Search Results (59)

Schistosomiasis mansoni is a neglected tropical disease caused by the parasite Schistosoma mansoni, affecting approximately 200 million people annually. Currently, treatment relies primarily on a single drug, praziquantel (PZQ), which shows limited efficacy against the parasite’s immature forms. As a result, Thioredoxin Glutathione Reductase from S. mansoni (SmTGR) has emerged as a promising target for novel drug development. This study presents the development of integrated in silico methods to identify alkaloids from medicinal plants with potential activity against S. mansoni. Fourteen alkaloids were identified, with predicted activity ranging from 61.3 to 85.2%. Among these, lindoldhamine and daibucarboline A demonstrated, for the first time, potential SmTGR inhibition, with probabilities of 85.2% and 75.8%, respectively. These findings highlight the potential of these alkaloids as promising candidates for the development of new therapies against schistosomiasis. Full article

Schistosomiasis is a parasitic disease caused by helminth parasites of the genus Schistosoma, affecting >200 million people worldwide. Current schistosomiasis treatment relies on a single drug, praziquantel, highlighting the urgent need for new therapies. We have identified a non-neuronal tegumental acetylcholinesterase from Schistosoma mansoni (SmTAChE) as a rational and molecularly defined drug target. Molecular modeling reveals significant structural differences between SmTAChE and human AChE, suggesting the potential for identifying parasite-specific inhibitors. Here, we screened recombinant SmTAChE (rSmTAChE) against two chemical libraries: the Broad Institute Drug Repurposing Hub (5440 compounds) and the Diversity-Oriented Synthesis (DOS)-A library (3840 compounds). High-throughput screening identified 116 hits from the Repurposing Hub (2.13% hit rate) and 44 from the DOS-A (1.14% hit rate) library that inhibited rSmTAChE ≥60% at 20 µM. Dose–response assays using both rSmTAChE and recombinant human AChE (rHsAChE) revealed 19 Repurposing Hub compounds (IC₅₀: 0.4–24 µM) and four DOS-A scaffolds (IC₅₀: 13–29 µM), with higher selectivity for rSmTAChE. Selective inhibitors such as cepharanthine, primaquine, mesalazine, and embelin emerged as promising candidates for further evaluation in schistosomiasis treatment. These 23 newly identified selective hits provide a foundation for the further development of novel anti-schistosome therapies. Full article

Schistosomiasis is a neglected tropical disease that affects over 240 million people worldwide. Currently, praziquantel is the only drug recommended by the World Health Organization for treatment. However, cases of drug resistance have been reported, which indicates an urgent need for new therapeutics. In this context, natural compounds represent valuable sources of pharmacological substances. Plant-derived natural products have been greatly explored for their potential antischistosomal activity, while animal-derived compounds have received little attention. Recent advances in the biotechnology field allow the wide exploration of animal-derived compounds in drug discovery, which may represent a cost-effective option to find bioactive molecules also against Schistosoma mansoni and other parasites. This review highlights the research into animal-derived products and compounds that have already been tested against schistosomes. Phenotypic effects on schistosomes have been observed upon incubation with some of these substances, which may, therefore, represent possible candidates to be used in the development of new drugs. Overall, these studies advance the discovery of antischistosomal compounds by exploring a yet understudied natural resource. The present review also discusses the challenges of testing animal-derived products and provides examples of the experimental in vitro testing of different selected animal natural products against S. mansoni. Full article

