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1.
J Enzyme Inhib Med Chem ; 37(1): 1479-1494, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35635137

RESUMO

The almost empty armamentarium to treat schistosomiasis, a neglected parasitic disorder caused by trematode flatworms of the genus Schistosoma, except Praziquantel (PZQ), urged to find new alternatives to fight this infection. Carbonic Anhydrase from Schistosoma mansoni (SmCA) is a possible new target against this nematode. Here, we propose new PZQ derivatives bearing a primary sulphonamide group in order to obtain hybrid drugs. All compounds were evaluated for their inhibition profiles on both humans and Schistosoma CAs, X-ray crystal data of SmCA and hCA II in adduct with some inhibitors were obtained allowing the understanding of the main structural factors responsible of activity. The compounds showed in vitro inhibition of immature and adult S. mansoni, but further optimisation is required for improved activity.


Assuntos
Anidrases Carbônicas , Esquistossomicidas , Animais , Humanos , Praziquantel/química , Praziquantel/farmacologia , Schistosoma mansoni , Esquistossomicidas/farmacologia , Sulfanilamida , Sulfonamidas/farmacologia
2.
Exp Parasitol ; 238: 108260, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35447136

RESUMO

OBJECTIVE: This study aimed to evaluate the efficacy of gamma-aminobutyric acid (GABA) alone or combined with praziquantel (PZQ) against Schistosoma (S) mansoni infection in a murine model. METHODS: Five groups, 8 mice each, were studied; GI served as normal controls; GII: S. mansoni-infected control group and the other three S. mansoni-infected groups received drug regimens for 5 consecutive days as follows GIII: Infected-PZQ treated group (200 mg/kg/day); GIV: Infected-GABA treated group (300 mg/kg/day) and GV: Infected-PZQ-GABA treated group (100 mg/kg/day for each drug). All animal groups were sacrificed two weeks later and different parasitological, histopathological and biochemical parameters were assessed. RESULTS: Combined GABA-PZQ treated group recorded the highest significant reduction in all parasitological, histopathological and biochemical parameters followed by PZQ and finally GABA groups. Combined GABA-PZQ treatment led to the complete disappearance of immature eggs and marked reduction of deposited eggs in liver tissues and improved liver pathology. Significant improvement in hepatic oxidative stress levels, serum albumin and total protein in response to GABA treatment alone or combined with PZQ. CONCLUSION: GABA had schistosomicidal, hepatoprotective and antioxidant activities against S. mansoni infection, GABA disrupted parasite pairing and activity, reduced the total number of worms recovered and the number of ova in the tissues. GABA may be considered an adjuvant therapy to potentiate PZQ antiparasitic activity and eradicate infection-induced liver damage and oxidative stress.


Assuntos
Anti-Helmínticos , Esquistossomose mansoni , Esquistossomicidas , Animais , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Modelos Animais de Doenças , Fígado/parasitologia , Camundongos , Praziquantel/farmacologia , Praziquantel/uso terapêutico , Schistosoma mansoni , Esquistossomose mansoni/patologia , Esquistossomicidas/farmacologia , Esquistossomicidas/uso terapêutico , Ácido gama-Aminobutírico/uso terapêutico
3.
Chem Biodivers ; 19(2): e202100909, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35020262

RESUMO

This review article covers literature on the antischistosomal activity of essential oils (EOs) between 2011 and 2021. Criteria for classifying results from in vitro schistosomicidal assays are proposed for the first time. Parameters to evaluate the in vitro antischistosomal potential of EOs other than their ability to cause the death of Schistosoma mansoni adult worms (e. g., couple separation, egg laying, and egg development inhibition) are also addressed and discussed.


