Biomaterial Database

5-Nitrofuranes and 5-nitrothiophenes with anti-Trypanosoma cruzi activity and ability to accumulate squalene. 2009

Alejandra Gerpe, and Guzmán Alvarez, and Diego Benítez, and Lucía Boiani, and Martín Quiroga, and Paola Hernández, and Maximiliano Sortino, and Susana Zacchino, and Mercedes González, and Hugo Cerecetto

Departamento de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.

Chagas disease represents a serious public health problem in South America. The first line of treatment is Nifurtimox and Benznidazole which generate toxic effects in treated patients. We have recently shown that a number of 5-nitrofuranes possess activity against Trypanosoma cruzi through oxidative stress and inhibition of parasite ergosterol biosynthesis, specifically at the level of squalene epoxidase. Here, we identify new 5-nitrofuranes and the thia-analogues with excellent effects on the viability of T. cruzi and adequate parasite/mammal selectivity indexes. Analysis of the free sterols from parasite incubated, during 120h, with the compounds showed that some of them accumulated squalene suggesting the squalene epoxidase activity inhibition of the parasite. Nifurtimox was able to accumulate squalene only at lower incubation times. Due to this fact some derivatives were also tested as antifungal agents. Quantitative structure-activity relationship studies were also performed showing relevant features for further new derivatives design. Taken together, the results obtained in the present work point to a more general effect of 5-nitrofuranes and 5-nitrothiophenes in trypanosomatids, opening potential therapeutic possibilities of them for these infectious diseases.

UI	MeSH Term	Description	Entries
D009581	Nitrofurans	Compounds containing FURANS attached to a nitro group.
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D013185	Squalene	A natural 30-carbon triterpene.
D013876	Thiophenes	A monocyclic heteroarene furan in which the oxygen atom is replaced by a sulfur.	Thiophene
D014344	Trypanocidal Agents	Agents destructive to the protozoal organisms belonging to the suborder TRYPANOSOMATINA.	Trypanocidal Drugs,Trypanocides,Trypanosomicidal Agents,Trypanosomicides,Agents, Trypanocidal,Agents, Trypanosomicidal,Drugs, Trypanocidal
D014349	Trypanosoma cruzi	The agent of South American trypanosomiasis or CHAGAS DISEASE. Its vertebrate hosts are man and various domestic and wild animals. Insects of several species are vectors.	Trypanosoma cruzus,cruzi, Trypanosoma
D014355	Chagas Disease	Infection with the protozoan parasite TRYPANOSOMA CRUZI, a form of TRYPANOSOMIASIS endemic in Central and South America. It is named after the Brazilian physician Carlos Chagas, who discovered the parasite. Infection by the parasite (positive serologic result only) is distinguished from the clinical manifestations that develop years later, such as destruction of PARASYMPATHETIC GANGLIA; CHAGAS CARDIOMYOPATHY; and dysfunction of the ESOPHAGUS or COLON.	Trypanosomiasis, South American,American Trypanosomiasis,Chagas' Disease,Trypanosoma cruzi Infection,Infection, Trypanosoma cruzi,Infections, Trypanosoma cruzi,South American Trypanosomiasis,Trypanosoma cruzi Infections,Trypanosomiasis, American
D015195	Drug Design	The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis.	Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D050603	Squalene Monooxygenase	The second enzyme in the committed pathway for CHOLESTEROL biosynthesis, this enzyme catalyzes the first oxygenation step in the biosynthesis of STEROLS and is thought to be a rate limiting enzyme in this pathway. Specifically, this enzyme catalyzes the conversion of SQUALENE to (S)-squalene-2,3-epoxide.	Squalene Epoxidase,Squalene Monooxygenase (2,3-Epoxidizing),Epoxidase, Squalene,Monooxygenase, Squalene