linked cycloalkyl substituent retained antiparasitic activity while displaying markedly lower toxicity toward mammalian cells. However, in the intracellular amastigote model, most derivatives demonstrated a substantial reduction in selectivity, indicating limited translation of extracellular activity to the intracellular parasite stage. Conclusions: Triazole functionalization of the jatrophone scaffold represents a viable strategy to modulate its biological properties and reduce host-cell toxicity. Nevertheless, the reduced efficacy observed in intracellular assays underscores the limitations of epimastigote-based screening and highlights the challenges in developing selective intracellular antitrypanosomal agents from the jatrophone scaffold. Full article

Background: Neglected diseases caused by protozoan parasites remain a major public health burden, particularly in low- and middle-income countries. Among the chemical motifs explored in antiparasitic drug discovery, guanidine-containing compounds have attracted considerable attention due to their strong cationic character, high capacity for hydrogen bonding, and versatility in interacting with biological targets. Methodology: This review summarizes advances reported in the last decade regarding guanidine derivatives with activity against pathogens associated with Chagas disease, human African trypanosomiasis, Leishmaniasis, tuberculosis, toxoplasmosis, dengue and schistosomiasis. Results: Evidence gathered from synthetic, natural, and drug-repurposing studies indicates that the guanidine, guanidine-containing and guanidine-related compounds contribute to modulating biological activity by changing electrostatic interactions, hydrogen-bonding networks, and physicochemical properties, with enzymes, nucleic acids, and membrane-associated targets essential for parasite survival. Across the analyzed studies, several emerging structure–activity relationship trends were identified, including the contribution of polycationic or dicationic architectures, the influence of halogenated or lipophilic substituents, and the dependence of biological activity on the complete molecular framework, including heterocyclic systems, macrocycles, peptide conjugates, hybrid scaffolds, and repurposed drugs. In addition to direct antiparasitic effects, certain guanidine-containing and guanidine-related compounds demonstrate immunomodulatory or host-protective properties, expanding the therapeutic relevance of this class. Despite promising in vitro results, protonation trapping, efflux pump susceptibility, and pharmacokinetic limitations such as poor oral absorption, high polarity, plasma protein binding and limited membrane permeability remain significant challenges for clinical translation. Nonetheless, the integration of medicinal chemistry, computational modeling, and biological screening continues to accelerate the identification of optimized scaffolds. Conclusions: Overall, guanidine-based compounds constitute a promising scaffold for the development of new therapeutic strategies targeting neglected parasitic diseases, and further structural optimization may enable the emergence of candidates with improved efficacy, selectivity, and drug-like properties. Full article

Toxoplasma gondii (T. gondi) is a widespread zoonotic parasite that poses a significant threat to global public health, yet effective therapeutic options remain limited. In this study, we found that the flavonoid compound myricetin (MYR) can significantly inhibit the proliferation of T. gondii. This effect is associated with the inhibition of dihydroorotase (TgDHO) activity in the de novo pyrimidine biosynthesis pathway, and this inhibition can be partially reversed by exogenous supplementation with uracil. Further studies revealed that MYR treatment can induce cell cycle arrest in tachyzoites and impair bradyzoite proliferation, concurrently disrupting the UDP-GlcNAc glycosylation of the cyst wall. In mouse models, MYR demonstrated significant efficacy, achieving an 80% survival rate in acute infection and inducing morphological abnormalities in intracerebral cysts during chronic infection. Collectively, these findings elucidate the anti-Toxoplasma activity and multifaceted mechanisms of MYR, providing valuable insights for developing novel therapeutics against toxoplasmosis. Full article