Assuntos
Óleos Voláteis , Esquistossomicidas , Animais , Óleos Voláteis/farmacologia , Schistosoma mansoni , Esquistossomicidas/farmacologia
4.
Chem Biodivers ; 19(2): e202100948, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34882967

RESUMO

Schistosomiasis, a tropical disease caused by flatworms, may affect the liver, spleen, bladder, and intestine. Casearia sylvestris Swartz, a medicinal plant, displays antiprotozoal, antimicrobial, antifungal, and antiulcer activities. We have evaluated the in vitro schistosomicidal activity of two C. sylvestris varieties against Schistosoma mansoni adult worms at concentrations between 12.5 and 200 µg/mL. At 100 and 200 µg/mL, the ethanolic C. sylvestris var. sylvestris leaf extract enriched in casearin-like diterpenes eliminated 100 % of the parasites after incubation for 72 h and 48 h, respectively, whilst the same extract at 200 µg/mL eliminated 96 %, 100 %, and 100 % of the parasites after incubation for 24, 48, and 72 h, respectively. On the other hand, the hydroalcoholic C. sylvestris var. lingua leaf extract at 200 µg/mL eliminated 60.4 and 66.7 % of the parasites after incubation for 48 and 72 h, respectively. The presence of casearin-like diterpenes and glycosylated flavonoids was confirmed based on chromatographic techniques and mass spectrometry data.


Assuntos
Casearia , Diterpenos , Plantas Medicinais , Esquistossomicidas , Casearia/química , Extratos Vegetais/química , Esquistossomicidas/farmacologia
5.
J Biomol Struct Dyn ; 40(3): 995-1009, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-32924851

RESUMO

Schistosomiasis is a neglected disease of considerable health importance in tropical and subtropical regions. Its treatment relies on the use of praziquantel or oxamniquine but there are reported cases of treatment failures due to resistance or tolerance. Again, derivatives of praziquantel and oxamniquine have not shown significant activities than their parent compounds. The study predicted approved drugs with possible antischistosomal activities. Four schistosomal drug targets were obtained from Protein Data Bank and six hundred and twelve (612) approved drugs including their isomers were selected based on their Molinspiration® bioscore similarities with reference compounds (praziquantel, oxamniquine, [(2S,3S,4S,5S,6S)-3,4,5-triacetyloxy-6-sulfanyloxan-2-yl] methyl acetate, [propylamino-3-hydroxy-buta-1,4-dionyl]-isoleucylproline). The selected drugs and drug targets were obtained and prepared for molecular docking simulations. The molecular docking simulations were performed using AutoDockvina®-1.1.2 after validation of docking protocols while molecular dynamics simulations were performed with GROMACS-4.5.5. The binding energies were calculated using MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area). Tolmetin was predicted as potential antischistosomal drug with binding energies of -231.064 ± 18.550 and -338.636 ± 36.900 KJ/mol for sulfotransferase and thioredoxin glutathione reductase (TGR) respectively. Also diflunisal was predicted as potential antischistosomal drug with binding energies of -168.641 ± 20.370 and -290.117 ± 43.800 KJ/mol for sulfotransferase and TGR respectively. Non-covalent interactions and conformational changes were responsible for molecular recognitions and specificities and average bond measurement showed that carboxylic functional groups in diflunisal and tolmetin may interact covalently with -SH group of Cys159 in TGR. Confirmation of covalent interactions and in vitro validations are recommended.Communicated by Ramaswamy H. Sarma.


Assuntos
Esquistossomose , Esquistossomicidas , Reposicionamento de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Oxamniquine/química , Oxamniquine/uso terapêutico , Esquistossomose/tratamento farmacológico , Esquistossomicidas/farmacologia , Esquistossomicidas/uso terapêutico
6.
Sci Rep ; 11(1): 23437, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34873205

RESUMO

Praziquantel is the only available drug to treat schistosomiasis, a parasitic disease that currently infects more than 240 million people globally. Due to increasing concerns about resistance and inadequate efficacy there is a need for new therapeutics. In this study, a series of 17 pyrazolines (15-31) and three pyrazoles (32-34) were synthesized and evaluated for their antiparasitic properties against ex vivo adult Schistosoma mansoni worms. Of the 20 compounds tested, six had a 50% effective concentration (EC50) below 30 µM. Our best hit, pyrazoline 22, showed promising activity against adult schistosomes, with an EC50 < 10 µM. Additionally, compound 22 had low cytotoxicity, with selectivity index of 21.6 and 32.2 for monkey and human cell lines, respectively. All active pyrazolines demonstrated a negative effect on schistosome fecundity, with a marked reduction in the number of eggs. Structure-activity relationship analysis showed that the presence of the non-aromatic heterocycle and N-substitution are fundamental to the antischistosomal properties. Pharmacokinetics, drug-likeness and medicinal chemistry friendliness studies were performed, and predicted values demonstrated an excellent drug-likeness profile for pyrazolines as well as an adherence to major pharmaceutical companies' filters. Collectively, this study demonstrates that pyrazoline derivatives are promising scaffolds in the discovery of novel antischistosomal agents.


