title: Benzophenone-based farnesyltransferase inhibitors with high activity against Trypanosoma cruzi.
abstract: 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.
authors.affiliation: Instituto Nacional de Parasitología Dr. M. Fatala Chabén, A.N.L.I.S., Dr. Carlos G. Malbrán, 1063 Buenos Aires, Argentina.
authors.forename: Mónica I
authors.initials: MI
authors.lastname: Esteva
authors.forename: Katja
authors.initials: K
authors.lastname: Kettler
authors.forename: Cristina
authors.initials: C
authors.lastname: Maidana
authors.forename: Laura
authors.initials: L
authors.lastname: Fichera
authors.forename: Andrés M
authors.initials: AM
authors.lastname: Ruiz
authors.forename: Esteban J
authors.initials: EJ
authors.lastname: Bontempi
authors.forename: Björn
authors.initials: B
authors.lastname: Andersson
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Dahse
authors.forename: Peter
authors.initials: P
authors.lastname: Haebel
authors.forename: Regina
authors.initials: R
authors.lastname: Ortmann
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
authors.forename: Martin
authors.initials: M
authors.lastname: Schlitzer
mesh_terms: 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
chemical_list: D001577:Benzophenones; D021122:Protein Subunits; D014344:Trypanocidal Agents; D051231:Farnesyltranstransferase