naphthoquinones and Schistosomiasis-mansoni

Schistosomiasis is the second most prevalent parasitic infectious disease after malaria, which affects millions of people worldwide and causes health and socioeconomic problems. The snail Biomphalaria glabrata is an intermediate host for the helminth, which is the causative agent of schistosomiasis: Schistosoma mansoni. One crucial strategy for controlling the disease is the eradication of the snail host. Niclosamide is the unique molluskicide applied in large-scale control programs, but its selectivity to other species is not adequate. Therefore, there is an urgent need to develop new molluskicides that are inexpensive, safe, and selective. Quinones are ubiquitous, playing important biological roles in fungi, plants, and others. Many synthetic molecules with relevant biological activities that contain the quinone nucleus in their structure are on the market in the therapy of cancer, malaria, or toxoplasmosis, for example. Derivatives of quinones are tools in the development of new molluskicides for Abbott laboratories. In the present work, 3-aryl-2‑hydroxy-1,4-naphthoquinones (ANs) were tested for molluskicide activity against Biomphalaria glabrata. The lethal concentration was determined for 48 h of continuous exposure. The naphthoquinones were found to have molluskicide properties. AN-15 was recorded as the highest mortality. Additionally, this analog exhibited in silico reduced ambient toxicity when compared to niclosamide. The findings of this study demonstrate that 3-aryl-2‑hydroxy-1,4-naphthoquinones are effective for the management of Biomphalaria glabrata under laboratory conditions.

Topics: Animals; Biomphalaria; Humans; Naphthoquinones; Niclosamide; Schistosoma mansoni; Schistosomiasis; Schistosomiasis mansoni

Snails of the genus Biomphalaria are intermediate hosts of Schistosoma mansoni, the main etiological agent of schistosomiasis mansoni, which affects about 236.6 million people in tropical and subtropical regions of the world. The World Health Organization recommends the population control of vector snails as one of the strategies to reduce the prevalence and incidence of schistosomiasis. In this study, molluscicidal and antiparasitic activities of plumbagin, a naturally sourced naphthoquinone with a range of biological effects, were evaluated against B. glabrata and cercariae of S. mansoni.. After 24 h of exposure, plumbagin demonstrated molluscicidal activity at low concentrations against embryos (LC. Plumbagin proved to be a promising substance for the control of B. glabrata population, intermediate host of S. mansoni, as well as the cercariae, infective stage for humans (definitive host), while being moderately toxic to A. salina, a crustacean widely used in ecotoxicity tests. © 2022 Society of Chemical Industry.

Topics: Animals; Biomphalaria; DNA Damage; Humans; Naphthoquinones; Schistosomiasis mansoni

Schistosomiasis is still a major health problem affecting nearly 250 million people worldwide and causes approximately 280,000 deaths per year. The disease causes a serious granulomatous inflammatory response that produces significant mortality. Plumbagin reportedly displays anti-inflammatory, anti-fibrotic, antioxidant and anthelmintic properties. This study further elucidates these properties. Mice were infected with schistosomes and divided into five groups: non-infected untreated (C); infected untreated (IU); non-infected treated with plumbagin (P); infected treated with plumbagin (PI) and infected treated with praziquantel (PZ). Mice treated with 20 mg plumbagin/kg body weight showed reduction of 64.28% and 59.88% in male and female animals, respectively. Also, the number of eggs/g tissue was reduced 69.39%, 68.79% and 69.11% in liver, intestine and liver/intestine combined, respectively. Plumbagin alleviated schistosome-induced hepatosplenomegaly and reduced hepatic granuloma and liver collagen content by 62.5% and 35.26%, respectively while PZQ reduced hepatic granuloma and liver collagen content by 41.11% and 11.21%, respectively. Further, plumbagin treatment significantly (p < .001) reduced IL-4, IL-13, IL-17, IL-37, IFN-γ, TGF-β and TNF-α levels and significantly (p < .001) upregulated IL-10. Plumbagin treatment restored hepatic enzymes activity to nearly normal levels and induced an increase in catalase, SOD, GSH, total thiol and GST in liver tissue homogenate. NO and LPO content was, however, decreased. Moreover, serum IgG levels significantly increased. The present study is the first to report immunomodulatory and schistosomicidal activities of plumbagin in schistosomiasis.

