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Antimicrob Agents Chemother. 2017 Jan 24;61(2). pii: e01590-16. doi: 10.1128/AAC.01590-16. Print 2017 Feb.

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

Author information

1
Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
2
Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, Georgia, USA.
3
Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, Georgia, USA smoreno@uga.edu jbr@qo.fcen.uba.ar.
4
Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina smoreno@uga.edu jbr@qo.fcen.uba.ar.

Abstract

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 sulfone-containing 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.

KEYWORDS:

Cryptosporidium parvum; Plasmodium falciparum; Toxoplasma gondii; bisphosphonates; farnesyl diphosphate synthase; isoprenoids

PMID:
27895021
PMCID:
PMC5278718
DOI:
10.1128/AAC.01590-16
[Indexed for MEDLINE]
Free PMC Article

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