In the present study, the hexane extract from branches of Drimys brasiliensis (Winteraceae) displayed potent activity against Schistosoma mansoni parasites (100% mortality of the worms at 200 μg/mL). Bioactivity-guided fractionation afforded, in addition to the previously reported bioactive sesquiterpene 3,6-epidioxy-bisabola-1,10-diene, two chemically related drimane sesquiterpenes—polygodial (1) and 9-deoxymuzigadial (2). The anti-S. mansoni effects for compounds 1 and 2 were determined in vitro, with compound 1 demonstrating significant potency (EC₅₀ value of 10 μM for both male and female worms), while 2 was inactive. Cytotoxicity assays against Vero cells revealed no toxicity for either compound (CC₅₀ > 200 μM). Additionally, an in silico analysis was conducted using the SwissADME platform for 1, revealing that this natural sesquiterpene exhibited adherence to several ADME parameters and no PAINS violations. Finally, in vivo studies with S. mansoni-infected mice treated with compound 1 demonstrated a 44.0% reduction in worm burden, accompanied by decreases in egg production of 71.8% in feces and 69.5% in intestines. These findings highlight the potential of polygodial (1) as a promising prototype for schistosomiasis treatment. Full article

The occurrence of hepatitis E virus (HEV) in patients with Schistosomiasis mansoni (SM) is still poorly understood in Brazil. The objective of this study was to estimate the seroprevalence of anti-HEV IgG in patients with SM and its association with the periportal fibrosis (PPF), assessed by serum markers and ultrasound criteria. This cross-sectional study was carried out in an endemic area in Pernambuco, Brazil, with schistosomal patients who underwent coproscopic survey. Anti-HEV antibody IgG were evaluated by using ELISA (Euroimmun^®, Lübeck, Germmany). In positive cases, HEV-RNA was tested by using real-time PCR. Among the 286 patients (60.8% women; 56% 18–44 years), 116 (40.6%) had advanced PPF (Niamey pattern D/E/F). Anti-HEV IgG was positive in 15 (5.24%), and all were HEV-RNA negative. Anti-HEV IgG was more frequent in patients with an advanced PPF (D/E/F) pattern (p = 0.034) and those with the largest spleen diameter (p = 0.039). In this study, the occurrence of anti-HEV IgG in patients with SM was higher than described in the same region and more frequent among patients with evidence of advanced liver fibrosis. Full article

Ψ-1,4-naphthoquinones (Ψ-NQ) are non-quinoid compounds in which aromaticity—found in 1,4-naphthoquinones—is broken by the introduction of an angular methyl at C-4a or -8a. This series was designed to act as prodrugs of 1,4-naphthoquinones in an oxidative environment. Furthermore, from a medicinal chemistry point of view, the loss of planarity of the scaffold might lead to an improved solubility and circumvent the bad reputation of quinones in the pharmaceutical industry. In this work, we illustrated the concept by the synthesis of Ψ -plasmodione regioisomers as prodrugs of the antimalarial plasmodione. The presence of a chiral center introduces a new degree of freedom to be controlled by enantioselectivity and regioselectivity of the cycloaddition in the Diels–Alder reaction. The first strategy that was followed was based on the use of a chiral enantiopure sulfoxide to govern the stereoselective formation of (+)Ψ-NQ or (−)Ψ-NQ, depending on the chirality of the sulfoxide (R or S). New sulfinylquinones were synthesized but were found to be ineffective in undergoing cycloaddition with different dienes under a wide range of conditions (thermal, Lewis acid). The second strategy was based on the use of boronic acid-substituted benzoquinones as auxiliaries to control the regioselectivity. Using this methodology to prepare the (±)Ψ-NQ racemates, promising results (very fast cycloaddition time: ~2 h) were obtained with boronic acid-based quinones 25 and 27 in the presence of 1-methoxy-1,3-butadiene, to generate the 4a- and the 8a-Ψ-plasmodione regioisomers 1 and 2 (synthesized in six steps with a total yield of 10.5% and 4.1%, respectively. As the expected prodrug effect can only be revealed if the molecule undergoes an oxidation of the angular methyl, e.g., in blood-feeding parasites that digest hemoglobin from the host, the antimalarial and the antischistosomal properties of both (±)Ψ-NQ regioisomers were determined in drug assays with Plasmodium falciparum and Schistosoma mansoni. Metabolic studies under quasi-physiological conditions and LC-MS analyses were undertaken to reveal the generation of plasmodione from both the 4a- and the 8a-Ψ-plasmodione regioisomers. Full article