Assuntos
Pirazóis/química , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/parasitologia , Esquistossomicidas/farmacologia , Animais , Antiparasitários/farmacologia , Chalconas/química , Química Farmacêutica/métodos , Chlorocebus aethiops , Simulação por Computador , Descoberta de Drogas , Haplorrinos , Humanos , Camundongos , Praziquantel/farmacologia , Solventes , Relação Estrutura-Atividade , Sais de Tetrazólio/química , Tiazóis/química , Células Vero
7.
Parasit Vectors ; 14(1): 550, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34702326

RESUMO

BACKGROUND: Schistosomiasis is a debilitating and neglected tropical disease for which praziquantel (PZQ) remains the first-choice drug for treatment and control of the disease. In our previous studies, we found that the patented compound DW-3-15 (patent no. ZL201110142538.2) displayed significant and stabilized antiparasitic activity through a mechanism that might be distinct from PZQ. Here, we investigated the antischistosomal efficacy of PZQ combined with DW-3-15 against schistosomula and adult worms of Schistosoma japonicum in vitro and in vivo, to verify whether there was a synergistic effect of the two compounds. METHODS: The antischistosomal efficacy of PZQ combined with DW-3-15 in comparison with an untreated control and monotherapy group against schistosomula and adult worms was assessed both in vitro and in vivo. Parasitological studies, scanning electron microscopy, combination index, and histopathological analysis were used for the assessment. RESULTS: The results showed significantly reduced viability of schistosomes, achieving 100% viability reduction for juveniles and males by combination chemotherapy using PZQ together with DW-3-15 in vitro. The combination index was 0.28, 0.27, and 0.53 at the higher concentration of PZQ combined with DW-3-15 against juveniles, males, and females, respectively, indicating that the two compounds display strong synergism. Scanning electron microscopy observations also demonstrated that the compound combination induced more severe and extensive alterations to the tegument and subtegument of S. japonicum than those with each compound alone. In vivo, compared with the single-compound-treated group, the group treated with the higher-dose combination demonstrated the best schistosomicidal efficacy, with significantly reduced worm burden, egg burden, and granuloma count and area, which was evident against schistosomula and adult worms. CONCLUSIONS: Our study provides a potential novel chemotherapy for schistosomiasis caused by S. japonicum. It would improve the antischistosomal effect on schistosomula and adult worms of S. japonicum, and decrease individual dosages.


Assuntos
Quimioterapia Combinada/métodos , Praziquantel/farmacologia , Praziquantel/uso terapêutico , Schistosoma japonicum/efeitos dos fármacos , Esquistossomicidas/farmacologia , Esquistossomicidas/uso terapêutico , Animais , Sinergismo Farmacológico , Feminino , Camundongos Endogâmicos ICR , Contagem de Ovos de Parasitas
8.
Arch Pharm (Weinheim) ; 354(12): e2100259, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34523746

RESUMO

Schistosomiasis is a neglected tropical disease caused by blood flukes of the genus Schistosoma and causes severe morbidity in infected patients. In 2018, 290.8 million people required treatment, and 200,000 deaths are reported per year. Treatment of this disease depends on a single drug, praziquantel (PZQ). However, in the past few years, reduced sensitivity of the parasites toward PZQ has been reported. Therefore, there is an urgent need for new drugs against this disease. In the past few years, we have focused on a new substance class called biaryl alkyl carboxylic acid derivatives, which showed promising antischistosomal activity in vitro. Structure-activity relationship (SAR) studies of the carboxylic acid moiety led to three promising carboxylic amides (morpholine, thiomorpholine, and methyl sulfonyl piperazine) with an antischistosomal activity down to 10 µM (morpholine derivative) and no cytotoxicity up to 100 µM. Here, we show our continued work on this substance class. We investigated, in extended SAR studies, whether modification of the linker and the thiophene ring could improve the antischistosomal activity. We found that the exchange of the alkyl linker by a pentadienyl or benzyl linker was tolerated and led to similar antischistosomal effects, whereas the exchange of the thiophene ring was not tolerated. Our data suggest that the thiophene ring is important for the antischistosomal activity of this compound class.


