Search Results (471)

Coumarins are compounds that are naturally found in various plants and are known for their potential pharmacological characteristics, such as anti-inflammatory, antibacterial, antiparasitic, and anticoagulant activities. Despite the potential pharmacological properties, structural modification of coumarins is important to enhance the biological activity, solubility, bioavailability, and various therapeutic characteristics. Microbial transformation is a promising method to modify coumarins since this method offers regioselective and stereospecific transformation, which is challenging to obtain through chemical synthesis. Various microorganisms, including bacteria and fungi, play an essential role in the microbial transformation of coumarins. These microorganisms employ enzymatic mechanisms involving various enzymes to catalyze several reactions, such as hydroxylation, oxidation, reduction, and demethylation. Among these microbial transformation processes, the demethylation process is a significant mechanism for altering the bioactivity of coumarins by converting methoxy groups into hydroxyl groups. Despite all the advantages, microbial transformation also has limitations such as low substrate specificity, contamination during inoculation, variable enzymatic activity, and challenges to scale up the production of bioactive coumarins. These challenges can be addressed through the optimization of the bioprocess to enhance the efficiency of microbial coumarin metabolism. This review provides a comprehensive overview of the microbial transformation of coumarins, highlighting the role of various microorganisms, enzymatic mechanisms, and the transformation processes. Full article

Toxoplasmosis remains a major global health concern, particularly in immunocompromised individuals and pregnant women, while currently available therapies are associated with significant toxicity and limited efficacy against chronic infection. Drug repurposing represents an attractive strategy for the identification of safer and more effective anti-Toxoplasma gondii agents. This study investigated the antiparasitic potential of loratadine, a second-generation antihistamine, using an integrated in silico, in vitro, and in vivo approach. The anti-T. gondii activity of loratadine was evaluated through β-galactosidase-based proliferation assays, reversibility assays, and experiments using pretreated tachyzoites. In vivo efficacy was assessed in murine models of acute and chronic toxoplasmosis. Disease progression, survival, parasite burden, and cerebral cyst formation were analyzed following treatment. Loratadine inhibited the intracellular proliferation of T. gondii tachyzoites in a concentration-dependent manner and induced partially irreversible effects on parasite viability after drug withdrawal. Pretreatment of extracellular tachyzoites produced limited effects, suggesting that loratadine predominantly acts during the intracellular stage of infection. In the acute toxoplasmosis model, loratadine treatment delayed disease progression, prolonged animal survival, and significantly reduced the number of tachyzoites recovered from the peritoneal cavity. In the chronic infection model, treatment significantly decreased both the number and size of cerebral cysts, although these findings do not demonstrate cyst eradication or direct bradyzoite killing. Despite its measurable biological activity, loratadine exhibited a relatively low in vitro selectivity index, highlighting the need for further optimization. These exploratory findings identify loratadine as a promising lead compound (hit) for further optimization rather than an immediately translatable therapeutic candidate. Additional medicinal chemistry, pharmacokinetic, mechanistic, and confirmatory preclinical studies will be required to determine its potential for anti-T. gondii drug development. Full article

Chagas disease, caused by Trypanosoma cruzi, remains a neglected tropical infection with limited therapeutic options and significant drug-related toxicity. Endophytic fungi are emerging as sustainable sources of bioactive metabolites with potential antiparasitic activity. In this study, endophytic fungi isolated from the medicinal plant Lippia alba were screened for trypanocidal activity. Crude extracts from seven isolates were tested against epimastigote and amastigote forms of T. cruzi, together with cytotoxicity assays in J774A.1 murine macrophages. The crude extract of Montagnula sp. exhibited the strongest trypanocidal activity (IC₅₀ = 22.1 ± 0.5 μg/mL for epimastigotes and 29.2 ± 3.0 μg/mL for amastigotes), comparable to benznidazole, with low toxicity (CC₅₀ > 600 μg/mL) and a high selectivity index (>26). Morphological and mitochondrial analyses demonstrated preservation of host-cell integrity and mitochondrial function, in contrast to the reference drug. UHPLC-ESI-HRMS profiling identified phenolic and terpenoid compounds, including caffeic acid, ferulic acid, naringenin, apigenin, and ursolic acid, which may underlie the observed biological activity. To our knowledge, this study provides the first evidence of trypanocidal activity in an endophytic Montagnula species and highlights endophytic fungi as promising platforms for the discovery of novel anti-T. cruzi agents. Full article

Long-acting spot-on formulations are widely used for parasite control in cats, yet the pharmacokinetics of combined fluralaner and moxidectin remain incompletely defined beyond the recommended dose. This study evaluated the pharmacokinetics, absolute bioavailability, and dose proportionality of a novel fixed-combination spot-on formulation in healthy cats after topical administration of fluralaner/moxidectin at 40/2, 80/4, and 120/6 mg/kg BW, and compared intravenous administration of each compound alone or in combination. Forty-eight healthy cats were allocated to six groups of eight cats each. Non-compartmental analysis and a power model were used to characterize systemic exposure and dose proportionality. After intravenous co-administration, fluralaner exposure increased whereas moxidectin exposure decreased compared with single-agent administration, indicating a potential pharmacokinetic interaction. Topical administration produced slow absorption and sustained systemic persistence, with T_max values occurring approximately 10–18 days after dosing and quantifiable concentrations maintained throughout the 160 days sampling period. Systemic exposure increased non-proportionally across the tested dose range, and absolute bioavailability was limited and dose-dependent, ranging from 9.7% to 26.9% for fluralaner and from 10.22% to 21.28% for moxidectin. No adverse reactions were observed. These findings demonstrate nonlinear topical absorption, and prolonged systemic persistence, supporting further dose optimization and formulation development of this long-acting feline antiparasitic delivery system. Full article

