Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents

As part of our efforts aimed at searching for new antiparasitic agents, 2-alkylmercaptoethyl-1,1-bisphosphonate derivatives were synthesized and evaluated against Trypanosoma cruzi, the etiologic agent of Chagas disease, and Toxoplasma gondii, the responsible agent for toxoplasmosis. Many of these s...

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Autores principales:	Szajnman, Sergio Hernán, Moreno, Silvia N. J., Rodríguez, Juan Bautista
Publicado:	2013
Materias:	Antiparasitic agents Chagas disease Farnesyl diphosphate synthase Toxoplasma gondii Toxoplasmosis Trypanosoma cruzi 1 [(ethylthio)ethyl] 1,1 bisphosphonic acid 1 [(n butylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n butylthio)ethyl] 1,1 bisphosphonic acid 1 [(n decylthio)ethyl] 1,1 bisphosphonic acid 1 [(n hept 2 ylamino)ethyl] 1,1 bisphosphonic acid 1 [(n heptylamino)ethyl] 1 hydroxy 1,1 bisphosphonic acid 1 [(n heptylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n heptylthio)ethyl] 1,1 bisphosphonic acid 1 [(n hexylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n hexylthio)ethyl] 1,1 bisphosphonic acid 1 [(n nonylthio)ethyl] 1,1 bisphosphonic acid 1 [(n octylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n octylthio)ethyl] 1,1 bisphosphonic acid 1 [(n pentylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n pentylthio)ethyl] 1,1 bisphosphonic acid 1 [(n propylthio)ethyl] 1,1 bisphosphonic acid antiinfective agent antiparasitic agent bisphosphonic acid derivative geranyltransferase tetraethyl 1 [(ethylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n but 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n dec 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n hept 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n hex 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n non 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n oct 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n pent 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n prop 1 ylthio)ethyl] 1,1 bisphosphonate unclassified drug unindexed drug amastigote antimicrobial activity article carbon nuclear magnetic resonance drug design drug screening drug structure drug synthesis enzyme activity high performance liquid chromatography nonhuman oxidation proton nuclear magnetic resonance tachyzoite toxoplasmosis Antiprotozoal Agents Diphosphonates Dose-Response Relationship, Drug Drug Design Molecular Structure Parasitic Sensitivity Tests Structure-Activity Relationship Sulfur Toxoplasma
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02235234_v60_n_p431_Recher http://hdl.handle.net/20.500.12110/paper_02235234_v60_n_p431_Recher
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	paper:paper_02235234_v60_n_p431_Recher
record_format	dspace
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Antiparasitic agents Chagas disease Farnesyl diphosphate synthase Toxoplasma gondii Toxoplasmosis Trypanosoma cruzi 1 [(ethylthio)ethyl] 1,1 bisphosphonic acid 1 [(n butylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n butylthio)ethyl] 1,1 bisphosphonic acid 1 [(n decylthio)ethyl] 1,1 bisphosphonic acid 1 [(n hept 2 ylamino)ethyl] 1,1 bisphosphonic acid 1 [(n heptylamino)ethyl] 1 hydroxy 1,1 bisphosphonic acid 1 [(n heptylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n heptylthio)ethyl] 1,1 bisphosphonic acid 1 [(n hexylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n hexylthio)ethyl] 1,1 bisphosphonic acid 1 [(n nonylthio)ethyl] 1,1 bisphosphonic acid 1 [(n octylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n octylthio)ethyl] 1,1 bisphosphonic acid 1 [(n pentylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n pentylthio)ethyl] 1,1 bisphosphonic acid 1 [(n propylthio)ethyl] 1,1 bisphosphonic acid antiinfective agent antiparasitic agent bisphosphonic acid derivative geranyltransferase tetraethyl 1 [(ethylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n but 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n dec 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n hept 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n hex 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n