1. In Vitro and In Vivo Activity of Sulfur-Containing Linear Bisphosphonates against Apicomplexan Parasites

We tested a series of sulfur-containing linear bisphosphonates against Toxoplasma gondii, the etiologic agent of toxoplasmosis. The most potent compound (compound 22; 1-[(n-decylsulfonyl)ethyl]-1,1-bisphosphonic acid) is a sulfonecontaining compound, which had a 50% effective concentration (EC50) of...

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Detalhes bibliográficos
Autores: Szajnman, Sergio Hernan, Galaka, Tamila Pavlivna, Li, Zhu-Hong, Li, Catherine, Howell, Nathan M., Chao, Maria Noelia, Striepen, Boris, Muralidharan, Vasant, Moreno, Silvia N. J., Rodriguez, Juan Bautista
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2016
País:Argentina
Recursos:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositório:CONICET Digital (CONICET)
Idioma:inglês
OAI Identifier:oai:ri.conicet.gov.ar:11336/60235
Acesso em linha:http://hdl.handle.net/11336/60235
Access Level:Acceso aberto
Palavra-chave:BISPHOSPHONATES
CRYPTOSPORIDIUM PARVUM
FARNESYL DIPHOSPHATE SYNTHASE
ISOPRENOIDS
PLASMODIUM FALCIPARUM
TOXOPLASMA GONDII
https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
Descrição
Resumo:We tested a series of sulfur-containing linear bisphosphonates against Toxoplasma gondii, the etiologic agent of toxoplasmosis. The most potent compound (compound 22; 1-[(n-decylsulfonyl)ethyl]-1,1-bisphosphonic acid) is a sulfonecontaining compound, which had a 50% effective concentration (EC50) of 0.11 ± 0.02 μM against intracellular tachyzoites. The compound showed low toxicity when tested in tissue culture with a selectivity index of >2,000. Compound 22 also showed high activity in vivo in a toxoplasmosis mouse model. The compound inhibited the Toxoplasma farnesyl diphosphate synthase (TgFPPS), but the concentration needed to inhibit 50% of the enzymatic activity (IC50) was higher than the concentration that inhibited 50% of growth. We tested compound 22 against two other apicomplexan parasites, Plasmodium falciparum (EC50 of 0.6 ± 0.01 μM), the agent of malaria, and Cryptosporidium parvum (EC50 of ∼65 μM), the agent of cryptosporidiosis. Our results suggest that compound 22 is an excellent novel compound that could lead to the development of potent agents against apicomplexan parasites.

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