title: New insights into molecular recognition of 1,1-bisphosphonic acids by farnesyl diphosphate synthase.
abstract: As part of our project pointed at the search of new antiparasitic agents against American trypanosomiasis (Chagas disease) and toxoplasmosis a series of 2-alkylaminoethyl-1-hydroxy-1,1-bisphosphonic acids has been designed, synthesized and biologically evaluated against the etiologic agents of these parasitic diseases, Trypanosoma cruzi and Toxoplasma gondii, respectively, and also towards their target enzymes, T. cruzi and T. gondii farnesyl pyrophosphate synthase (FPPS), respectively. Surprisingly, while most pharmacologically active bisphosphonates have a hydroxyl group at the C-1 position, the additional presence of an amino group at C-3 resulted in decreased activity towards either T. cruzi cells or TcFPPS. Density functional theory calculations justify this unexpected behavior. Although these compounds were devoid of activity against T. cruzi cells and TcFPPS, they were efficient growth inhibitors of tachyzoites of T. gondii. This activity was associated with a potent inhibition of the enzymatic activity of TgFPPS. Compound 28 arises as a main example of this family of compounds exhibiting an ED₅₀ value of 4.7 μM against tachyzoites of T. gondii and an IC₅₀ of 0.051 μM against TgFPPS.
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: Mariana
authors.initials: M
authors.lastname: Ferrer-Casal
authors.affiliation: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Li
authors.affiliation: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Melina
authors.initials: M
authors.lastname: Galizzi
authors.affiliation: Departamento de Química Orgánica and CIHIDECAR, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA Buenos Aires, Argentina.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Stortz
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: Sergio H
authors.initials: SH
authors.lastname: Szajnman
authors.affiliation: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Docampo
authors.affiliation: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Silvia N J
authors.initials: SN
authors.lastname: Moreno
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. Electronic address: jbr@qo.fcen.uba.ar.
authors.forename: Juan B
authors.initials: JB
authors.lastname: Rodriguez
mesh_terms: D000977:Antiparasitic Agents / Q000494:pharmacology*; D004164:Diphosphonates / Q000494:pharmacology*; D015195:Drug Design; D051228:Geranyltranstransferase / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014122:Toxoplasma / Q000201:enzymology* / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000201:enzymology* / Q000378:metabolism
chemical_list: D000977:Antiparasitic Agents; D004164:Diphosphonates; D051228:Geranyltranstransferase
keywords: Antiparasitic agents; Bisphosphonates; Farnesyl pyrophosphate synthase; Toxoplasma gondii; Trypanosoma cruzi