Assuntos
Ácidos Carboxílicos/farmacologia , Schistosoma/efeitos dos fármacos , Esquistossomicidas/farmacologia , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Feminino , Masculino , Esquistossomose/tratamento farmacológico , Esquistossomicidas/síntese química , Esquistossomicidas/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologia
9.
Acta Trop ; 222: 106044, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34273313

RESUMO

In this study we evaluated the in vitro effect of divaricatic acid against coupled worms of Schistosoma mansoni. The schistosomicidal effect was evaluated through the bioassay of motility and mortality, cellular viability of the worms and ultrastructural analysis through Scanning Electron Microscopy. To evaluate the cytotoxicity of divaricatic acid, a cell viability assay was performed with human peripheral blood mononuclear cells. Divaricatic acid proved effect against S. mansoni after 3 hours of exposure. At the end of 24 h the concentrations of 100 - 200 µM presented lethality to the worms. Motility changes were observed at sublethal concentrations. The IC50 obtained by the cell viability assay for S. mansoni was 100.6 µM (96.24 - 105.2 µM). Extensive damage to the worm's tegument was observed such as peeling, erosion, bubbles, edema, damage and loss of tubercles and spines, fissures and tissue ruptures. No cytotoxicity was observed in human peripheral blood mononuclear cells. This report provides data showing the schistosomicidal effect of divaricatic acid on S. mansoni, causing death, motile changes and ultrastructural damage to worms. In addition, divaricatic acid was shown to be non-toxic to human peripheral blood mononuclear cells at concentrations effective on S. mansoni.


Assuntos
Depsídeos/farmacologia , Parmeliaceae/química , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas , Animais , Humanos , Leucócitos Mononucleares , Líquens/química , Microscopia Eletrônica de Varredura , Esquistossomicidas/farmacologia
10.
Antimicrob Agents Chemother ; 65(10): e0061521, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34310210

RESUMO

In recent years, N,N'-diarylureas have emerged as a promising chemotype for the treatment of schistosomiasis, a parasite-caused disease that poses a considerable health burden to millions of people worldwide. Here, we report a novel series of N,N'-diarylureas featuring the scarcely explored pentafluorosulfanyl group (SF5). Low 50% inhibitory concentration (IC50) values for Schistosoma mansoni newly transformed schistosomula (0.6 to 7.7 µM) and adult worms (0.1 to 1.6 µM) were observed. Four selected compounds that were highly active in the presence of albumin (>70% at 10 µM), endowed with decent cytotoxicity profiles (selectivity index [SI] against L6 cells >8.5), and good microsomal hepatic stability (>62.5% of drug remaining after 60 min) were tested in S. mansoni-infected mice. Despite the promising in vitro worm-killing potency, none of them showed significant activity in vivo. Pharmacokinetic data showed a slow absorption, with maximal drug concentrations reached after 24 h of exposure. Finally, no direct correlation between drug exposure and in vivo activity was found. Thus, further investigations are needed to better understand the underlying mechanisms of SF5-containing N,N'-diarylureas.


Assuntos
Esquistossomose mansoni , Esquistossomicidas , Animais , Fígado , Camundongos , Schistosoma mansoni , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/farmacologia , Esquistossomicidas/uso terapêutico
11.
PLoS Negl Trop Dis ; 15(5): e0009432, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34033658

