Search Results (11)

Giardiasis is a common intestinal infection caused by Giardia lamblia. The standard treatment for this parasitic infection involves the administration of nitroimidazoles, albendazoles, and nitrothiazoles. However, in recent years, Giardia lamblia strains resistant to these treatments have been reported. Additionally, the current therapies exhibit considerable side effects, highlighting the need for new compounds that specifically target this parasite. The aim of this study was to evaluate nitrothiazole analogs and assess their impact on the metabolic, redox, and structural gene expression of this parasite. First, the compounds CNZ-7, CNZ-8, FLP-2, FLP-6, and FLP-8 were tested at concentrations ranging from 0 to 50 µM to determine their IC₅₀ in G. lamblia cultures. Subsequently, gene expression changes and structural cell damage in trophozoites were analyzed following incubation with the IC₅₀ of each compound. The giardicidal activity of the compounds was also evaluated in a nitazoxanide-resistant strain. The results showed that FLP-2, FLP-6, and FLP-8 exhibited a stronger effect on trophozoite viability compared to nitazoxanide (NTZ) and metronidazole (MTZ). Both compounds induced an increase in the expression of phosphofructokinase (PFK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase (PK), pyruvate phosphate dikinase (PPDK), and pyruvate:ferredoxin oxidoreductase (PFOR). Additionally, FLP-2 caused ultrastructural alterations in trophozoites. Furthermore, FLP-2, FLP-6, and FLP-8 demonstrated efficacy against drug-resistant strains. These findings suggest that FLP-2, FLP-6, and FLP-8 are promising candidates for the treatment of giardiasis, as they effectively reduce parasite viability, modify gene expression, and exhibit activity against drug-resistant G. lamblia strains. Full article

Giardiasis, which is caused by Giardia lamblia infection, is a relevant cause of morbidity and mortality worldwide. Because no vaccines are currently available to treat giardiasis, chemotherapeutic drugs are the main options for controlling infection. Evidence has shown that the nitro drug nitazoxanide (NTZ) is a commonly prescribed treatment for giardiasis; however, the mechanisms underlying NTZ’s antigiardial activity are not well-understood. Herein, we identified the glucose-6-phosphate::6-phosphogluconate dehydrogenase (GlG6PD::6PGL) fused enzyme as a nitazoxanide target, as NTZ behaves as a GlG6PD::6PGL catalytic inhibitor. Furthermore, fluorescence assays suggest alterations in the stability of GlG6PD::6PGL protein, whereas the results indicate a loss of catalytic activity due to conformational and folding changes. Molecular docking and dynamic simulation studies suggest a model of NTZ binding on the active site of the G6PD domain and near the structural NADP⁺ binding site. The findings of this study provide a novel mechanistic basis and strategy for the antigiardial activity of the NTZ drug. Full article

Protozoan parasites, such as Giardia lamblia and Trichomonas vaginalis, cause the most prevalent infections in humans in developing countries and provoke significant morbidity and mortality in endemic countries. Despite its side-effects, metronidazole is still the drug of choice as a giardiacidal and trichomonacidal tissue-active agent. However, the emergence of metronidazole resistance and its evolved strategies of parasites to evade innate host defenses have hindered the identification and development of new therapeutic strategies against these parasites. Here, we tested five synthesized benzimidazole derivatives as possible drugs for treating giardiasis and trichomoniasis, probing the bifunctional enzyme glucose 6-phosphate dehydrogenase::6-phosphogluconolactone from G. lamblia (GlG6PD::6PGL) and T. vaginalis (TvG6PD::6PGL) as a drug target. The investigated benzimidazole derivatives were H-B2M1, H-B2M2, H₂N-BZM6, O₂N-BZM7, and O₂N-BZM9. The recombinant enzymes were used in inhibition assays, and in silico computational predictions and spectroscopic studies were applied to follow the structural alteration of the enzymes and identify the possible mechanism of inhibition. We identified two potent benzimidazole compounds (O₂N-BZM7 and O₂N-BZM9), which are capable of inhibiting both protozoan G6PD::6PGL enzymes and in vitro assays with these parasites, showing that these compounds also affect their viability. These results demonstrate that other therapeutic targets of the compounds are the enzymes GlG6PD::6PGL and TvG6PD::6PGL, which contribute to their antiparasitic effect and their possible use in antigiardial and trichomonacidal therapies. Full article

