Search Results (99)

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

Sargassum filipendula is a widely distributed, edible brown alga that possesses a rich nutritional profile. Several studies have demonstrated that the components/extracts of S. filipendula (SFE) possess diverse pharmacological potential against both infectious and non-infectious diseases. These include antibacterial and antifungal properties, as well as antioxidant, anti-aging, anti-osteoporosis, antiviral, antiprotozoal, and immunomodulatory effects. Furthermore, SFE has shown significant anticancer activity across various malignant cell lines. The unique phytochemical profile of this species, characterized by the presence of sulfated polysaccharides (primarily fucoidan), carotenoids, phenols, glycolipids, and phlorotannins, serves as the foundation for these wide-ranging pharmacological activities. Studies have demonstrated that SFE can modulate key molecular targets, such as glycogen synthase kinase-3 beta, and activate the mitochondrial-dependent apoptosis pathway, providing a robust mechanistic basis for the observed pharmacological activities. Recent evaluations of nutritional parameters and techno-functional properties confirm the rich nutritional profile of S. filipendula, supporting its application in a diverse range of food products. Despite its diverse bioactive phytochemicals and broad efficacy against infectious and non-infectious diseases, research on S. filipendula remains largely restricted to in vitro preclinical studies. The lack of a comprehensive compilation of its pharmacological activities, phytochemical profiles, and molecular targets hinders its development as a therapeutic agent. This review aims to bridge this gap by compiling the existing knowledge, identifying research deficiencies, particularly the lack of in vivo data and safety assessments for high-dose therapeutic applications, while proposing suggestions for transitioning S. filipendula into a viable therapeutic or functional supplement. Full article

Imidazole is, from a structural point of view, a heterocycle consisting of three C atoms and two N atoms, belonging to the class of diazoles, having two N atoms at the first and third positions in the aromatic ring. Being a polar and ionizable aromatic compound, it has the role of improving the pharmacological properties of lead molecules, thus being used to optimize their solubility and bioavailability. Imidazole is a constituent of many important biological compounds, like histidine, histamine, and purine compounds, the most widespread heterocyclic compound in nature. In current practice, substituted imidazole derivatives play a major role in antifungal, antibacterial, anti-inflammatory, CNS active compounds, antiprotozoal, as well as anticancer therapy. Thus, imidazole derivatives have demonstrated significant anticancer activities by inhibiting the key metabolic pathways essential for tumor cell growth and survival. Nitroimidazoles, for instance, have been employed as hypoxia-directed therapeutic agents, targeting oxygen-deprived tumor tissues, while mercaptopurine derivatives are well-established in oncological treatments. Structural modifications of the imidazole nucleus have led to the novel compounds exhibiting increased selective cytotoxicity against cancer cells, while sparing normal healthy cells. In accordance with what has been stated, this review highlights recent research on the medicinal and pharmaceutical interest of novel imidazole derivatives, emphasizing their potential in the development of new drugs. Full article

Plant-derived natural products are an invaluable source of structurally diverse secondary metabolites with ecological and pharmacological significance. Geranium macrorrhizum, a species known for producing essential oils rich in monoterpenoids and sesquiterpenes, has been scarcely explored for its antiparasitic potential. This study represents the first comprehensive evaluation of the antiprotozoal activity of G. macrorrhizum obtained from cultivated plants. Plant material was produced under controlled greenhouse cultivation systems, ensuring high-quality and reproducible metabolite profiles. Essential oils were obtained through hydrodistillation and chemically characterized by Gas Chromatography-Mass Spectrometry (GC–MS). In vitro assays were conducted against Giardia duodenalis, Trichomonas gallinae, and Leishmania infantum to assess antiparasitic efficacy and cytotoxicity. The results demonstrated strong activity of essential oils against Trichomonas gallinae, and Leishmania infantum, indicating the relevance of lipophilic compounds—especially germacrone—as key bioactive constituents. Germacrone exhibited strong and selective antiparasitic activity, outperforming its structural analogues. Microscopic analyses revealed distinct parasite-specific morphological alterations, differing from those induced by conventional drugs such as metronidazole and amphotericin B. These findings highlight G. macrorrhizum obtained through biotechnological cultivation as a novel and sustainable source of natural antiprotozoal agents. The study underscores the importance of integrating controlled cultivation with phytochemical and biological evaluation to advance the discovery of innovative bioactive compounds. Full article