RESUMO

BACKGROUND: Anthelminthic treatment options against schistosomiasis are limited. The current treatment relies almost exclusively on a single drug, praziquantel (PZQ). As a consequence, the development of resistance to PZQ and limited activity of PZQ against earlier development stages are respectively a risk and a limitation to achieving the goals of the new WHO roadmap towards elimination. For the discovery of new chemical starting points, the in vitro drug screening on Schistosoma mansoni (S. mansoni) against newly transformed schistosomula (NTS) is still the most predominant approach. The use of only NTS in the initial screening limits sensitivity to potential new compounds which are predominantly active in later developmental stages. Using our recently described highly standardized, straightforward and reliable culture method that generates high rates of juvenile worms, we aimed to repurpose a subset of the National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection (340 compounds) to identify new hits with an in vitro worm culture assay. METHODOLOGY/PRINCIPAL FINDINGS: Cercariae were mechanically transformed into skin-stage (SkS) schistosomula and continuously cultured for 3-6 weeks to the liver stage (LiS). A commercial source of serum was identified, and decrease of NTS/well along with optimal drug testing conditions was established to test compounds on early and late LiS worms. The library was screened in 96-well format assays using praziquantel (PZQ) as a positive control. Primary screening allowed a 5.9% hit rate and generated two confirmed hits on adult worms; a prophylactic antianginal agent and an antihistaminic drug. CONCLUSION: With this standardized and reliable in vitro assay, important S. mansoni developmental stages up to LiS worms can be generated and cultured over an extended period. When exposed to a subset of the NCATS Pharmaceutical Collection, 3 compounds yielded a defined anti-schistosomal phenotype on juvenile worms. Translation of activity on perfused adult S. mansoni worms was achieved only for perhexiline (a prophylactic antianginal agent) and astemizole (an antihistaminic drug).


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas/farmacologia , Animais , Astemizol/farmacologia , Técnicas In Vitro , Perexilina/farmacologia , Schistosoma mansoni/crescimento & desenvolvimento , Esquistossomose mansoni/tratamento farmacológico
12.
Trop Biomed ; 38(1): 22-27, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33797519

RESUMO

This work was carried out to investigate the effect of silymarin combination in the therapeutic plane of schistosomiasis with praziquantel or mirazid to enhance the liver and reduce fibrosis. Mice were divided into 2 main groups, the 1st uninfected group served as control and the 2nd group infected subcutaneously with 60 cercaria of S. mansoni per each. The infected group was subdivided into 5 subgroups, the 1st kept untreated, the 2nd and 3rd treated at the 7th week of infection with (600 mg/kg) of PZQ orally for 3 consecutive days, while the 3rd treated also orally with (150 mg/kg) of silymarin daily for 11 weeks. The 4th and 5th groups treated orally at the 7th week of infection with 600 mg/kg of MZ for 3 consecutive days, while the 5th group treated orally also with 150 mg/kg of silymarin daily for 11weeks. IgG determination showed high level in the untreated infected group. Furthermore, the infected groups treated with PZQ and PZQ with silymarin displayed the lower levels than treated with MZ. Additionally, the untreated infected group showed severe pathological changes as hyaline degeneration, inflammation, presence of worm burdens in dilated portal veins, granulomas as well as depositions of collagenous and reticular fibers indicated intense fibrosis. Treatment with PZQ alone resulted in reduction of pathological signs and decreasing of granulomas. Combination with silymarin to PZQ therapy revealed more improvement for liver besides to lowering of granulomas areas and volumes and decreasing of fibrosis. Whereas, treatment with MZ was less effective than PZQ to reduce granulomas areas, volumes and fibrosis. Although, combination of silymarin to MZ treatment resulted in more curative signs and reduction of granulomas areas, volumes and fibrosis. Furthermore, the present study concluded that PZQ still the more effective drug of schistosomiasis treatment than MZ. The silymarin is very useful in schistosomiasis treatment when combined with PZQ or MZ due to its anti-fibrotic effect.


Assuntos
Praziquantel/farmacologia , Resinas Vegetais/farmacologia , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/farmacologia , Silimarina/farmacologia , Animais , Commiphora , Quimioterapia Combinada , Granuloma/tratamento farmacológico , Granuloma/parasitologia , Fígado/parasitologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/parasitologia , Masculino , Camundongos
13.
Mar Drugs ; 19(5)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922065

RESUMO

Schistosomiasis is a parasitic disease that affects more than 250 million people. The treatment is limited to praziquantel and the control of the intermediate host with the highly toxic molluscicidal niclosamide. Marine algae are a poorly explored and promising alternative that can provide lead compounds, and the use of multivariate analysis could contribute to quicker discovery. As part of our search for new natural compounds with which to control schistosomiasis, we screened 45 crude extracts obtained from 37 Brazilian seaweed species for their molluscicidal activity against Biomphalaria glabrata embryos and schistosomicidal activities against Schistosoma mansoni. Two sets of extracts were taxonomically grouped for metabolomic analysis. The extracts were analyzed by GC-MS, and the data were subjected to Pattern Hunter and Pearson correlation tests. Overall, 22 species (60%) showed activity in at least one of the two models. Multivariate analysis pointed towards 3 hits against B. glabrata veliger embryos in the Laurencia/Laurenciella set, 5 hits against B. glabrata blastula embryos, and 31 against S. mansoni in the Ochrophyta set. Preliminary annotations suggested some compounds such as triquinane alcohols, prenylated guaianes, dichotomanes, and xenianes. Despite the putative identification, this work presents potential candidates and can guide future isolation and identification.