non 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n oct 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n pent 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n prop 1 ylthio)ethyl] 1,1 bisphosphonate unclassified drug unindexed drug amastigote antimicrobial activity article carbon nuclear magnetic resonance Chagas disease drug design drug screening drug structure drug synthesis enzyme activity high performance liquid chromatography nonhuman oxidation proton nuclear magnetic resonance tachyzoite Toxoplasma gondii toxoplasmosis Trypanosoma cruzi Antiprotozoal Agents Diphosphonates Dose-Response Relationship, Drug Drug Design Molecular Structure Parasitic Sensitivity Tests Structure-Activity Relationship Sulfur Toxoplasma Trypanosoma cruzi
spellingShingle	Antiparasitic agents Chagas disease Farnesyl diphosphate synthase Toxoplasma gondii Toxoplasmosis Trypanosoma cruzi 1 [(ethylthio)ethyl] 1,1 bisphosphonic acid 1 [(n butylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n butylthio)ethyl] 1,1 bisphosphonic acid 1 [(n decylthio)ethyl] 1,1 bisphosphonic acid 1 [(n hept 2 ylamino)ethyl] 1,1 bisphosphonic acid 1 [(n heptylamino)ethyl] 1 hydroxy 1,1 bisphosphonic acid 1 [(n heptylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n heptylthio)ethyl] 1,1 bisphosphonic acid 1 [(n hexylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n hexylthio)ethyl] 1,1 bisphosphonic acid 1 [(n nonylthio)ethyl] 1,1 bisphosphonic acid 1 [(n octylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n octylthio)ethyl] 1,1 bisphosphonic acid 1 [(n pentylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n pentylthio)ethyl] 1,1 bisphosphonic acid 1 [(n propylthio)ethyl] 1,1 bisphosphonic acid antiinfective agent antiparasitic agent bisphosphonic acid derivative geranyltransferase tetraethyl 1 [(ethylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n but 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n dec 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n hept 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n hex 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n non 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n oct 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n pent 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n prop 1 ylthio)ethyl] 1,1 bisphosphonate unclassified drug unindexed drug amastigote antimicrobial activity article carbon nuclear magnetic resonance Chagas disease drug design drug screening drug structure drug synthesis enzyme activity high performance liquid chromatography nonhuman oxidation proton nuclear magnetic resonance tachyzoite Toxoplasma gondii toxoplasmosis Trypanosoma cruzi Antiprotozoal Agents Diphosphonates Dose-Response Relationship, Drug Drug Design Molecular Structure Parasitic Sensitivity Tests Structure-Activity Relationship Sulfur Toxoplasma Trypanosoma cruzi Szajnman, Sergio Hernán Moreno, Silvia N. J. Rodríguez, Juan Bautista Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents
topic_facet	Antiparasitic agents Chagas disease Farnesyl diphosphate synthase Toxoplasma gondii Toxoplasmosis Trypanosoma cruzi 1 [(ethylthio)ethyl] 1,1 bisphosphonic acid 1 [(n butylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n butylthio)ethyl] 1,1 bisphosphonic acid 1 [(n decylthio)ethyl] 1,1 bisphosphonic acid 1 [(n hept 2 ylamino)ethyl] 1,1 bisphosphonic acid 1 [(n heptylamino)ethyl] 1 hydroxy 1,1 bisphosphonic acid 1 [(n heptylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n heptylthio)ethyl] 1,1 bisphosphonic acid 1 [(n hexylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n hexylthio)ethyl] 1,1 bisphosphonic acid 1 [(n nonylthio)ethyl] 1,1 bisphosphonic acid 1 [(n octylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n octylthio)ethyl] 1,1 bisphosphonic acid 1 [(n pentylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n pentylthio)ethyl] 1,1 bisphosphonic acid 1 [(n propylthio)ethyl] 1,1 bisphosphonic acid antiinfective agent antiparasitic agent bisphosphonic acid derivative geranyltransferase tetraethyl 1 [(ethylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n but 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n dec 