Background: Infections caused by the protozoan Trichomonas vaginalis affect millions of people worldwide and are responsible for one of the most common sexually transmitted diseases. Despite the efficacy of 5-nitroimidazoles like metronidazole, concerns regarding widespread resistance and the absence of viable alternatives for specific patient populations necessitate the development of structurally diverse pharmacological agents. In this study, we investigated the antiparasitic activity of 1,3-thiazolidin-4-one derivatives against T. vaginalis. Methods: Thiazolidines were synthesized via multicomponent reaction (MCR) using one-pot methodology and tested in vitro against the parasite and mammalian cell lines. Results: Seventy percent of the compounds showed more than 80% antiparasitic activity at 100 μM, with compounds 4a, 4b, and 4f exhibiting IC₅₀ ≤ 20 µM. None of the molecules exhibited cytotoxic against Vero CCL-81 and HeLa cells. Evaluation of the structure–activity relationship (SAR) indicates that the substituent at the nitrogen position of the heterocycle may be involved in the antiparasitic effect of these compounds. In silico studies also revealed that the three compounds possess adequate oral bioavailability and do not present mutagenic, tumorigenic or irritating risks. Finally, molecular docking predicted strong interactions of compounds 4a, 4b, and 4f with T. vaginalis enzymes lactate dehydrogenase and purine nucleoside phosphorylase; compound 4f also interacted with methionine Ƴ-lyase. Conclusions: These preliminary results suggest that 1,3-thiazolidin-4-ones are promising scaffolds for developing new trichomonacidal agents. Full article

Endoperoxides constitute a distinctive class of highly oxygenated terpenoids defined by the presence of a cyclic peroxide (–O–O–) bond, a structural motif responsible for their pronounced chemical reactivity and diverse biological effects. Naturally occurring endoperoxide-containing terpenoids are broadly distributed across terrestrial and marine taxa, including higher plants, algae, fungi, and bryophytes, where they are believed to participate in chemical defense and ecological interactions. This review provides a comprehensive overview of naturally occurring endoperoxide terpenoids, focusing on their natural sources, structural diversity, and reported biological activities. Particular emphasis is placed on compounds exhibiting antiprotozoal and antitumor activities, exemplified by artemisinin and its derivatives, which remain cornerstone agents in antimalarial therapy and continue to attract interest for their anticancer potential. Structure–activity relationship (SAR) analysis, supported by computational prediction using the PASS (Prediction of Activity Spectra for Substances) platform, is employed to examine correlations between peroxide-containing frameworks and biological function. Comparative assessment of experimental data and predicted activity profiles identifies key structural features associated with antiprotozoal, antineoplastic, and anti-inflammatory effects. Collectively, this review highlights endoperoxides as a valuable and chemically distinctive class of bioactive natural products and discusses their promise and limitations as leads for further pharmacological development, particularly in light of their intrinsic reactivity and stability challenges. Full article

A five-month-old, intact, female Miniature Schnauzer Terrier presented with persistent severe hemolytic anemia following an initial infection with Babesia gibsoni and B. vogeli. Despite treatment, severe regenerative anemia persisted, and the patient was unresponsive to antibiotics, as well as antiprotozoal and immunosuppressive agents. Subsequent laboratory tests and diagnostic imaging ruled out persistent hemiparasitic infections, immune-mediated diseases, or neoplasia. Genomic DNA and cDNA sequencing identified a point mutation in exon 8 (g.4978G>T) that introduced a premature termination codon, leading to exon 8 skipping and a single-nucleotide deletion at the exon 7–intron 7 boundary (c.966delG) during splicing. A 151 bp deletion in the coding region of the patient’s PKLR cDNA was subsequently detected, which ultimately resulted in pyruvate kinase deficiency. This missplicing results in a premature stop codon and disrupts PKLR tetramer formation owing to the partial loss of domain A and complete loss of domain C. Enzyme activity assays confirmed a complete loss of function in the mutant PKLR protein compared to the wild-type, supporting the causal role of this deletion in non-spherocytic hemolytic anemia. This is the first report as per our knowledge documenting truncated PKLR variant in a dog, and notably, the first such case in a Miniature Schnauzer breed. Full article