Rhizophora mangle is commonly used in traditional medicine to treat infections, reduce inflammation, and promote healing. This study aimed to analyze the phytochemical profile of the methanolic extract of R. mangle leaves (MELRm) and evaluate its in vitro schistosomicidal activity against Schistosoma mansoni as well as its cytotoxicity. Plant material was collected in Itamaracá City, Pernambuco, Brazil. The extract was analyzed using UV/Vis spectrophotometry and high-performance liquid chromatography (HPLC). The motility, mortality, and cell viability of adult worms were assessed in a schistosomicidal assay, while cytotoxicity was evaluated through a colorimetric assay with MTT on RAW 264.7 cells. The primary compounds identified in MELRm were phenolic compounds. In the schistosomicidal assay, all concentrations of MELRs induced changes in the motility of adult worms. At a concentration of 400 μg/mL, MELRs resulted in 56.25% mortality after 72 h of incubation. After 120 h, mortality rates of 75%, 62.5%, and 50% were observed at MELRm concentrations of 400, 200, and 100 μg/mL, respectively. No eggs were detected at any MELRm concentration. MELRs did not show cytotoxicity towards RAW 264.7 cells at the concentrations tested. These results indicate that MELRs demonstrate schistosomicidal activity in vitro, suggesting they are promising candidates for in vivo studies. Full article

Schistosomiasis, a neglected tropical disease impacting over 250 million individuals globally, remains a major public health challenge due to its prevalence and significant impact on affected communities. Praziquantel, the sole available treatment, highlights the urgency of the need for novel anthelmintic agents to achieve the World Health Organization (WHO) goal of schistosomiasis elimination. Previous studies reported the promising antiparasitic activity of different terpenoids against Schistosoma mansoni Sambon (Diplostomida: Schistosomatidae). In the present work, the hexane extract from branches of Drimys brasiliensis afforded a diastereomeric mixture of endoperoxide sesquiterpenes, including 3,6-epidioxy-bisabola-1,10-diene (EDBD). This compound was evaluated in vitro and in vivo against S. mansoni. EDBD exhibited a significant reduction in S. mansoni viability in vitro, with an effective concentration (EC₅₀) value of 4.1 µM. Additionally, EDBD demonstrated no toxicity to mammalian cells. In silico analysis predicted good drug-likeness properties, adhering to pharmaceutical industry standards, including favorable ADME profiles. Furthermore, oral treatment of S. mansoni-infected mice with EDBD (400 mg/kg) resulted in a remarkable egg burden reduction (98% and 99% in tissues and feces, respectively) surpassing praziquantel’s efficacy. These findings suggest the promising potential of EDBD as a lead molecule for developing a novel schistosomiasis treatment. Full article

The burden of human schistosomiasis, a known but neglected tropical disease in Sub-Saharan Africa, has been worrisome in recent years. It is becoming increasingly difficult to tackle schistosomiasis with praziquantel, a drug known to be effective against all Schistosoma species, due to reports of reduced efficacy and resistance. Therefore, this study seeks to investigate the antischistosomal potential of phytochemicals from Azadirachta indica against proteins that have been implicated as druggable targets for the treatment of schistosomiasis using computational techniques. In this study, sixty-three (63) previously isolated and characterized phytochemicals from A. indica were identified from the literature and retrieved from the PubChem database. In silico screening was conducted to assess the inhibitory potential of these phytochemicals against three receptors (Schistosoma mansoni Thioredoxin glutathione reductase, dihydroorotate dehydrogenase, and Arginase) that may serve as therapeutic targets for schistosomiasis treatment. Molecular docking, ADMET prediction, ligand interaction, MMGBSA, and molecular dynamics simulation of the hit compounds were conducted using the Schrodinger molecular drug discovery suite. The results show that Andrographolide possesses a satisfactory pharmacokinetic profile, does not violate the Lipinski rule of five, binds with favourable affinity with the receptors, and interacts with key amino acids at the active site. Importantly, its interaction with dihydroorotate dehydrogenase, an enzyme responsible for the catalysis of the de novo pyrimidine nucleotide biosynthetic pathway rate-limiting step, shows a glide score and MMGBSA of −10.19 and −45.75 Kcal/mol, respectively. In addition, the MD simulation shows its stability at the active site of the receptor. Overall, this study revealed that Andrographolide from Azadirachta indica could serve as a potential lead compound for the development of an anti-schistosomal drug. Full article