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n hept 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n hex 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n non 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n oct 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n pent 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n prop 1 ylthio)ethyl] 1,1 bisphosphonate unclassified drug unindexed drug amastigote antimicrobial activity article carbon nuclear magnetic resonance Chagas disease drug design drug screening drug structure drug synthesis enzyme activity high performance liquid chromatography nonhuman oxidation proton nuclear magnetic resonance tachyzoite Toxoplasma gondii toxoplasmosis Trypanosoma cruzi Antiprotozoal Agents Diphosphonates Dose-Response Relationship, Drug Drug Design Molecular Structure Parasitic Sensitivity Tests Structure-Activity Relationship Sulfur Toxoplasma Trypanosoma cruzi
description	As part of our efforts aimed at searching for new antiparasitic agents, 2-alkylmercaptoethyl-1,1-bisphosphonate derivatives were synthesized and evaluated against Trypanosoma cruzi, the etiologic agent of Chagas disease, and Toxoplasma gondii, the responsible agent for toxoplasmosis. Many of these sulfur-containing bisphosphonates were potent inhibitors against the intracellular form of T. cruzi, the clinically more relevant replicative form of this parasite, and tachyzoites of T. gondii targeting T. cruzi or T. gondii farnesyl diphosphate synthases (FPPSs), which constitute valid targets for the chemotherapy of these parasitic diseases. Interestingly, long chain length sulfur-containing bisphosphonates emerged as relevant antiparasitic agents. Taking compounds 37, 38, and 39 as representative members of this class of drugs, they exhibited ED50 values of 15.8 μM, 12.8 μM, and 22.4 μM, respectively, against amastigotes of T. cruzi. These cellular activities matched the inhibition of the enzymatic activity of the target enzyme (TcFPPS) having IC50 values of 6.4 μM, 1.7 μM, and 0.097 μM, respectively. In addition, these compounds were potent anti-Toxoplasma agents. They had ED50 values of 2.6 μM, 1.2 μM, and 1.8 μM, respectively, against T. gondii tachyzoites, while they exhibited a very potent inhibitory action against the target enzyme (TgFPPS) showing IC50 values of 0.024 μM, 0.025 μM, and 0.021 μM, respectively. Bisphosphonates bearing a sulfoxide unit at C-3 were also potent anti-Toxoplasma agents, particularly those bearing long aliphatic chains such as 43-45, which were also potent antiproliferative drugs against tachyzoites of T. gondii. These compounds inhibited the enzymatic activity of the target enzyme (TgFPPS) at the very low nanomolar range. These bisphosphonic acids have very good prospective not only as lead drugs but also as potential chemotherapeutic agents.
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	Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents
title_short	Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents
title_full	Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents
title_fullStr	Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents
title_full_unstemmed	Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents
title_sort	design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents
publishDate	2013
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02235234_v60_n_p431_Recher http://hdl.handle.net/20.500.12110/paper_02235234_v60_n_p431_Recher
work_keys_str_mv	AT szajnmansergiohernan designsynthesisandbiologicalevaluationofsulfurcontaining11bisphosphonicacidsasantiparasiticagents AT morenosilvianj designsynthesisandbiologicalevaluationofsulfurcontaining11bisphosphonicacidsasantiparasiticagents AT rodriguezjuanbautista designsynthesisandbiologicalevaluationofsulfurcontaining11bisphosphonicacidsasantiparasiticagents