The Amaryllidaceae family is a rich source of structurally diverse alkaloids with recognized neuroactive and antiparasitic properties. This study provides the first phytochemical and biological characterization of Pyrolirion boliviense and wild Stenomesson miniatum from Bolivia. Alkaloid extracts from bulbs and leaves were analysed by GC–MS and evaluated for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and Trypanosoma cruzi inhibitory activities. Thirty-two Amaryllidaceae alkaloids were identified, with P. boliviense exhibiting greater alkaloid diversity (25 compounds) and S. miniatum a higher total alkaloid content (227.86 vs. 138.92 μg Gal/100 mg DW). P. boliviense bulb extracts showed the strongest cholinesterase inhibition (AChE IC₅₀ = 6.07 ± 0.47 μg·mL⁻¹; BuChE IC₅₀ = 30.93 ± 1.17 μg·mL⁻¹), whereas S. miniatum extracts displayed weaker AChE inhibition and no detectable BuChE activity. In anti-T. cruzi assays, bulb extracts were the most active, with S. miniatum showing an IC₅₀ of 0.90 ± 0.15 μg·mL⁻¹ (SI = 20.12) and selective anti-amastigote activity (IC₅₀ = 1.42 ± 0.66 μg·mL⁻¹; SI = 12.77). These findings identify Bolivian Andean Amaryllidaceae as promising sources of bioactive alkaloids with potential applications for Alzheimer’s disease and Chagas disease drug discovery. Full article

Praziquantel (PZQ) is a widely used antiparasitic drug in aquaculture; however, data on its environmental fate, tissue distribution, and metabolite kinetics in fish following bath treatment remain limited, particularly with respect to its metabolites. This study investigated the long-term elimination of PZQ and its two major metabolites, trans-4-hydroxypraziquantel (TPZQ) and cis-4-hydroxypraziquantel (CPZQ), in water and selected biological matrices of grass carp (Ctenopharyngodon idella) following a 24 h therapeutic bath with PZQ administered at 4 mg/L. Results showed a rapid decrease in PZQ in water after the transfer of fish to clean water, accompanied by a transient increase in its metabolites, with TPZQ as the predominant metabolite. PZQ tissue residues were highest in the hepatopancreas, caudal kidney, and skin, where the parent compound remained detectable up to day 14 of the experiment. Among the metabolites, higher concentrations of CPZQ were detected across all examined tissues; however, its elimination rate was faster than that of TPZQ. This difference was most pronounced in plasma and skin, where TPZQ remained detectable until day 7 of the experiment, whereas the cis-form was detected only up to day 3. Similar to the parent compound, the highest concentrations of both monitored metabolites were observed in the hepatopancreas and caudal kidney, where they remained detectable until day 7 of the experiment. These findings provide comprehensive insight into the distribution and elimination of PZQ in grass carp following 24 h bath administration and contribute valuable data that may support environmental risk assessment and future withdrawal-period evaluation in aquaculture. Full article

Ornamental aquarium keeping collectively involves millions of freshwater, marine, and reef systems in which fish, corals, invertebrates, biofilters, microbial communities, and human husbandry practices are closely interconnected. In these domestic aquatic animal systems, preventive and curative treatments may include antimicrobials, antiparasitics, antiseptics, oxidizing agents, copper-based products, dips, and commercial formulations targeting microbial proliferations or visible system deterioration. Many interventions occur without veterinary diagnosis, microbiological confirmation, standardized dosing, active-ingredient transparency, or post-treatment monitoring. This raises concerns for aquatic animal health and welfare, as whole-system treatments may affect not only the intended pathogen or pest but also non-target organisms, biofilter communities, animal-associated microbiota, and water quality stability. Digital communities and online platforms can rapidly circulate empirical treatment protocols, although they may also provide opportunities for stewardship education and improved husbandry guidance. Current evidence does not support interpreting ornamental aquaria as major independent drivers of antimicrobial resistance. The more defensible concern is stewardship: biologically active compounds may be used repeatedly and empirically in animal systems without diagnosis, professional guidance, or systematic monitoring. This Perspective argues that ornamental aquaria should be recognized as an overlooked interface between aquatic animal health, welfare, antimicrobial stewardship, and One Health. It proposes a research and communication agenda focused on treatment transparency, diagnosis, prevention, biofilter protection, and responsible care practices. Full article

In this study, 86 veterinary antiparasitic drugs were investigated for their ability to cross the human placenta, expressed as the Clearance Index (CI) relative to antipyrine. It was established that the CI is positively correlated with the permeability of compounds through Caco-2 cells (caco2) and with ATSC7i—the centered Broto-Moreau autocorrelation—lag 7/weighted by the first ionization potential, and inversely correlated with Topological Polar Surface Area (TPSA_Mord). All the studied drugs might cross the placenta, some rapidly, as suggested by their CI values. For some of the antiparasitic drugs (especially those from the pyrethroid family) investigated in this study, the placental permeability predicted using the CI values differed from predictions based on the equilibrium fetus-to-mother concentration ratio (FM), indicating the possibility of rapid clearance or metabolism. According to our QSAR analysis, almost all of the studied drugs have AChE inhibition constants (K_i) comparable to those of AChE inhibitors registered in the CHEMBL database. Molecular docking studies revealed that the drugs might engage in several types of bonds/interactions, mainly with tryptophan (Trp86, Trp286), tyrosine (Tyr124, Tyr227, Tyr341), and phenylalanine (Phe295, Phe297, and Phe338)—and with at least one amino acid from the AChE catalytic triad. Full article

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

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

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

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

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