Schistosomiasis, acquired by skin-penetrating cercariae of dioecious digenean schistosomes during freshwater contact, afflicts nearly 260 and 440 million people with active infections and residual morbidity, respectively. About 10 million women at reproductive age contract schistosomiasis during gestation every year. Acute schistosomiasis is characterized by pre-patent pro-inflammatory CD4+ T-helper 1 or CD4+ Th1/T-helper 17 reactivity against immature schistosomulae. Chronic schistosomiasis is dominated by post-patent anti-inflammatory CD4+ T-helper 2 reactivity against ova epitopes. Flukes co-exist in immunocompetent definitive hosts as they are capable of evading their defense mechanisms. Preventive measures should be complemented by vaccination, inducing long-term protection against transmission, infection, and disease recurrence, given the latest advancements in schistosomal vaccines. Vaccines become pivotal when considering constraints of chemotherapy, i.e., lack of protection against re-infection, and evolving resistance or reduced sensitivity. Transmission models for human non-zoonotic schistosomiasis incorporating vaccination available in PubMed, Embase and Web of Science up to 31 December 2023 are presented. Besides conceptual model differences, predictions meant to guide decision- and policymaking reveal continued worm harboring that facilitates transmission besides residual infections. In addition, increased susceptibility to re-infection and rebound morbidity, both shifted to later life stages following the intervention, are forecasted. Consequently, a vaccination schedule is pivotal that considers the optimal age for initial immunization, i.e., pre-schoolchildren or schoolchildren in a cohort-based or population-based manner, while incorporating potential non-adherers promoting ongoing transmission. Longevity over magnitude of vaccine protection to antigenic schistosomal moieties is crucial. Accounting for pre-acquired immunity from natural exposure, in utero priming in addition to herd immunity, and induced by chemotherapy is crucial. Combining, as a multi-component approach, long-term effects of vaccination with short-term effects of chemotherapy as regular repeated vaccine-linked therapy seems most promising to achieve WHO’s endpoints of transmission elimination and morbidity control. Full article

The existing treatment strategy for Schistosomiasis centers on praziquantel, a single drug, but its effectiveness is limited due to resistance and lack of preventive benefits. Thus, there is an urgent need for novel antischistosomal agents. Schistosoma glutathione S-transferase (GST) is an essential parasite enzyme, with a high potential for targeted drug discovery. In this study, we conducted a screening of compounds possessing antihelminth properties, focusing on their interaction with the Schistosoma mansoni glutathione S-transferase (SmGST) protein. We demonstrated the unique nature of SmGST in comparison to human GST. Evolutionary analysis indicated its close relationship with other parasitic worms, setting it apart from free-living worms such as C. elegans. Through an assessment of binding pockets and subsequent protein–ligand docking, we identified Scutiaquinone A and Scutiaquinone B, both naturally derived Perylenequinones, as robust binders to SmGST. These compounds have exhibited effectiveness against similar parasites and offer promising potential as antischistosomal agents. Full article