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spelling	paper:paper_02235234_v60_n_p431_Recher2023-06-08T15:21:45Z Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents Szajnman, Sergio Hernán Moreno, Silvia N. J. Rodríguez, Juan Bautista Antiparasitic agents Chagas disease Farnesyl diphosphate synthase Toxoplasma gondii Toxoplasmosis Trypanosoma cruzi 1 [(ethylthio)ethyl] 1,1 bisphosphonic acid 1 [(n butylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n butylthio)ethyl] 1,1 bisphosphonic acid 1 [(n decylthio)ethyl] 1,1 bisphosphonic acid 1 [(n hept 2 ylamino)ethyl] 1,1 bisphosphonic acid 1 [(n heptylamino)ethyl] 1 hydroxy 1,1 bisphosphonic acid 1 [(n heptylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n heptylthio)ethyl] 1,1 bisphosphonic acid 1 [(n hexylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n hexylthio)ethyl] 1,1 bisphosphonic acid 1 [(n nonylthio)ethyl] 1,1 bisphosphonic acid 1 [(n octylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n octylthio)ethyl] 1,1 bisphosphonic acid 1 [(n pentylsulfinyl)ethyl] 1,1 bisphosphonic acid 1 [(n pentylthio)ethyl] 1,1 bisphosphonic acid 1 [(n propylthio)ethyl] 1,1 bisphosphonic acid antiinfective agent antiparasitic agent bisphosphonic acid derivative geranyltransferase tetraethyl 1 [(ethylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n but 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n dec 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n hept 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n hex 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n non 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n oct 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n pent 1 ylthio)ethyl] 1,1 bisphosphonate tetraethyl 1 [(n prop 1 ylthio)ethyl] 1,1 bisphosphonate unclassified drug unindexed drug amastigote antimicrobial activity article carbon nuclear magnetic resonance Chagas disease drug design drug screening drug structure drug synthesis enzyme activity high performance liquid chromatography nonhuman oxidation proton nuclear magnetic resonance tachyzoite Toxoplasma gondii toxoplasmosis Trypanosoma cruzi Antiprotozoal Agents Diphosphonates Dose-Response Relationship, Drug Drug Design Molecular Structure Parasitic Sensitivity Tests Structure-Activity Relationship Sulfur Toxoplasma Trypanosoma cruzi As part of our efforts aimed at searching for new antiparasitic agents, 2-alkylmercaptoethyl-1,1-bisphosphonate derivatives were synthesized and evaluated against Trypanosoma cruzi, the etiologic agent of Chagas disease, and Toxoplasma gondii, the responsible agent for toxoplasmosis. Many of these sulfur-containing bisphosphonates were potent inhibitors against the intracellular form of T. cruzi, the clinically more relevant replicative form of this parasite, and tachyzoites of T. gondii targeting T. cruzi or T. gondii farnesyl diphosphate synthases (FPPSs), which constitute valid targets for the chemotherapy of these parasitic diseases. Interestingly, long chain length sulfur-containing bisphosphonates emerged as relevant antiparasitic agents. Taking compounds 37, 38, and 39 as representative members of this class of drugs, they exhibited ED50 values of 15.8 μM, 12.8 μM, and 22.4 μM, respectively, against amastigotes of T. cruzi. These cellular activities matched the inhibition of the enzymatic activity of the target enzyme (TcFPPS) having IC50 values of 6.4 μM, 1.7 μM, and 0.097 μM, respectively. In addition, these compounds were potent anti-Toxoplasma agents. They had ED50 values of 2.6 μM, 1.2 μM, and 1.8 μM, respectively, against T. gondii tachyzoites, while they exhibited a very potent inhibitory action against the target enzyme (TgFPPS) showing IC50 values of 0.024 μM, 0.025 μM, and 0.021 μM, respectively. Bisphosphonates bearing a sulfoxide unit at C-3 were also potent anti-Toxoplasma agents, particularly those bearing long aliphatic chains such as 43-45, which were also potent antiproliferative drugs against tachyzoites of T. gondii. These compounds inhibited the enzymatic activity of the target enzyme (TgFPPS) at the very low nanomolar range. These bisphosphonic acids have very good prospective not only as lead drugs but also as potential chemotherapeutic agents. 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. 2013 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02235234_v60_n_p431_Recher http://hdl.handle.net/20.500.12110/paper_02235234_v60_n_p431_Recher

Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents

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