Assuntos
Biomphalaria/efeitos dos fármacos , Bioprospecção , Descoberta de Drogas , Moluscocidas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/prevenção & controle , Esquistossomicidas/farmacologia , Alga Marinha/metabolismo , Animais , Biomphalaria/parasitologia , Brasil , Metaboloma , Metabolômica , Moluscocidas/isolamento & purificação , Schistosoma mansoni/crescimento & desenvolvimento , Esquistossomose mansoni/parasitologia , Esquistossomicidas/isolamento & purificação
14.
Future Med Chem ; 13(11): 945-957, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33896196

RESUMO

Background: Praziquantel is the only drug available to treat schistosomiasis, and there is an urgent demand for new anthelmintic agents. Methodology & results: We conducted in-depth in vitro and in vivo studies and report a target fishing investigation. In vitro, tamoxifen was active against adult and immature worms at low concentrations (<5 µM). Tamoxifen at a single dose (400 mg/kg) or once daily for five consecutive days (100 mg/kg/day) in mice harboring either adult (patent infection) or juvenile (prepatent infection) significantly reduced worm burden (30-70%) and egg production (70-90%). Target fishing studies revealed propionyl-CoA carboxylase as a potential target for tamoxifen in Schistosoma mansoni and glucose uptake by S. mansoni was also significantly reduced. Conclusion: Our results provide news evidence of antiparasitic effect of tamoxifen and reveal propionyl-CoA carboxylase as a potential target.


Assuntos
Schistosoma mansoni/efeitos dos fármacos , Esquistossomose/tratamento farmacológico , Esquistossomicidas/farmacologia , Tamoxifeno/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Esquistossomicidas/química , Tamoxifeno/química
15.
Drug Dev Ind Pharm ; 47(4): 663-672, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33826458

RESUMO

WHO considers praziquantel (PZQ) as the drug of choice for treatment of Schistosoma mansoni infection but this requires high dose due to poor solubility and first pass metabolism. The aim of this work was to optimize nanostructured lipid carriers (NLCs) for enhanced PZQ oral delivery. The optimization involved testing the effect of surface charge of NLCs. NLCs comprised precirol ATO as solid lipid with oleic acid, Span 60 and Tween 80 as liquid components. Dicetyl phosphate and stearyl amine were the negative and positive charging agents, respectively. NLCs were prepared by microemulsification technique and were characterized. The schistosomicidal activity of PZQ loaded NLCs was monitored in vitro and in vivo using infected mice. PZQ showed high entrapment efficiency in all types of NLCs (ranged from 93.97 to 96.29%) with better PZQ loading in standard NLCs. This was clarified by thermal analysis which reflected displacement of PZQ by charging agents. In vitro schistosomicidal study revealed the superiority of PZQ loaded positively charged NLCs (LC50 and LC95 equal 0.147 and 0.193 µg/ml respectively) with traditional and negatively charged NLCs being inferior to simple PZQ solution after short incubation period. Scanning electron micrographs showed that PZQ loaded positively charged NLCs resulted in more intense ultrastructural changes in worms. The superiority of positively charged NLCs was confirmed by in vivo assessment as they showed better improvement in histopathological features of the liver of the infected mice compared with other formulations. The study introduced positively charged NLCs as promising carriers for oral delivery of PZQ.