Background/Objectives: Giardia lamblia is an intestinal protozoan responsible for giardiasis, a globally prevalent parasitic disease. Current therapeutic options, including nitroimidazoles and benzimidazoles, have increasing treatment failures due to resistance, adverse reactions, and patient non-compliance. Drug repositioning offers a cost-effective strategy for identifying new antigiardial agents. This study aimed to evaluate the in vitro antiparasitic effects and possible mechanisms of action of the tricyclic antidepressant imipramine against G. lamblia trophozoites. Methods: Trophozoites were exposed to increasing concentrations of imipramine (25–125 µM). Growth inhibition and adhesion capacity were quantified using cell counts. Apoptosis- or necrosis-like death was evaluated through Annexin V/PI staining. The expression and distribution of α-tubulin and lipid rafts were analyzed by immunofluorescence microscopy. Finally, the effect of the drug on encystment efficiency was assessed in vitro. Results: Imipramine inhibited G. lamblia trophozoite growth in a concentration-dependent manner, with an IC₅₀ of 42.31 µM at 48 h. The drug significantly reduced adhesion capacity (>90% at 125 µM) and induced apoptosis-like cell death, as evidenced by Annexin V positivity. Immunofluorescence revealed disruption of α-tubulin distribution and lipid raft organization, accompanied by morphological rounding. Moreover, encystment efficiency decreased in a concentration-dependent mode, suggesting interference in the differentiation process. Conclusions: This investigation describes, for the first time, the antigiardial potential of imipramine, which alters cytoskeletal organization, membrane microdomains, and differentiation pathways, ultimately leading to apoptosis-like cell death. These findings position this compound as a promising lead structure and support further exploration of tricyclic antidepressants as scaffolds for the development and optimization of new antiparasitic agents, as well as future studies on their molecular targets and in vivo efficacy. Full article

Compounds based on an isoquinoline scaffold (benzo[c]pyridine) display a broad spectrum of biological activities. In recent years, studies have focused mainly on their anticancer properties. Their antiproliferative effects are associated with diverse mechanisms that include targeting PI3K/Akt/mTOR signaling pathways and reactive oxygen species or inducing apoptosis and cell cycle arrest. Furthermore, isoquinolines may inhibit microtubule polymerization, topoisomerase, or tumor multidrug resistance. Recent studies have also shown that these compounds may act as effective antimicrobial, antifungal, antiviral, and antiprotozoal agents. Moreover, it has also been demonstrated that isoquinoline derivatives exhibit potent anti-Alzheimer effects, alleviating central nervous system functions. Additionally, they possess anti-inflammatory and antidiabetic properties. Due to the presence of donor nitrogen, the isoquinoline core constitutes an appropriate ligand that may be employed for the development of metal complexes with improved pharmacological properties. A number of chelates containing copper, iridium, or platinum were found to exhibit prominent biological activity, which places them in a leading position for the development of effective medications. This review summarizes the recent development of synthetic isoquinoline-based compounds with proven pharmacological properties in the period of 2020–2025. Also, other biomedical applications for synthetic isoquinoline derivatives are provided. Full article

