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Szajnman, S.H.; García Liñares, G.E.; Li, Z.-H.; Jiang, C.; Galizzi, M.; Bontempi, E.J.; Ferella, M.; Moreno, S.N.J.; Docampo, R.; Rodriguez, J.B. "Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase" (2008) Bioorganic and Medicinal Chemistry. 16(6):3283-3290
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Abstract:

The effect of a series of 2-alkylaminoethyl-1,1-bisphosphonic acids against proliferation of the clinically more relevant form of Trypanosoma cruzi, the etiologic agent of American trypanosomiasis (Chagas' disease), and against tachyzoites of Toxoplasma gondii has been studied. Most of these drugs exhibited an extremely potent inhibitory action against the intracellular form of T. cruzi, exhibiting IC50 values at the low micromolar level. This cellular activity was associated with a strong inhibition of the enzymatic activity of T. cruzi farnesyl diphosphate synthase (TcFPPS), which constitutes a valid target for Chagas' disease chemotherapy. Compound 17 was an effective agent against amastigotes exhibiting an IC50 value of 0.84 μM, while this compound showed an IC50 value of 0.49 μM against the target enzyme TcFPPS. Interestingly, compound 19 was very effective against both T. cruzi and T. gondii exhibiting IC50 values of 4.1 μM and 2.6 μM, respectively. In this case, 19 inhibited at least two different enzymes of T. cruzi (TcFPPS and solanesyl diphosphate synthase (TcSPPS); 1.01 μM and 0.25 μM, respectively), while it inhibited TgFPPS in T. gondii. In general, this family of drugs was less effective against the activity of T. cruzi SPPS and against T. gondii growth in vitro. As bisphosphonate-containing compounds are FDA-approved drugs for the treatment of bone resorption disorders, their potential low toxicity makes them good candidates to control tropical diseases. © 2007 Elsevier Ltd. All rights reserved.

Registro:

Documento: Artículo
Título:Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase
Autor:Szajnman, S.H.; García Liñares, G.E.; Li, Z.-H.; Jiang, C.; Galizzi, M.; Bontempi, E.J.; Ferella, M.; Moreno, S.N.J.; Docampo, R.; Rodriguez, J.B.
Filiación:Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellon 2, Ciudad Universitaria, C1428EHA Buenos Aires, Argentina
Center for Tropical and Emerging Global Diseases, Department of Cellular Biology, University of Georgia, Athens, GA 30602, United States
Instituto Nacional de Parasitologia Dr. Mario Fatala Chabén, Administración Nacional de Laboratorios e Institutos de Salud, Ministerio de Salud, Paseo Colón 568, Buenos Aires C1063ACT, Argentina
Palabras clave:Bisphosphonates; Chagas' disease; Farnesyl diphosphate synthase; Solanesyl diphosphate synthase; Toxoplasma gondii; Toxoplasmosis; Trypanosoma cruzi; 1 [(2 methylprop 1 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(2 piperidin 1 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(2 pyrrolidin 1 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(3 methyl but 1 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(but 2 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(cyclohexylamino)ethyl] 1,1 bisphosphonic acid; 1 [(n but 1 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(n hept 1 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(n hex 1 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(n oct 1 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(n pent 1 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(prop 1 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(prop 2 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(tert butylamino)ethyl] 1,1 bisphosphonic acid; antiprotozoal agent; bisphosphonic acid derivative; geranyltransferase; unclassified drug; amastigote; antiprotozoal activity; article; biological activity; Chagas disease; comparative study; concentration response; controlled study; drug indication; drug mechanism; drug potency; drug safety; drug screening; drug synthesis; drug targeting; enzyme activity; enzyme inhibition; food and drug administration; growth inhibition; IC 50; nonhuman; parasite cultivation; toxicity testing; Toxoplasma gondii; Trypanosoma cruzi; Animals; Antiprotozoal Agents; Diphosphonates; Enzyme Inhibitors; Geranyltranstransferase; Inhibitory Concentration 50; Structure-Activity Relationship; Toxoplasma; Trypanosoma cruzi; Toxoplasma gondii; Trypanosoma cruzi
Año:2008
Volumen:16
Número:6
Página de inicio:3283
Página de fin:3290
DOI: http://dx.doi.org/10.1016/j.bmc.2007.12.010
Título revista:Bioorganic and Medicinal Chemistry
Título revista abreviado:Bioorg. Med. Chem.
ISSN:09680896
CODEN:BMECE
CAS:geranyltransferase, 37277-79-5, 50812-36-7; Antiprotozoal Agents; Diphosphonates; Enzyme Inhibitors; Geranyltranstransferase, 2.5.1.10
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v16_n6_p3283_Szajnman

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Citas:

---------- APA ----------
Szajnman, S.H., García Liñares, G.E., Li, Z.-H., Jiang, C., Galizzi, M., Bontempi, E.J., Ferella, M.,..., Rodriguez, J.B. (2008) . Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase. Bioorganic and Medicinal Chemistry, 16(6), 3283-3290.
http://dx.doi.org/10.1016/j.bmc.2007.12.010
---------- CHICAGO ----------
Szajnman, S.H., García Liñares, G.E., Li, Z.-H., Jiang, C., Galizzi, M., Bontempi, E.J., et al. "Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase" . Bioorganic and Medicinal Chemistry 16, no. 6 (2008) : 3283-3290.
http://dx.doi.org/10.1016/j.bmc.2007.12.010
---------- MLA ----------
Szajnman, S.H., García Liñares, G.E., Li, Z.-H., Jiang, C., Galizzi, M., Bontempi, E.J., et al. "Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase" . Bioorganic and Medicinal Chemistry, vol. 16, no. 6, 2008, pp. 3283-3290.
http://dx.doi.org/10.1016/j.bmc.2007.12.010
---------- VANCOUVER ----------
Szajnman, S.H., García Liñares, G.E., Li, Z.-H., Jiang, C., Galizzi, M., Bontempi, E.J., et al. Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase. Bioorg. Med. Chem. 2008;16(6):3283-3290.
http://dx.doi.org/10.1016/j.bmc.2007.12.010