Benzophenone-based farnesyltransferase inhibitors with high activity against Trypanosoma cruzi.
Less toxic drugs are needed to combat the human parasite Trypanosoma cruzi (Chagas's disease). One novel target for antitrypanosomal drug design is farnesyltransferase. Several farnesyltransferase inhibitors based on the benzophenone scaffold were assayed in vitro and in vivo with the parasite. The common structural feature of all inhibitors is an amino function which can be protonated. Best in vitro activity (LC50 values 1 and 10 nM, respectively) was recorded for the R-phenylalanine derivative 4a and for the N-propylpiperazinyl derivative 2f. These inhibitors showed no cytotoxicity to cells. When tested in vivo, the survival rates of infected animals receiving the inhibitors at 7 mg/kg body weight/day were 80 and 60% at day 115 postinfection, respectively.
Esteva
Mónica I
MI
Instituto Nacional de Parasitología Dr. M. Fatala Chabén, A.N.L.I.S., Dr. Carlos G. Malbrán, 1063 Buenos Aires, Argentina.
Kettler
Katja
K
Maidana
Cristina
C
Fichera
Laura
L
Ruiz
Andrés M
AM
Bontempi
Esteban J
EJ
Andersson
Björn
B
Dahse
Hans-Martin
HM
Haebel
Peter
P
Ortmann
Regina
R
Klebe
Gerhard
G
Schlitzer
Martin
M
D000818:Animals; D001577:Benzophenones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014355:Chagas Disease / Q000401:mortality / Q000469:parasitology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D021122:Protein Subunits / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
D001577:Benzophenones; D021122:Protein Subunits; D014344:Trypanocidal Agents; D051231:Farnesyltranstransferase