Treatments to combat giardiasis have been reported to have several drawbacks, partly due to the drug resistance and toxicity of current antiparasitic agents. These constraints have prompted many researchers to investigate new drugs that act against protozoan parasites. Enzyme inhibition is an important means of regulating pathogen metabolism and has recently been identified as a significant alternative target in the search for new treatments. Glucose-6-phosphate dehydrogenase and 6-phosphogluconolactonase (G6PD::6PGL) is a bifunctional enzyme involved in the pentose phosphate pathway (PPP) in Giardia lamblia (G. lamblia). The G. lamblia enzyme is unusual since, unlike the human enzyme, it is a fused enzyme. Here, we show, through inhibition assays, that an in-house chemical library of 120 compounds and four target compounds, named CNZ-7, CNZ-8, CMC-1, and FLP-2, are potent inhibitors of the G. lamblia G6PD::6PGL fused enzyme. With a constant (k₂) of 2.3, 3.2, and 2.8 M⁻¹ s⁻¹, respectively, they provoke alterations in the secondary and tertiary protein structure and global stability. As a novel approach, target compounds show antigiardial activity, with IC₅₀ values of 8.7, 15.2, 15.3, and 24.1 µM in trophozoites from G. lamblia. Moreover, these compounds show selectivity against G. lamblia, since, through counter-screening in Caco-2 and HT29 human cells, they were found to have low toxicity. This finding positions these compounds as a potential and attractive starting point for new antigiardial drugs. Full article

Foeniculum vulgare is used for the treatment of diarrhea in Mexican traditional medicine. Hexane extract showed 94 % inhibition of Giardia duodenalis trophozoites at 300 μg/mL. Therefore, 20 constituents of hexane extract were evaluated to determine their antigiardial activity. Interestingly, six compounds showed good activity toward the parasite. These compounds were (1R,4S) (+)-Camphene (61%), (R)(−)-Carvone (66%), estragole (49%), p-anisaldehyde (67%), 1,3-benzenediol (56%), and trans, trans-2,4-undecadienal (97%). The aldehyde trans, trans-2,4-undecadienal was the most active compound with an IC₅₀ value of 72.11 µg/mL against G. duodenalis trophozoites. This aldehyde was less toxic (IC₅₀ 588.8 µg/mL) than positive control metronidazole (IC₅₀ 83.5 µg/mL) against Vero cells. The above results could support the use of F. vulgare in Mexican traditional medicine. Full article

Giardia lamblia is a flagellated protozoan responsible for giardiasis, a worldwide diarrheal disease. The adverse effects of the pharmacological treatments and the appearance of drug resistance have increased the rate of therapeutic failures. In the search for alternative therapeutics, drug repositioning has become a popular strategy. Acetylsalicylic acid (ASA) exhibits diverse biological activities through multiple mechanisms. However, the full spectrum of its activities is incompletely understood. In this study we show that ASA displayed direct antigiardial activity and affected the adhesion and growth of trophozoites in a time-dose-dependent manner. Electron microscopy images revealed remarkable morphological alterations in the membrane, ventral disk, and caudal region. Using mass spectrometry and real-time quantitative reverse transcription (qRT-PCR), we identified that ASA induced the overexpression of heat shock protein 70 (HSP70). ASA also showed a significant increase of five ATP-binding cassette (ABC) transporters (giABC, giABCP, giMDRP, giMRPL and giMDRAP1). Additionally, we found low toxicity on Caco-2 cells. Taken together, these results suggest an important role of HSPs and ABC drug transporters in contributing to stress tolerance and protecting cells from ASA-induced stress. Full article

Giardiasis is a diarrheal disease that is highly prevalent in developing countries. Several drugs are available for the treatment of this parasitosis; however, failures in drug therapy are common, and have adverse effects and increased resistance of the parasite to the drug, generating the need to find new alternative treatments. In this study, we synthesized a series of 2-mercaptobenzimidazoles that are derivatives of omeprazole, and the chemical structures were confirmed through mass, ¹H NMR, and ¹³C NMR techniques. The in vitro efficacy compounds against Giardia, as well as its effect on the inhibition of triosephosphate isomerase (TPI) recombinant, were investigated, the inactivation assays were performed with 0.2 mg/mL of the enzyme incubating for 2 h at 37 °C in TE buffer, pH 7.4 with increasing concentrations of the compounds. Among the target compounds, H-BZM2, O₂N-BZM7, and O₂N-BZM9 had greater antigiardial activity (IC₅₀: 36, 14, and 17 µM on trophozoites), and inhibited the TPI enzyme (K₂: 2.3, 3.2, and 2.8 M⁻¹ s⁻¹) respectively, loading alterations on the secondary structure, global stability, and tertiary structure of the TPI protein. Finally, we demonstrated that it had low toxicity on Caco-2 and HT29 cells. This finding makes it an attractive potential starting point for new antigiardial drugs. Full article

Lannea schweinfurthii is a valuable medicinal plant species among different ethnic groups in tropical Africa. The aim of the current study was to review existing literature on the ethnomedicinal uses, phytochemistry and pharmacological properties of L. schweinfurthii in an effort to evaluate the therapeutic potential of the species. The relevant information on the ethnomedicinal uses, phytochemistry and pharmacological properties of L. schweinfurthii was generated from several sources including books, book chapters, theses, scientific reports and journal articles obtained from the library and internet sources such as SciFinder, Wiley, Web of Science, American Chemical Society publications, PubMed, BMC, Elsevier, Science Direct, Scielo and Scopus. Traditionally, L. schweinfurthii is used against reproductive system disorders, respiratory disorders, injuries, headache, blood system disorders, infections or infestations and gastro-intestinal disorders. The phytochemical compounds that have been isolated from L. schweinfurthii include alkaloids, anthocyanins, flavonoids, glycosides, phenols, saponins, steroids, tannins and terpenoids. The in vitro and animal studies carried out so far from the crude extracts and compounds isolated from the species exhibited acetylcholinesterase inhibitory, anti-apoptotic, antibacterial, antiviral, anti-giardial, anti-inflammatory, antioxidant, antiplasmodial, antitrypanosomal, hepatoprotective, larvicidal and cytotoxicity activities. Detailed ethnopharmacological studies emphasizing clinical and toxicological evaluations are needed to assess efficacy and safety of the species as herbal medicine. Full article

