oxadiazoles and Schistosomiasis

After malaria, schistosomiasis (or bilharzia) is the second most prevalent disease in Africa, and is occurring in over 70 countries in tropical and subtropical regions. It is estimated that 600 million people are at risk of infection, 200 million people are infected, and at least 200,000 deaths per year are associated with the disease. All schistosome species are transmitted through contact with fresh water that is infested with free-swimming forms of the parasite, which is known as cercariae and produced by snails. When located in the blood vessels of the host, larval and adult schistosomes digest red cells to acquire amino acids for growth and development. Vaccine candidates have been unsuccessful up to now. Against such devastating parasitic disease, the antischistosomal arsenal is currently limited to a single drug, praziquantel, which has been used for more than 35 years. Because the question of the reduction of the activity of praziquantel was raised recently, it is thus urgent to create new and safe antischistosomal drugs that should be combined with praziquantel to develop efficient bitherapies.

Topics: Animals; Drug Resistance; Hemeproteins; Hemoglobins; Humans; Imidazoles; Lucanthone; Niacin; Oxadiazoles; Praziquantel; Schistosoma; Schistosomiasis

Topics: Administration, Oral; Animals; Antimony; Chemosterilants; Child; Cricetinae; Cysteine; Drug Evaluation; Drug Evaluation, Preclinical; Ethylenediamines; Haplorhini; Humans; Injections, Intramuscular; Mice; Nitro Compounds; Nitrofurans; Oxadiazoles; Propylamines; Pyrimidines; Pyrroles; Quinolines; Ribonucleosides; Schistosoma mansoni; Schistosomiasis; Schistosomicides; Thiazoles; Thioxanthenes; Trypsin Inhibitors; Vinyl Compounds

The only drug currently available for treatment of the neglected disease Schistosomiasis is Praziquantel, and the possible emergence of resistance makes research on novel therapeutic agents necessary and urgent. To this end, the targeting of

Topics: Animals; Helminth Proteins; Humans; Kinetics; Larva; Lysine; Niacinamide; Oxadiazoles; Peptides; Pyrimidines; Schistosoma mansoni; Schistosomiasis; Sirtuin 2; Structure-Activity Relationship; Substrate Specificity

Schistosomiasis is a chronic parasitic disease affecting hundreds of millions of individuals worldwide. Current treatment depends on a single agent, praziquantel, raising concerns of emergence of resistant parasites. Here, we continue our explorations of an oxadiazole-2-oxide class of compounds we recently identified as inhibitors of thioredoxin glutathione reductase (TGR), a selenocysteine-containing flavoenzyme required by the parasite to maintain proper cellular redox balance. Through systematic evaluation of the core molecular structure of this chemotype, we define the essential pharmacophore, establish a link between the nitric oxide donation and TGR inhibition, determine the selectivity for this chemotype versus related reductase enzymes, and present evidence that these agents can be modified to possess appropriate drug metabolism and pharmacokinetic properties. The mechanistic link between exogenous NO donation and parasite injury is expanded and better defined. The results of these studies verify the utility of oxadiazole-2-oxides as novel inhibitors of TGR and as efficacious antischistosomal agents.

Topics: Animals; Biological Availability; Drug Discovery; Enzyme Inhibitors; Humans; Inhibitory Concentration 50; Models, Molecular; Multienzyme Complexes; NADH, NADPH Oxidoreductases; Nitric Oxide; Oxadiazoles; Protein Conformation; Rats; Schistosoma; Schistosomiasis; Schistosomicides; Solubility; Structure-Activity Relationship; Substrate Specificity

Topics: Animals; Anthelmintics; Antioxidants; Cell Line; Drug Evaluation, Preclinical; Drug Resistance; Humans; Mice; Oxadiazoles; Praziquantel; Schistosoma mansoni; Schistosomiasis

Several 5-substituted amino-1,3,4-oxadiazol-2-yl and 5-substituted amino-1,3,4-thiadiazol-2-yl derivatives with different 8-hydroxyquinoline moieties in the 2-position were prepared and tested for their antiparasitic activity. Preliminary biological tests on mice experimentally infested with Schistosoma mansoni revealed that the new compounds show moderate schistosomicidal activity.

Topics: Animals; Hycanthone; Hydroxyquinolines; Intestine, Small; Liver; Mice; Oxadiazoles; Schistosoma mansoni; Schistosomiasis; Schistosomicides; Thiadiazoles

Topics: Animals; Dogs; Haplorhini; Mice; Nitrofurans; Oxadiazoles; Rabbits; Schistosoma japonicum; Schistosomiasis; Schistosomicides

Topics: Albumins; Animals; Anthelmintics; Autopsy; Blood Proteins; Feces; gamma-Globulins; Hematocrit; Hemoglobins; Japan; Kidney; Leukocyte Count; Leukocytosis; Liver; Liver Diseases, Parasitic; Lymphocytes; Neutrophils; Nitrofurans; Oxadiazoles; Pan troglodytes; Parasite Egg Count; Schistosomiasis; Schistosomicides; Vinyl Compounds

Topics: Animals; Anthelmintics; Benzenesulfonates; Female; Hybridization, Genetic; Liberia; Lucanthone; Male; Mice; Nitrofurans; Oxadiazoles; Puerto Rico; Schistosoma mansoni; Schistosomiasis; Schistosomicides; Vinyl Compounds

Topics: Carcinogens; Diethylamines; Disease Models, Animal; Inflammation; Neoplasms, Experimental; Oxadiazoles; Schistosoma haematobium; Schistosomiasis; Sulfonamides; Urinary Bladder; Urinary Bladder Calculi; Urinary Bladder Neoplasms

Topics: Administration, Oral; Animals; Drug Evaluation, Preclinical; Eosinophils; Female; Leukocyte Count; Liver; Male; Oxadiazoles; Rats; Schistosoma mansoni; Schistosomiasis; Succinate Dehydrogenase; Time Factors

Topics: Animals; Anthelmintics; Female; Liver; Liver Diseases; Mice; Nitrofurans; Ovum; Oxadiazoles; Schistosomiasis

Topics: Administration, Oral; Animals; Anthelmintics; Female; Injections, Intramuscular; Liver; Mice; Nitrofurans; Oxadiazoles; Schistosoma mansoni; Schistosomiasis; Time Factors; Vinyl Compounds