UMYMFOR   05516
UNIDAD DE MICROANALISIS Y METODOS FISICOS EN QUIMICA ORGANICA
Unidad Ejecutora - UE
artículos
Título:
New Insights into Molecular Recognition of 1,1-Bisphosphonic Acids by Farnesyl Pyrophosphate Synthase
Autor/es:
MARIANA FERRER-CASAL; CATHERINE LI; MELINA GALLIZI; CARLOS A. STORTZ; SERGIO H. SZAJNMAN; ROBERTO DOCAMPO; SILVIA N. J. MORENO; JUAN B. RODRÍGUEZ
Revista:
BIOORGANIC & MEDICINAL CHEMISTRY.
Editorial:
PERGAMON-ELSEVIER SCIENCE LTD
Referencias:
Lugar: Amsterdam; Año: 2014 vol. 22 p. 398 - 405
ISSN:
0968-0896
Resumen:
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