Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1- bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase
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, compoun...
Guardado en:
| Autores principales: | , , |
|---|---|
| Publicado: |
2011
|
| Materias: | |
| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v19_n7_p2211_Rosso http://hdl.handle.net/20.500.12110/paper_09680896_v19_n7_p2211_Rosso |
| Aporte de: |
| id |
paper:paper_09680896_v19_n7_p2211_Rosso |
|---|---|
| record_format |
dspace |
| spelling |
paper:paper_09680896_v19_n7_p2211_Rosso2023-06-08T15:58:54Z Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1- bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase Szajnman, Sergio Hernán Moreno, Silvia N. J. Rodríguez, Juan Bautista 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 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. Fil:Szajnman, S.H. 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. 2011 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v19_n7_p2211_Rosso http://hdl.handle.net/20.500.12110/paper_09680896_v19_n7_p2211_Rosso |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Szajnman, Sergio Hernán Moreno, Silvia N. J. Rodríguez, Juan Bautista Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1- bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase |
| topic_facet |
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 |
| description |
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. |
| author |
Szajnman, Sergio Hernán Moreno, Silvia N. J. Rodríguez, Juan Bautista |
| author_facet |
Szajnman, Sergio Hernán Moreno, Silvia N. J. Rodríguez, Juan Bautista |
| author_sort |
Szajnman, Sergio Hernán |
| title |
Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1- bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase |
| title_short |
Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1- bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase |
| title_full |
Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1- bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase |
| title_fullStr |
Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1- bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase |
| title_full_unstemmed |
Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1- bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase |
| title_sort |
synthesis and biological evaluation of new 2-alkylaminoethyl-1,1- bisphosphonic acids against trypanosoma cruzi and toxoplasma gondii targeting farnesyl diphosphate synthase |
| publishDate |
2011 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v19_n7_p2211_Rosso http://hdl.handle.net/20.500.12110/paper_09680896_v19_n7_p2211_Rosso |
| work_keys_str_mv |
AT szajnmansergiohernan synthesisandbiologicalevaluationofnew2alkylaminoethyl11bisphosphonicacidsagainsttrypanosomacruziandtoxoplasmagondiitargetingfarnesyldiphosphatesynthase AT morenosilvianj synthesisandbiologicalevaluationofnew2alkylaminoethyl11bisphosphonicacidsagainsttrypanosomacruziandtoxoplasmagondiitargetingfarnesyldiphosphatesynthase AT rodriguezjuanbautista synthesisandbiologicalevaluationofnew2alkylaminoethyl11bisphosphonicacidsagainsttrypanosomacruziandtoxoplasmagondiitargetingfarnesyldiphosphatesynthase |
| _version_ |
1768541904889184256 |