Assuntos
Nanoestruturas , Esquistossomicidas , Animais , Portadores de Fármacos , Lipídeos , Camundongos , Praziquantel/farmacologia , Esquistossomicidas/farmacologia
16.
Acta Trop ; 218: 105909, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33789153

RESUMO

Schistosomiasis is an infectious disease caused by helminth parasites of the genus Schistosoma; it is transmitted in over 78 countries. The main strategy for schistosomiasis control is treatment of infected people with praziquantel (PZQ). As PZQ-resistant strains have emerged, new anti-schistosomal agents have become necessary. We evaluated the in vitro and in vivo effect of P-MAPA, an aggregated polymer of protein magnesium ammonium phospholinoleate-palmitoleate anhydride with immunomodulatory properties; it is produced by Aspergillus oryzae fermentation. In vitro, P-MAPA (5, 50, and 100 µg/mL) damaged the Schistosoma mansoni tegument, causing thorn losses and tuber destruction in male worms and peeling and erosion in females after 24-h incubation. In vivo, P-MAPA (5 and 100 mg/kg, alone and combined with PZQ - 50 mg/kg) reduced the number of eggs by up to 69.20% in the liver and 88.08% in the intestine. Furthermore, granulomas were reduced up to 83.13%, and there was an increase in the number of dead eggs and a reduction of serum aspartate aminotransferase levels. These data suggest that P-MAPA activity can help improve schistosomiasis treatment and patients' quality of life.


Assuntos
Ácidos Linoleicos/farmacologia , Ácidos Oleicos/farmacologia , Praziquantel/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Animais , Feminino , Granuloma/tratamento farmacológico , Granuloma/patologia , Humanos , Fatores Imunológicos/farmacologia , Intestinos/parasitologia , Fígado/parasitologia , Fígado/patologia , Masculino , Camundongos , Compostos Organofosforados , Esquistossomicidas/farmacologia
17.
Acta Trop ; 213: 105741, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33159900

RESUMO

Schistosomiasis is a neglected disease caused by helminth flatworms of the genus Schistosoma, affecting over 240 million people in more than 70 countries. The treatment relies on a single drug, praziquantel, making urgent the discovery of new compounds. Aurones are a natural type of flavonoids that display interesting pharmacological activities, particularly as chemotherapeutic agents against parasites. In pursuit of treatment alternatives, the present work conducted an in vitro and in vivo antischistosomal investigation with aurone derivatives against Schistosoma mansoni. After preparation of aurone derivatives and their in vitro evaluation on adult schistosomes, the three most active aurones were evaluated in cytotoxicity and haemolytic assays, as well as in confocal laser-scanning microscope studies, showing tegumental damage in parasites in a concentration-dependent manner with no haemolytic or cytotoxic potential toward mammalian cells. In a mouse model of schistosomiasis, at a single oral dose of 400 mg/kg, the selected aurones showed worm burden reductions of 35% to 65.0% and egg reductions of 25% to 70.0%. The most active thiophenyl aurone derivative 18, unlike PZQ, had efficacy in mice harboring juvenile S. mansoni, also showing significant inhibition of oviposition by parasites, giving support for the antiparasitic potential of aurones as lead compounds for novel antischistosomal drugs.


Assuntos
Benzofuranos/farmacologia , Flavonoides/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Flavonoides/uso terapêutico , Camundongos , Testes de Sensibilidade Parasitária , Praziquantel/uso terapêutico , Esquistossomose mansoni/parasitologia , Esquistossomicidas/uso terapêutico
18.
Parasitol Res ; 120(4): 1321-1333, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33164156

RESUMO

Schistosomiasis, caused by a blood fluke of the genus Schistosoma, afflicts over 230 million people worldwide. Treatment of the disease relies on just one drug, praziquantel. Cnicin (Cn) is the sesquiterpene lactone found in blessed thistle (Centaurea benedicta) that showed antiparasitic activities but has not been evaluated against Schistosoma. However, cnicin has poor water solubility, which may limit its antiparasitic activities. To overcome these restrictions, inclusion complexes with cyclodextrins may be used. In this work, we evaluated the in vitro and in vivo antischistosomal activities of cnicin and its complexes with ß-cyclodextrin (ßCD) and 2-hydroxypropyl-ß-cyclodextrin (HPßCD) against Schistosoma mansoni. Cnicin were isolated from C. benedicta by chromatographic fractionation. Complexes formed by cnicin and ßCD (Cn/ßCD), as well as by cnicin and HPßCD (Cn/HPßCD), were prepared by coprecipitation and characterized. In vitro schistosomicidal assays were used to evaluate the effects of cnicin and its complexes on adult schistosomes, while the in vivo antischistosomal assays were evaluated by oral and intraperitoneal routes. Results showed that cnicin caused mortality and tegumental alterations in adult schistosomes in vitro, also showing in vivo efficacy after intraperitoneal administration. The oral treatment with cnicin or Cn/ßCD showed no significant worm reductions in a mouse model of schistosomiasis. In contrast, Cn/HPßCD complex, when orally or intraperitoneally administered to S. mansoni-infected mice, decreased the total worm load, and markedly reduced the number of eggs, showing high in vivo antischistosomal effectiveness. Permeability studies, using Nile red, indicated that HPßCD complex may reach the tegument of adult schistosomes in vivo. These results demonstrated the antischistosomal potential of cnicin in preparations with HPßCD.


