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Abstract:

The effect of long-chain 2-alkylaminoethyl-1,1-bisphosphonates 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 was investigated. Particularly, compound 26 proved to be an extremely potent inhibitor against the intracellular form of T. cruzi, exhibiting IC50 values at the nanomolar range. 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 26 was an effective agent against T. cruzi (amastigotes) exhibiting an IC50 value of 0.67 μM, while this compound showed an IC50 value of 0.81 μM against the target enzyme TcFPPS. This drug was less effective against the enzymatic activity of T. cruzi solanesyl diphosphate synthase TcSPPS showing an IC50 value of 3.2 μM. Interestingly, compound 26 was also very effective against T. gondii (tachyzoites) exhibiting IC50 values of 6.23 μM. This cellular activity was also related to the inhibition of the enzymatic activity towards the target enzyme TgFPPS (IC50 = 0.093 μM) 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 different tropical diseases. © 2011 Elsevier Ltd. All rights reserved.

Registro:

Documento: Artículo
Título:Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1- bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase
Autor:Rosso, V.S.; Szajnman, S.H.; Malayil, L.; Galizzi, 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, Pabellón 2, C1428EHA Buenos Aires, Argentina
Center for Tropical and Emerging Global Diseases, Department of Cellular Biology, University of Georgia, Athens, GA 30602, United States
Palabras clave:Chagas' disease; Farnesyl pyrophosphate synthase; Toxoplasma gondii; Toxoplasmosis; Trypanosoma cruzi; 1 (2 alkylaminoethyl) 1,1 bisphosphonic acid derivative; 1 [(benzylamino)ethyl] 1,1 bisphosphonic acid; 1 [(n dec 1 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(n dodec 1 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(n hexadec 1 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(n non 1 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(n octadec 1 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(n tetradec 1 ylamino)ethyl] 1,1 bisphosphonic acid; 1 [(n undec 1 ylamino)ethyl] 1,1 bisphosphonic acid; antiprotozoal agent; benznidazole; geranyltransferase; microorganism protein; octaprenyltransferase; tetraethyl 1 [(benzylamino)ethyl] 1,1 bisphosphonate; tetraethyl 1 [(n dec 1 ylamino)ethyl] 1,1 bisphosphonate; tetraethyl 1 [(n dodec 1 ylamino)ethyl] 1,1 bisphosphonate; tetraethyl 1 [(n hexadec 1 ylamino)ethyl] 1,1 bisphosphonate; tetraethyl 1 [(n non 1 ylamino)ethyl] 1,1 bisphosphonate; tetraethyl 1 [(n octadec 1 ylamino)ethyl] 1,1 bisphosphonate; tetraethyl 1 [(n tetradec 1 ylamino)ethyl] 1,1 bisphosphonate; tetraethyl 1 [(n undec 1 ylamino)ethyl] 1,1 bisphosphonate; unclassified drug; amastigote; article; Chagas disease; controlled study; drug screening; drug synthesis; drug targeting; enzyme activity; enzyme inhibition; IC 50; nonhuman; tachyzoite; Toxoplasma gondii; Trypanosoma cruzi; Animals; Antiprotozoal Agents; Cercopithecus aethiops; Diphosphonates; Enzyme Inhibitors; Geranyltranstransferase; Molecular Targeted Therapy; Structure-Activity Relationship; Toxoplasma; Trypanosoma cruzi; Vero Cells; Toxoplasma gondii; Trypanosoma cruzi
Año:2011
Volumen:19
Número:7
Página de inicio:2211
Página de fin:2217
DOI: http://dx.doi.org/10.1016/j.bmc.2011.02.037
Título revista:Bioorganic and Medicinal Chemistry
Título revista abreviado:Bioorg. Med. Chem.
ISSN:09680896
CODEN:BMECE
CAS:benznidazole, 22994-85-0; 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_v19_n7_p2211_Rosso

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Citas:

---------- APA ----------
Rosso, V.S., Szajnman, S.H., Malayil, L., Galizzi, M., Moreno, S.N.J., Docampo, R. & Rodriguez, J.B. (2011) . Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1- bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase. Bioorganic and Medicinal Chemistry, 19(7), 2211-2217.
http://dx.doi.org/10.1016/j.bmc.2011.02.037
---------- CHICAGO ----------
Rosso, V.S., Szajnman, S.H., Malayil, L., Galizzi, M., Moreno, S.N.J., Docampo, R., et al. "Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1- bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase" . Bioorganic and Medicinal Chemistry 19, no. 7 (2011) : 2211-2217.
http://dx.doi.org/10.1016/j.bmc.2011.02.037
---------- MLA ----------
Rosso, V.S., Szajnman, S.H., Malayil, L., Galizzi, M., Moreno, S.N.J., Docampo, R., et al. "Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1- bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase" . Bioorganic and Medicinal Chemistry, vol. 19, no. 7, 2011, pp. 2211-2217.
http://dx.doi.org/10.1016/j.bmc.2011.02.037
---------- VANCOUVER ----------
Rosso, V.S., Szajnman, S.H., Malayil, L., Galizzi, M., Moreno, S.N.J., Docampo, R., et al. Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1- bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase. Bioorg. Med. Chem. 2011;19(7):2211-2217.
http://dx.doi.org/10.1016/j.bmc.2011.02.037