Topics: Animals; Anthelmintics; Anti-Inflammatory Agents; Antioxidants; Catalase; Female; Granuloma; Immunoglobulin G; Interleukin-10; Interleukin-13; Interleukin-17; Interleukin-4; Liver; Male; Mice; Naphthoquinones; Praziquantel; Schistosoma mansoni; Schistosomiasis; Schistosomiasis mansoni; Schistosomicides; Sulfhydryl Compounds; Superoxide Dismutase; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Schistosomiasis remains one of the world's leading health concerns, affecting millions. The granulomatous reaction is the most significant immunopathological change associated with Schistosoma mansoni infection, resulting in significant mortality. Recent progress has been made in the search for new natural compounds to reduce schistosomiasis and its immunopathology. Walnuts contain the phenolic compound Juglone (5-hydroxy-1,4-naphthoquinone), which has antiparasitic, anti-inflammatory, immunoregulatory, and antioxidant properties. There were three groups of infected mice: untreated (IU), Juglone-treated (JUG T), and praziquantel-treated (PZ). In mice treated at 8 mg Juglone /kg body weight, a reduction of 63.1 % and 52.1 % were observed in the number of male and female worms, respectively. In addition, the number of eggs/g tissue was reduced by 65.7 % in the liver, 58.58 % in the intestine, and 62.31 % in the liver and intestine combined. In addition, Juglone decreased hepatic granuloma size by 55.1 % and collagen fiber deposition by 23.4 % compared to PZQ (41.18 % and 11.2 %, respectively). Interestingly, the JUG T group had significantly lower levels of IL-4, IL-13, IL-37, TNF-α, TGF-β, and IFN-γ than PZ mice (p < 0.05). While IL-10 and IL-17 levels rose (p < 0.01), Juglone could restore hepatic ALT, AST, GGT, and LDH activities following infection. In addition, it increased catalase, SOD, GSH, and GST while decreasing NO and LPO in comparison to the infected group. Moreover, anti-SWAP, SEA, and CAP IgG levels increased significantly. IgE levels did not change significantly, however. Juglone could be used as an antifibrotic, immunomodulatory, and schistosomicidal agent; thus, it could be used in place of PZQ.

Topics: Animals; Female; Liver; Male; Mice; Naphthoquinones; Schistosomiasis mansoni; Schistosomicides

Investigations regarding the chemistry and mechanism of action of 2-methyl-1,4-naphthoquinone (or menadione) derivatives revealed 3-phenoxymethyl menadiones as a novel anti-schistosomal chemical series. These newly synthesized compounds (1-7) and their difluoromethylmenadione counterparts (8, 9) were found to be potent and specific inhibitors of Schistosoma mansoni thioredoxin-glutathione reductase (SmTGR), which has been identified as a potential target for anti-schistosomal drugs. The compounds were also tested in enzymic assays using both human flavoenzymes, i.e. glutathione reductase (hGR) and selenium-dependent human thioredoxin reductase (hTrxR), to evaluate the specificity of the inhibition. Structure-activity relationships as well as physico- and electro-chemical studies showed a high potential for the 3-phenoxymethyl menadiones to inhibit SmTGR selectively compared to hGR and hTrxR enzymes, in particular those bearing an α-fluorophenol methyl ether moiety, which improves anti-schistosomal action. Furthermore, the (substituted phenoxy)methyl menadione derivative (7) displayed time-dependent SmTGR inactivation, correlating with unproductive NADPH-dependent redox cycling of SmTGR, and potent anti-schistosomal action in worms cultured ex vivo. In contrast, the difluoromethylmenadione analog 9, which inactivates SmTGR through an irreversible non-consuming NADPH-dependent process, has little killing effect in worms cultured ex vivo. Despite ex vivo activity, none of the compounds tested was active in vivo, suggesting that the limited bioavailability may compromise compound activity. Therefore, future studies will be directed toward improving pharmacokinetic properties and bioavailability.

Topics: Animals; Cell Line; Drug Evaluation, Preclinical; Electrochemistry; Enzyme Inhibitors; Glutathione; Glutathione Reductase; Humans; In Vitro Techniques; Mice; Multienzyme Complexes; NADH, NADPH Oxidoreductases; Naphthoquinones; Schistosoma mansoni; Schistosomiasis mansoni; Schistosomicides; Structure-Activity Relationship; Thioredoxin-Disulfide Reductase

The activity of β-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione, β-lap) against different stages of Schistosoma mansoni was investigated in mice. Mice infected with 50 cercariae (BH strain) were intraperitoneally treated at a dose of 50 mg/kg for 5 consecutive days, starting on the 1st, 14th, 28th and 45th days after infection, to evaluate the effect of β-lap on skin schistosomula, lung schistosomula, young worms (before oviposition) and adult worms (after oviposition), respectively. All animals were euthanized 60 days after infection. β-Lap significantly reduced (p<0.001) the number of worms in 29.78%, 37.2%, 24.2% and 40.22% when administered during the phases of skin schistosomula, lung schistosomula, young worms and adult worms, respectively. Significant reduction was also achieved in terms of female burden. In all groups, there was significant reduction in the number of eggs and granulomas in the hepatic tissue. When the intervention was performed during the phase of adult worms, β-lap reduced the size of hepatic granulomas and changed the oogram pattern, lowering the percentage of immature eggs and increasing the percentage of mature and dead eggs. Our data indicate that β-lap has moderate antischistosomal properties. Its molecule may also be used as a prototype for synthesis of new naphthoquinone derivatives with potential schistosomicidal properties. Further studies with different formulations containing β-lap are needed to clearly establish the best dose and route of administration and its mechanism of action against schistosomes.