Assuntos
Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/farmacologia , Sesquiterpenos/farmacologia , 2-Hidroxipropil-beta-Ciclodextrina , Administração Oral , Animais , Centaurea/química , Modelos Animais de Doenças , Composição de Medicamentos , Fezes/parasitologia , Feminino , Injeções Intraperitoneais , Masculino , Camundongos , Contagem de Ovos de Parasitas , Carga Parasitária , Permeabilidade , Praziquantel/farmacologia , Praziquantel/uso terapêutico , Esquistossomose mansoni/parasitologia , Esquistossomicidas/administração & dosagem , Esquistossomicidas/química , Esquistossomicidas/farmacocinética , Sesquiterpenos/administração & dosagem , Sesquiterpenos/química , Sesquiterpenos/farmacocinética , Solubilidade , beta-Ciclodextrinas
19.
ACS Infect Dis ; 7(5): 1032-1043, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32786285

RESUMO

Praziquantel is the only widely available drug to treat schistosomiasis. With very few candidates currently in the drug development pipeline, there is an urgent need to discover and develop novel antischistosomal drugs. In this regard, the pyrido[1,2-a]benzimidazole (PBI) scaffold has emerged as a promising chemotype in hit-to-lead efforts. Here, we report a novel series of antischistosomal PBIs with potent in vitro activity (IC50 values of 0.08-1.43 µM) against Schistosoma mansoni newly transformed schistosomula and adult worms. Moreover, the current PBIs demonstrated good hepatic microsomal stability (>70% of drug remaining after 30 min) and were nontoxic to the Chinese hamster ovarian and human liver HepG2 cells, though toxicity (selectivity index, SI < 10) against the rat L6 myoblast cell line was observed. The compounds showed a small therapeutic window but were efficacious in vivo, exhibiting moderate to high worm burden reductions of 35.8-89.6% in S. mansoni-infected mice.


Assuntos
Esquistossomose mansoni , Esquistossomicidas , Animais , Benzimidazóis/farmacologia , Cricetinae , Camundongos , Fenetilaminas , Schistosoma mansoni , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/farmacologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-33361311

RESUMO

Schistosomiasis poses a serious threat to human health and remains a major tropical and parasitic disease in more than 70 countries. Praziquantel (PZQ) has been the primary treatment for schistosomiasis for nearly 4 decades. However, its efficacy against migratory-stage schistosomula is limited. Radicicol (RAD), a ß-resorcylic acid lactone derived from Paecilomyces sp. strain SC0924, was investigated as an alternative treatment for Schistosoma japonicum In vitro tests showed that within 72 h, RAD (10 µmol/liter) completely killed schistosomula of both skin and liver stages with an efficacy significantly higher than that of PZQ, although it was less potent against adult worms than PZQ. In vivo, RAD reduced worm burdens and liver eggs by 91.18% and 86.01%, respectively, by killing migratory-stage schistosomula. Optical microscopy and scanning electron microscopy revealed that RAD damaged the epiderm and tegument morphology of S. japonicum worms at various stages and altered their motility to different degrees. RAD exhibited schistosomicidal effects at different stages in vitro and in vivo, especially at the migratory stage, implying that its mechanism could be different from that of PZQ. Collectively, these results showed that RAD is promising as a lead for the development of drugs to control the migratory-stage schistosomula of S. japonicum.


Assuntos
Schistosoma japonicum , Esquistossomicidas , Animais , Humanos , Chumbo , Macrolídeos , Praziquantel/farmacologia , Schistosoma mansoni , Esquistossomicidas/farmacologia
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