Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase

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 dr...

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Autores principales:	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.
Formato:	JOUR
Materias:	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 Animals Antiprotozoal Agents Diphosphonates Enzyme Inhibitors Geranyltranstransferase Inhibitory Concentration 50 Structure-Activity Relationship Toxoplasma
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_09680896_v16_n6_p3283_Szajnman
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_09680896_v16_n6_p3283_Szajnman
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institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	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
spellingShingle	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 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
topic_facet	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
description	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.
format	JOUR
author	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.
author_facet	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.
author_sort	Szajnman, S.H.
title	Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase
title_short	Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase
title_full	Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase
title_fullStr	Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase
title_full_unstemmed	Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase
title_sort	synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against trypanosoma cruzi and toxoplasma gondii targeting farnesyl diphosphate synthase
url	http://hdl.handle.net/20.500.12110/paper_09680896_v16_n6_p3283_Szajnman
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spelling	todo:paper_09680896_v16_n6_p3283_Szajnman2023-10-03T15:55:11Z Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase 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. 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 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. Fil:Szajnman, S.H. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:García Liñares, G.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Bontempi, E.J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Moreno, S.N.J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Rodriguez, J.B. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_09680896_v16_n6_p3283_Szajnman

Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase

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