title: Biphenylquinuclidines as inhibitors of squalene synthase and growth of parasitic protozoa.
abstract: In this paper we describe the preparation of some biphenylquinuclidine derivatives and their evaluation as inhibitors of squalene synthase in order to explore their potential in the treatment of the parasitic diseases leishmaniasis and Chagas disease. The compounds were screened against recombinant Leishmania major squalene synthase and against Leishmania mexicana promastigotes, Leishmania donovani intracellular amastigotes and Trypanosoma cruzi intracellular amastigotes. Compounds that inhibited the enzyme, also reduced the levels of steroids and caused growth inhibition of L. mexicana promastigotes. However there was a lower correlation between inhibition of the enzyme and growth inhibition of the intracellular parasites, possibly due to delivery problems. Some compounds also showed growth inhibition of T. brucei rhodesiense trypomastigotes, although in this case alternative modes of action other than inhibition of SQS are probably involved.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Orenes Lorente
authors.forename: Rosario
authors.initials: R
authors.lastname: Gómez
authors.forename: Carmen
authors.initials: C
authors.lastname: Jiménez
authors.forename: Simon
authors.initials: S
authors.lastname: Cammerer
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.forename: Kate
authors.initials: K
authors.lastname: de Luca-Fradley
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
authors.forename: Luis M
authors.initials: LM
authors.lastname: Ruiz Perez
authors.forename: Julio
authors.initials: J
authors.lastname: Urbina
authors.forename: Dolores
authors.initials: D
authors.lastname: Gonzalez Pacanowska
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D016503:Drug Delivery Systems; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification; D006801:Humans; D007624:KB Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D007893:Leishmania donovani / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D018320:Leishmania major / Q000187:drug effects / Q000201:enzymology; D007894:Leishmania mexicana / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D007896:Leishmaniasis / Q000188:drug therapy* / Q000469:parasitology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000469:parasitology; D051379:Mice; D011812:Quinuclidines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D013261:Sterols / Q000378:metabolism*; D013329:Structure-Activity Relationship; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D014352:Trypanosomiasis / Q000188:drug therapy* / Q000469:parasitology
chemical_list: D000981:Antiprotozoal Agents; D011812:Quinuclidines; D013261:Sterols; D013186:Farnesyl-Diphosphate Farnesyltransferase