title: In Vitro and In Vivo Activities of Sulfur-Containing Linear Bisphosphonates against Apicomplexan Parasites.
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 (EC50of 0.6 ± 0.01 μM), the agent of malaria, and Cryptosporidium parvum (EC50of ∼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.
authors.affiliation: Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Szajnman
authors.affiliation: Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Tamila
authors.initials: T
authors.lastname: Galaka
authors.affiliation: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, Georgia, USA.
authors.forename: Zhu-Hong
authors.initials: ZH
authors.lastname: Li
authors.affiliation: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, Georgia, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Li
authors.affiliation: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, Georgia, USA.
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Howell
authors.affiliation: Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: María N
authors.initials: MN
authors.lastname: Chao
authors.affiliation: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, Georgia, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Striepen
authors.affiliation: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, Georgia, USA.
authors.forename: Vasant
authors.initials: V
authors.lastname: Muralidharan
authors.affiliation: 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.
authors.forename: Silvia N J
authors.initials: SN
authors.lastname: Moreno
authors.affiliation: 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.
authors.forename: Juan B
authors.initials: JB
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D016785:Cryptosporidium parvum / Q000187:drug effects* / Q000254:growth & development; D004164:Diphosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors; D006801:Humans; D008815:Mice, Inbred Strains; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D013455:Sulfur / Q000737:chemistry / Q000494:pharmacology; D014122:Toxoplasma / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D014123:Toxoplasmosis / Q000188:drug therapy
chemical_list: D000981:Antiprotozoal Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D013455:Sulfur; D051228:Geranyltranstransferase
keywords: Cryptosporidium parvum; Plasmodium falciparum; Toxoplasma gondii; bisphosphonates; farnesyl diphosphate synthase; isoprenoids