In continuation of our recent report on the antileishmanial activity of an ethanolic extract from leaves of Ptilostemon chamaepeuce subsp. cyprius (Pcc, Asteraceae), we have now isolated the main sesquiterpene lactone, deacylcynaropicrin, along with a minor derivative, 13-hydroxy-11β,13-dihydro-deacylcynaropicrin. The main constituent was tested for antileishmanial activity against promastigotes and amastigotes of Leishmania infantum (Lin), the causative agent of visceral leishmaniasis. Both STLs were tested against additional protozoan pathogens, including L. donovani, Trypanosoma brucei rhodesiense (Tbr), and Plasmodium falciparum. The STL cynaropicrin from Artichoke (Cynara cardunculus), a congener of deacylcynaropicrin with a hydroxymethacrylate ester group, previously known to possess antiprotozoal activity, was retested against Lin for direct comparison. Cynaropicrin was found to be much more potent than either its deacyl congener or the hydroxylated derivative from Pcc against all tested parasites and also against an isolated parasite enzyme, Tbr pteridine reductase (TbPTR1). The ester moiety of cynaropicrin significantly enhances the antiprotozoal activity of this STL. Since cynaropicrin also displayed significant cytotoxicity against mammalian cells (L6 and J774A.1 cell lines), its utility as candidate for further development appears limited. However, this study provides valuable new insight into the structure–activity relationships of these compounds. Full article

Background/Objectives: Carvacrol and thymol are monoterpenes present in phenolic-rich essential oils extracted from aromatic plants that exhibit antimicrobial activity. This study evaluates the antiprotozoal effect of carvacrol, thymol and their precursor, p-Cymene, against Giardia lamblia and investigates their mechanism of action and cytotoxicity profile. Methods: G. lamblia susceptibility, cell viability, swelling and adhesion abilities following application of carvacrol, thymol and p-Cymene were assessed. Ultrastructural changes were evaluated using electron microscopy. Cytotoxicity was determined in mammalian cell lines (murine macrophages RAW 264.7 and bovine aortic endothelial cells) exposed to the same IC₅₀ concentrations effective against G. lamblia. Results: Carvacrol and thymol led to significant inhibition of G. lamblia trophozoite proliferation (IC₅₀ ≅ 50 µg/mL). After 7 h of incubation, total cell number decreased by 30% (p < 0.01) with carvacrol and by 50% (p < 0.001) with thymol, accompanied by reduced motility and adhesion (<20% attached cells). At IC₅₀ concentrations, G. lamblia trophozoites exposed to carvacrol and thymol underwent considerable ultrastructural alterations (e.g., aberrant-shaped cells, mitochondrial swelling and autophagosomal structures). Reduced trophozoite motility and adhesion capacity were also observed. In mammalian cells, thymol showed no significant cytotoxicity, whereas carvacrol significantly reduced viability in both cell lines. In contrast, p-Cymene showed no antigiardial activity. Conclusions: Our data suggests that carvacrol and thymol disrupt G. lamblia trophozoite integrity, possibly through alterations in membrane permeability and osmoregulatory processes. In conclusion, these compounds reveal in vitro antigiardial activity, supporting their potential as antigiardial drugs. Full article

Background: Trichomonas vaginalis is the causative agent of human trichomoniasis, the most common non-viral sexually transmitted infection. This disease is associated with an increased susceptibility to HIV and HPV infections. Currently, resistance to metronidazole (MTZ), the main drug used for treatment, has been reported in up to 9.6% of cases; additionally, the compound is also associated with adverse side effects. Therefore, it is urgent to identify new treatment options. Objective: In this study, we investigated for the first time the in vitro and in silico activity against T. vaginalis of betulin and stigmasterol isolated from Tagetes nelsonii Greenm, as well as their hemolytic activity. Methods: Plant specimen was collected in Chiapas, Mexico. Hexane and methanol extracts were prepared through sonication-assisted maceration. The antiprotozoal and hemolytic activities were evaluated in vitro against Trichomonas vaginalis trophozoites and human erythrocytes. The most active extract was fractionated using chromatographic techniques in a bioassay-guided study. The active metabolites were identified by ¹H and ¹³C-NMR spectroscopy, and their biological activity was further assessed in silico against lactate dehydrogenase (LDH), pyruvate ferredoxin oxidoreductase (PFOR) methionine gamma-lyase (MGL) and purine nucleoside phosphorylase (PNP) T. vaginalis enzymes. Results: Both triterpenes showed anti-trichomonal activity and no hemolytic activity at 100 µg/mL. Molecular docking studies predicted promising interactions of triterpenes with T. vaginalis drug target proteins, TvpFOR and TvLDH. Conclusions: Our results revealed that betulin and stigmasterol are potential molecules for the development of new trichomonacidal therapies against T. vaginalis. Full article