Topics: Animals; Antiparasitic Agents; Female; Granuloma; Life Cycle Stages; Liver; Liver Diseases; Lung; Lung Diseases; Magnoliopsida; Mice; Naphthoquinones; Phytotherapy; Plant Extracts; Schistosoma mansoni; Schistosomiasis mansoni; Skin; Skin Diseases

Praziquantel is the current drug of choice against schistosomiasis. The dependency on praziquantel exclusively is problematic, given the spread of the disease and the threat of drug resistance. This study investigates an alternative antischistosomal drug using the compound naphthoquine phosphate tablet, which is a novel single oral dose antimalarial drug, containing a combination of naphthoquine phosphate and artemisinin. In the present study, the therapeutic efficacies of different artemisinin-naphthoquine phosphate combination-dosing protocols were evaluated in experimentally infected mice harbouring juvenile or adult stages of Schistosoma mansoni (Egyptian strain). The study shows that the oral administration of artemisinin-naphthoquine phosphate combination in a single dose of 400 mg/kg on day 7 p.i. resulted in a significant worm burden reduction of 95.07%. When used at a dose of 600 mg/kg on day 21 p.i., all female worms were killed before depositing eggs, resulting in complete absence of eggs in hepatic and intestinal tissues. The same dose given on day 42 p.i. reduced total and female worm burdens by 93.36% and 94.17%, respectively. In addition, artemisinin-naphthoquine phosphate combination induced significant reductions of 80.18% and 76.73% in the hepatic and intestinal tissue egg loads, respectively. Artemisinin-naphthoquine phosphate combination also induced significant alterations in the oogram pattern with elevated levels of dead eggs. Antipathological activities were evident in the amelioration of hepatic granulomata. Our findings hold promise for the development of a novel antischistosomal drug using an artemisinin-naphthoquine phosphate combination. Further in vitro and in vivo studies should be launched to elucidate the possible mechanism/s of action and to study the effect of artemisinin-naphthoquine phosphate combination on other human schistosomes.

Topics: Administration, Oral; Animals; Anthelmintics; Artemisinins; Disease Models, Animal; Female; Histocytochemistry; Intestines; Liver; Mice; Mice, Inbred BALB C; Naphthoquinones; Parasite Egg Count; Parasite Load; Schistosoma mansoni; Schistosomiasis mansoni; Treatment Outcome

Improving the solubility of polysubstituted 1,4-naphthoquinone derivatives was achieved by introducing nitrogen in two different positions of the naphthoquinone core, at C-5 and at C-8 of menadione through a two-step, straightforward synthesis based on the regioselective hetero-Diels-Alder reaction. The antimalarial and the antischistosomal activities of these polysubstituted aza-1,4-naphthoquinone derivatives were evaluated and led to the selection of distinct compounds for antimalarial versus antischistosomal action. The Ag(II)-assisted oxidative radical decarboxylation of the phenyl acetic acids using AgNO(3) and ammonium peroxodisulfate was modified to generate the 3-picolinyl-menadione with improved pharmacokinetic parameters, high antimalarial effects and capacity to inhibit the formation of β-hematin.

Topics: Animals; Antimalarials; Hemin; Humans; Malaria, Falciparum; Methemoglobin; Mice; Naphthoquinones; Plasmodium falciparum; Quinolines; Schistosoma mansoni; Schistosomiasis mansoni; Schistosomicides; Solubility

Schistosomiasis--infection with helminth parasites in the genus Schistosoma, including S. mansoni--is a widespread, devastating tropical disease affecting more than 200 million people. No vaccine is available, and praziquantel, the only drug extensively utilized, is currently administered more than 100 million people yearly. Because praziquantel resistance may develop it is essential to identify novel drug targets. Our goal was to investigate the potential of a unique, selenium-containing parasite enzyme thioredoxin glutathione reductase (TGR) as a drug target.. Using RNA interference we found that TGR is essential for parasite survival; after silencing of TGR expression, in vitro parasites died within 4 d. We also found that auranofin is an efficient inhibitor of pure TGR (Ki = 10 nM), able to kill parasites rapidly in culture at physiological concentrations (5 microM), and able to partially cure infected mice (worm burden reductions of ~60%). Furthermore, two previously used antischistosomal compounds inhibited TGR activity, suggesting that TGR is a key target during therapy with those compounds.. Collectively, our results indicate that parasite TGR meets all the major criteria to be a key target for antischistosomal chemotherapy. To our knowledge this is the first validation of a Schistosoma drug target using a convergence of both genetic and biochemical approaches.

Topics: Animals; Auranofin; Drug Design; Female; Kinetics; Male; Mice; Mice, Inbred C57BL; Multienzyme Complexes; NADH, NADPH Oxidoreductases; Naphthoquinones; Oxidation-Reduction; Recombinant Proteins; RNA Interference; Schistosoma mansoni; Schistosomiasis mansoni; Schistosomicides; Signal Transduction