title: Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase.
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 IC(50) 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 IC(50) value of 0.67 μM, while this compound showed an IC(50) 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 IC(50) value of 3.2 μM. Interestingly, compound 26 was also very effective against T. gondii (tachyzoites) exhibiting IC(50) values of 6.23 μM. This cellular activity was also related to the inhibition of the enzymatic activity towards the target enzyme TgFPPS (IC(50)=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.
authors.affiliation: Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA Buenos Aires, Argentina.
authors.forename: Valeria S
authors.initials: VS
authors.lastname: Rosso
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Szajnman
authors.forename: Leena
authors.initials: L
authors.lastname: Malayil
authors.forename: Melina
authors.initials: M
authors.lastname: Galizzi
authors.forename: Silvia N J
authors.initials: SN
authors.lastname: Moreno
authors.forename: Roberto
authors.initials: R
authors.lastname: Docampo
authors.forename: Juan B
authors.initials: JB
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D004164:Diphosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D013329:Structure-Activity Relationship; D014122:Toxoplasma / Q000187:drug effects* / Q000201:enzymology; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology; D014709:Vero Cells
chemical_list: D000981:Antiprotozoal Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D051228:Geranyltranstransferase