Giardiasis, a diarrheal disease, is highly prevalent in developing countries. Several drugs are available for the treatment of this parasitosis; unfortunately, all of them have variable efficacies and adverse effects. Bursera fagaroides has been known for its anti-inflammatory and antidiarrheal properties in Mexican traditional medicine. We investigated the in vitro anti-giardial activities of four podophyllotoxin-type lignans from Bursera fagaroides var. fagaroides, namely, 5′-desmethoxy-β-peltatin-A-methylether (5-DES), acetylpodophyllotoxin (APOD), burseranin (BUR), and podophyllotoxin (POD). All lignans affected the Giardia adhesion and electron microscopy images revealed morphological alterations in the caudal region, ventral disk, membrane, and flagella, to different extents. Only 5-DES, APOD, and POD caused growth inhibition. Using the Caco-2 human cell line as a model of the intestinal epithelium, we demonstrated that APOD displayed direct antigiardial killing activity and low toxicity on Caco-2 cells. This finding makes it an attractive potential starting point for new antigiardial drugs. Full article

Chemical investigation of the leaves from Ageratina glabrata yielded four new thymol derivatives, namely: 10-benzoyloxy-8,9-dehydro-6-hydroxythymol isobutyrate (4), 10-benzoyloxy-8,9-dehydrothymol (5), 10-benzoyloxythymol (6) and 10-benzoyloxy-6,8-dihydroxy-9-isobutyryl-oxythymol (7). In addition, (8S)-10-benzoyloxy-8,9-epoxy-6-hydroxythymol isobutyrate (1), together with other two already known thymol derivatives identified as 10-benzoyloxy-8,9-epoxy-6-methoxythymol isobutyrate (2) and 10-benzoyloxy-8,9-epoxythymol isobutyrate (3) were also obtained. In this paper, we report the structures and complete assignments of the ¹H and ¹³C-NMR data of compounds 1–7, and the absolute configuration for compound 1, unambiguously established by single crystal X-ray diffraction, and evaluation of the Flack parameter. The in vitro antiprotozoal assay showed that compound 1 and its derivative 1a were the most potent antiamoebic and antigiardial compounds. Both compounds showed selectivity and good antiamoebic activity comparable to emetine and metronidazole, respectively, two antiprotozoal drugs used as positive controls. In relation to anti-propulsive effect, compound 1 and 1a showed inhibitory activity, with activities comparable to quercetin and compound 9, two natural antipropulsive compounds used as positive controls. These data suggest that compound 1 may play an important role in antidiarrheal properties of Ageratina glabrata. Full article

Three novel new compounds derived from antiparasitic precursors have been synthesized and tested for their antiamoebic and antigiardial activities. The condensation of 2-(2-methyl-5-1H-nitroimidazolyl)ethylamine (6) with 5-nitro-2-furylacrylic acid (7) gave 3-(5-nitrofuran-2-yl)-N-[2-(5-nitroimidazol-1-yl)ethyl]acrylamide (8). Condensation of 7 with 7-chloro-4-(piperazin-1-yl)quinoline (9) afforded 1-[4-(7-chloroquinolin-4-yl)piperazin-1-yl)-3-(5-nitrofuran-2-yl)propenone as a mixture of two isomers; 10-a (the E-isomer) and 10-b (the Z-isomer). In addition, the reaction of 9 with 1-(2-bromoethyl)-2-methyl-5-nitroimidazole (11) in the presence of K₂CO₃ and NaI yielded 7-chloro-4-(4-[2-(5-nitroimidazol-1-yl)ethyl]-piprazin-1-yl)quinoline (12). On the basis of preliminary screening data for these new compounds, compound 12 exhibited potent lethal activities against Entamoeba histolytica and Giardia intestinalis; its IC₅₀ ( about 1 µM) was lower, at least by a factor of five, compared to the standard drug, metronidazole. In addition, the IC₅₀ of compound 12 against the tested parasites is 600 times below that against Hep-2 and Vero cells. Compounds 8 and 10-a also exhibited potent or moderate antiamoebic and antigiardial activities with IC_{50 values} of about 5.5 µM, and 140 µM, respectively, against the tested parasites. These two hybrid molecules, 8, 10-a, were also non-cytotoxic at the lethal concentrations against the parasites. Full article