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Szajnman, S.H.; Galaka, T.; Li, Z.-H.; Li, C.; Howell, N.M.; Chao, M.N.; Striepen, B.; Muralidharan, V.; Moreno, S.N.J.; Rodriguez, J.B. "In Vitro and in Vivo activities of sulfur-containing linear bisphosphonates against apicomplexan parasites" (2017) Antimicrobial Agents and Chemotherapy. 61(2)
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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 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. © 2017 American Society for Microbiology. All Rights Reserved.

Registro:

Documento: Artículo
Título:In Vitro and in Vivo activities of sulfur-containing linear bisphosphonates against apicomplexan parasites
Autor:Szajnman, S.H.; Galaka, T.; Li, Z.-H.; Li, C.; Howell, N.M.; Chao, M.N.; Striepen, B.; Muralidharan, V.; Moreno, S.N.J.; Rodriguez, J.B.
Filiación:Departamento de Química Orgánica, UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Center for Tropical and Emerging Global Diseases, Department of Cellular Biology, University of Georgia, Athens, GA, United States
Palabras clave:Bisphosphonates; Cryptosporidium parvum; Farnesyl diphosphate synthase; Isoprenoids; Plasmodium falciparum; Toxoplasma gondii; (2,2 diphosphonoethyl)(methyl)(hexyl)sulfonium tetrafluoroborate; (2,2 diphosphonoethyl)(methyl)(pentyl)sulfonium tetrafluoroborate; 1 [(n decylsulfonyl)ethyl] 1,1 biphosphonic acid; 1 [(n heptylsulfonyl)ethyl] 1,1 biphosphonic acid; 1 [(n hexylsulfonyl)ethyl] 1,1 biphosphonic acid; 1 [(n nonylsulfonyl)ethyl] 1,1 biphosphonic acid; 1 [(n octylsulfonyl)ethyl] 1,1 biphosphonic acid; atorvastatin; bisphosphonic acid derivative; geranyltransferase; hydroxymethylglutaryl coenzyme A reductase inhibitor; pamidronic acid; risedronic acid; sulfone; sulfur; unclassified drug; zoledronic acid; antiprotozoal agent; bisphosphonic acid derivative; enzyme inhibitor; sulfur; animal cell; animal experiment; animal model; Apicomplexa; Article; controlled study; cryptosporidiosis; Cryptosporidium parvum; EC50; enzyme activity; experimental model; IC50; in vitro study; in vivo study; malaria; mouse; nonhuman; Plasmodium falciparum; priority journal; selectivity index; tachyzoite; tissue culture; toxicity; Toxoplasma; toxoplasmosis; animal; antagonists and inhibitors; chemistry; dose response; drug effects; enzymology; growth, development and aging; human; inbred mouse strain; preclinical study; procedures; synthesis; toxoplasmosis; Animals; Antiprotozoal Agents; Chemistry Techniques, Synthetic; Cryptosporidium parvum; Diphosphonates; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Inhibitors; Geranyltranstransferase; Humans; Mice, Inbred Strains; Plasmodium falciparum; Sulfur; Toxoplasma; Toxoplasmosis
Año:2017
Volumen:61
Número:2
DOI: http://dx.doi.org/10.1128/AAC.01590-16
Título revista:Antimicrobial Agents and Chemotherapy
Título revista abreviado:Antimicrob. Agents Chemother.
ISSN:00664804
CODEN:AMACC
CAS:atorvastatin, 134523-00-5, 134523-03-8; geranyltransferase, 37277-79-5, 50812-36-7; pamidronic acid, 40391-99-9, 57248-88-1; risedronic acid, 105462-24-6, 122458-82-6; sulfone, 67015-63-8; sulfur, 13981-57-2, 7704-34-9; zoledronic acid, 118072-93-8, 131654-46-1, 165800-06-6, 165800-07-7; Antiprotozoal Agents; Diphosphonates; Enzyme Inhibitors; Geranyltranstransferase; Sulfur
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00664804_v61_n2_p_Szajnman

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Citas:

---------- APA ----------
Szajnman, S.H., Galaka, T., Li, Z.-H., Li, C., Howell, N.M., Chao, M.N., Striepen, B.,..., Rodriguez, J.B. (2017) . In Vitro and in Vivo activities of sulfur-containing linear bisphosphonates against apicomplexan parasites. Antimicrobial Agents and Chemotherapy, 61(2).
http://dx.doi.org/10.1128/AAC.01590-16
---------- CHICAGO ----------
Szajnman, S.H., Galaka, T., Li, Z.-H., Li, C., Howell, N.M., Chao, M.N., et al. "In Vitro and in Vivo activities of sulfur-containing linear bisphosphonates against apicomplexan parasites" . Antimicrobial Agents and Chemotherapy 61, no. 2 (2017).
http://dx.doi.org/10.1128/AAC.01590-16
---------- MLA ----------
Szajnman, S.H., Galaka, T., Li, Z.-H., Li, C., Howell, N.M., Chao, M.N., et al. "In Vitro and in Vivo activities of sulfur-containing linear bisphosphonates against apicomplexan parasites" . Antimicrobial Agents and Chemotherapy, vol. 61, no. 2, 2017.
http://dx.doi.org/10.1128/AAC.01590-16
---------- VANCOUVER ----------
Szajnman, S.H., Galaka, T., Li, Z.-H., Li, C., Howell, N.M., Chao, M.N., et al. In Vitro and in Vivo activities of sulfur-containing linear bisphosphonates against apicomplexan parasites. Antimicrob. Agents Chemother. 2017;61(2).
http://dx.doi.org/10.1128/AAC.01590-16