Malaria and schistosomiasis are two of the neglected tropical diseases that persistently wreak havoc worldwide. Although many antimalarial drugs such as chloroquine are readily available, the emergence of drug resistance necessitates the development of new therapies to combat this disease. Conversely, Praziquantel (PZQ) remains the sole effective drug against schistosomiasis, but its extensive use raises concerns about the potential for drug resistance to develop. In this project, the concept of molecular hybridization was used as a strategy to design the synthesis of new molecular hybrids with potential antimalarial and antischistosomal activity. A total of seventeen molecular hybrids and two PZQ analogues were prepared by coupling 6-alkylpraziquanamines with cinnamic acids and cyclohexane carboxylic acid, respectively. The synthesised compounds were evaluated for their antimalarial and antischistosomal activity; while all of the above compounds were inactive against Plasmodium falciparum (IC₅₀ > 6 µM), many were active against schistosomiasis with four particular compounds exhibiting up to 100% activity against newly transformed schistosomula and adult worms at 50 µM. Compared to PZQ, the reference drug, the activity of which is 91.7% at 1 µM, one particular molecular hybrid, compound 32, which bears a para-isopropyl group on the cinnamic acid moiety, exhibited a notable activity at 10 µM (78.2% activity). This compound has emerged as the front runner candidate that might, after further optimization, hold promise as a potential lead compound in the fight against schistosomiasis. Full article

A synthesis of bridged 1,2,4-trioxolanes (bridged ozonides) from 1,5-diketones and hydrogen peroxide catalyzed by SnCl₄ was developed. It was shown that the ratio of target ozonides can be affected by the application of SnCl₄ as a catalyst and varying the solvent. A wide range of bridged 1,2,4-trioxolanes (ozonides) was obtained in yields from 50 to 84%. The ozonide cycle was moderately resistant to the reduction of the ester group near the peroxide cycle to alcohol with LiAlH₄. The bridged ozonides were evaluated for their antischistosomal activity. These ozonides exhibited a very high activity against newly transformed schistosomula and adult Schistosoma mansoni. Full article

Schistosomiasis is a neglected tropical disease with a significant socioeconomic impact. It is caused by several species of blood trematodes from the genus Schistosoma, with S. mansoni being the most prevalent. Praziquantel (PZQ) is the only drug available for treatment, but it is vulnerable to drug resistance and ineffective in the juvenile stage. Therefore, identifying new treatments is crucial. SmHDAC8 is a promising therapeutic target, and a new allosteric site was discovered, providing the opportunity for the identification of a new class of inhibitors. In this study, molecular docking was used to screen 13,257 phytochemicals from 80 Saudi medicinal plants for inhibitory activity on the SmHDAC8 allosteric site. Nine compounds with better docking scores than the reference were identified, and four of them (LTS0233470, LTS0020703, LTS0033093, and LTS0028823) exhibited promising results in ADMET analysis and molecular dynamics simulation. These compounds should be further explored experimentally as potential allosteric inhibitors of SmHDAC8. Full article

Schistosomiasis is one of the most important neglected tropical diseases. Until an effective vaccine is registered for use, the cornerstone of schistosomiasis control remains chemotherapy with praziquantel. The sustainability of this strategy is at substantial risk due to the possibility of praziquantel insensitive/resistant schistosomes developing. Considerable time and effort could be saved in the schistosome drug discovery pipeline if available functional genomics, bioinformatics, cheminformatics and phenotypic resources are systematically leveraged. Our approach, described here, outlines how schistosome-specific resources/methodologies, coupled to the open-access drug discovery database ChEMBL, can be cooperatively used to accelerate early-stage, schistosome drug discovery efforts. Our process identified seven compounds (fimepinostat, trichostatin A, NVP-BEP800, luminespib, epoxomicin, CGP60474 and staurosporine) with ex vivo anti-schistosomula potencies in the sub-micromolar range. Three of those compounds (epoxomicin, CGP60474 and staurosporine) also demonstrated potent and fast-acting ex vivo effects on adult schistosomes and completely inhibited egg production. ChEMBL toxicity data were also leveraged to provide further support for progressing CGP60474 (as well as luminespib and TAE684) as a novel anti-schistosomal compound. As very few compounds are currently at the advanced stages of the anti-schistosomal pipeline, our approaches highlight a strategy by which new chemical matter can be identified and quickly progressed through preclinical development. Full article