Toward anthelmintic drug candidates for toxocariasis: Challenges and recent developments.

Infections caused by parasitic helminths rank among the most prevalent infections of humans and animals. Toxocariasis, caused by nematodes of the genus Toxocara, is one of the most widespread and economically important zoonotic parasitic infections that humans share with dogs and cats. Despite the completion of the Toxocara canis draft genome project, which has been an important step towards advancing the understanding of this parasite and the search for drug targets, the treatment of toxocariasis has been dependent on a limited set of drugs, necessitating the search for novel anthelmintic agents, specially against Toxocara larvae in tissues. Given that research, development, and innovation are crucial to finding appropriate solutions in the fight against helminthiasis, this paper reviews the progress made in the discovery of anthelmintic drug candidates for toxocariasis. The main compounds reported in the recent years regards on analogues of albendazole, reactive quinone derivatives and natural produts and its analogues. Nanoparticles and formulations were also reviewed. The in vitro and/or in vivo anthelmintic properties of such alternatives are herein discussed as well as the opportunities and challenges for treatment of human toxocariasis. The performed review clarify that the scarcity of validated molecular targets and limited chemical space explored are the main bottlenecks for advancing in the field of anti-Toxocara agents.

N-(4-Methoxyphenyl)Pentanamide, a Simplified Derivative of Albendazole, Displays Anthelmintic Properties against the Nematode Toxocara canis.

Infections caused by parasitic helminths have enormous health, social, and economic impacts worldwide. The treatment and control of these diseases have been dependent on a limited set of drugs, many of which have become less effective, necessitating the search for novel anthelmintic agents. In this study, a simplified compound, N-(4-methoxyphenyl)pentanamide (N4MP), based on the structure of the most widely used anthelmintic (albendazole), was chemically prepared using 4-anisidine and pentanoic acid. N-(4-Methoxyphenyl)pentanamide was evaluated in vitro against the nematode Toxocara canis, an ascarid roundworm of animals that can infect humans. Similar to albendazole, bioassays showed that N-(4-methoxyphenyl)pentanamide affected the viability of parasites in a time- and concentration-dependent manner. Interestingly, N-(4-methoxyphenyl)pentanamide showed a profile of lower cytotoxicity to human and animal cell lines than albendazole. Pharmacokinetic, drug-likeness, and medicinal chemistry friendliness studies demonstrated an excellent drug-likeness profile for N-(4-methoxyphenyl)pentanamide as well as an adherence to major pharmaceutical companies' filters. Collectively, the results of this study demonstrate that the molecular simplification of albendazole to give N-(4-methoxyphenyl)pentanamide may be an important pipeline in the discovery of novel anthelmintic agents. IMPORTANCE Infections caused by parasitic helminths have enormous health, social, and economic impacts worldwide. The treatment and control of these diseases have been dependent on a limited set of drugs, many of which have become less effective, necessitating the search for novel anthelmintic agents. Considering this scenario, the present study reports the preparation of N-(4-methoxyphenyl)pentanamide (N4MP), a simplified molecule based on the structure of the most widely used anthelmintic (albendazole). N4MP was evaluated in vitro against the nematode Toxocara canis, a common ascarid roundworm of domestic animals that can infect humans. Similar to albendazole, bioassays showed that N4MP affected the viability of parasites in a time- and concentration-dependent manner but displayed a profile of lower cytotoxicity to human and animal cell lines than albendazole. Therefore, this study demonstrates that the molecular simplification of albendazole to give N4MP may be an important pipeline in the discovery of novel anthelmintic agents.

New evidence for tamoxifen as an antischistosomal agent: in vitro, in vivo and target fishing studies.

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.

Therapeutic Effect of Diminazene Aceturate on Parasitic Blood Fluke Schistosoma mansoni Infection.

Praziquantel is currently the only drug available to treat schistosomiasis, a disease of enormous public health significance caused by a blood fluke of the genus Schistosoma Diminazene, a drug approved by the FDA, has been successfully used to treat diseases caused by blood protozoan parasites. In this study, we evaluated the antiparasitic properties of diminazene against Schistosoma mansoniex vivo and in mice harboring either chronic or early S. mansoni infections. In vitro, we monitored phenotypic and tegumental changes as well as the effects of the drug on pairing and egg production. In mice infected with either adult (chronic infection) or immature (early infection) worms, diminazene was administered intraperitoneally (10 to 100 mg/kg of body weight) or by oral gavage (100 to 400 mg/kg), and we studied the influence of the drug on worm burden and egg production. Liver and spleen pathologies and serum aminotransferase levels were also analyzed. In vitro, 50% effective concentrations (EC50) and EC90 revealed that diminazene is able to kill both immature and adult parasites, and its effect was time and concentration dependent. In addition, confocal laser scanning microscopy showed morphological alterations in the teguments of schistosomes. In an animal model, the influence of the drug on worm burden, egg production, hepatomegaly, and splenomegaly depended on the dosing regimen applied and the route of administration. Diminazene also caused a significant reduction in aminotransferase levels. Comparatively, diminazene treatment was more effective in chronic infection than in early infection. In tandem, our study revealed that diminazene possesses anthelmintic properties and inhibits liver injury caused by Schistosoma eggs.

In Vitro and In Vivo Studies of Spironolactone as an Antischistosomal Drug Capable of Clinical Repurposing.

Schistosomiasis is a parasitic flatworm disease that infects over 200 million people worldwide, especially in poor communities. Treatment and control of the disease rely on just one drug, praziquantel. Since funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, from a screening of 13 marketed diuretics, we identified that spironolactone, a potassium-sparing diuretic, had potent antischistosomal effects on Schistosoma mansoniin vitro and in vivo in a murine model of schistosomiasis. In vitro, spironolactone at low concentrations (<10 µM) is able to alter worm motor activity and the morphology of adult schistosomes, leading to parasitic death. In vivo, oral treatment with spironolactone at a single dose (400 mg/kg) or daily for five consecutive days (100 mg/kg/day) in mice harboring either patent or prepatent infections significantly reduced worm burden, egg production, and hepato- and splenomegaly (P < 0.05 to P < 0.001). Taken together, with the safety profile of spironolactone, supported by its potential to affect schistosomes, these results indicate that spironolactone could be a potential treatment for schistosomiasis and make it promising for repurposing.