1-(Fluoroalkylidene)-1,1-bisphosphonic acids are potent and selective inhibitors of the enzymatic activity of Toxoplasma gondii farnesyl pyrophosphate synthase.
α-Fluorinated-1,1-bisphosphonic acids derived from fatty acids were designed, synthesized and biologically evaluated against Trypanosoma cruzi, the etiologic agent of Chagas disease, and against Toxoplasma gondii, the agent responsible for toxoplasmosis, and also towards the target parasitic enzymes farnesyl pyrophosphate synthase of T. cruzi (TcFPPS) and T. gondii (TgFPPS). Interestingly, 1-fluorononylidene-1,1-bisphosphonic acid (compound 43) proved to be an extremely potent inhibitor of the enzymatic activity of TgFPPS at the low nanomolar range, exhibiting an IC(50) of 30 nM. This compound was two-fold more potent than risedronate (IC(50) = 74 nM) that was taken as a positive control. This enzymatic activity was associated with a strong cell growth inhibition against tachyzoites of T. gondii, with an IC(50) value of 2.7 μM.
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.
Sergio H
SH
Szajnman
Valeria S
VS
Rosso
Leena
L
Malayil
Alyssa
A
Smith
Silvia N J
SN
Moreno
Roberto
R
Docampo
Juan B
JB
Rodriguez
D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014122:Toxoplasma / Q000201:enzymology* / Q000378:metabolism
C574211:1-fluorononylidene-1,1-bisphosphonic acid; D000981:Antiprotozoal Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D051228:Geranyltranstransferase