Background: Chagas disease and leishmaniasis remain public health concerns. Despite the existence of approved medications for the treatment of these diseases, most patients discontinue treatment due to long drug regimens and/or the severe side effects of these drugs. This leads to treatment failure and potential future drug resistance. Therefore, the search for new molecules with trypanocidal activity, low cytotoxicity, and high selectivity is essential to address this challenge. Methods: In this work, three series (a, b, and c) of pyridine-2,5-dicarboxylate esters were synthesized using different β-keto-esters bearing naturally occurring fragments and 1,2,3-triazine-1-oxides via the inverse electron demand Diels–Alder (IEDDA) reaction. The structural elucidation of the compounds was performed using NMR (¹H and ¹³C) and HRMS, and the crystal structure of compound 6a was also obtained. Furthermore, a biological assay was performed for all synthesized and characterized compounds to determine their cytotoxicity against Trypanosoma cruzi, Leishmania mexicana, and the J774.2 macrophage cell line. Finally, the in silico determination of their pharmacokinetic and toxicological properties was performed using the SwissADME and ProTox 3.0 platforms. Results: Compounds 3a, 4a, 5a, 4b, and 8c had the highest anti-Trypanosoma cruzi activity against both strains (IC₅₀ ≤ 56.68 µM). Compounds 8b, 10a, 9b, and 12b had considerable leishmanicidal activity against Leishmania mexicana against both strains (IC₅₀ ≤ 161.53 µM). Furthermore, in silico prediction of ADMET properties suggest that these pyridine compounds possess good pharmacokinetic profile. The results are also consistent with low in vitro cytotoxicity and high selectivity. Conclusions: The synthesized pyridine-2,5-dicarboxylate esters have promising activity against Trypanosoma cruzi and Leishmania mexicana, with low cytotoxicity and good drug-like properties, suggesting that these compounds are potential candidates for further evaluation as new treatments for Chagas disease and leishmaniasis. Full article

Blastocystis, a common intestinal protozoan in humans, is associated with gastrointestinal disorders, irritable bowel syndrome, urticaria, and colorectal cancer. Its genetic diversity and potential for treatment resistance make it a focus of ongoing research. This study evaluated the in vitro antiprotozoal activity of a postbiotic derived from Pediococcus acidilactici as a natural alternative treatment. P. acidilactici cultures were grown in MRS broth under anaerobic conditions, and the postbiotic was collected and characterized for pH, yield, organic acid composition, and phenolic compound content. Human isolates of Blastocystis subtypes ST1 and ST3 were cultured in Jones’ medium and exposed to varying postbiotic concentrations for 72 h. Viability was assessed microscopically. The cytotoxic effect of the postbiotic-derived P. acidilactici was evaluated by investigating its impact on the viability of HT-29 cells using the Cell Counting Kit 8. The postbiotic showed a 7% yield and a pH of 4.52 ± 0.11. It contained seven different organic acids, predominantly lactic acid, and eleven phenolic compounds, with naringin as the most abundant. At 4.38 mg/mL, the postbiotic achieved over 94% inhibition and 100% inhibition at 8.75 mg/mL and above. A pH analysis confirmed that the inhibition was independent of the culture medium acidity. Cell viability was not affected at the postbiotic concentration showing 100% antiprotozoal activity (8.75 mg/mL). These findings suggest that the P. acidilactici postbiotic is effective on a mixed culture of ST1 and ST3 subtypes and holds promise as a safe, natural antiprotozoal agent. Further in vivo studies are needed to confirm this. Full article