title: Quinuclidine derivatives as potential antiparasitics.
abstract: There is an urgent need for the development of new drugs for the treatment of tropical parasitic diseases such as Chagas' disease and leishmaniasis. One potential drug target in the organisms that cause these diseases is sterol biosynthesis. This paper describes the design and synthesis of quinuclidine derivatives as potential inhibitors of a key enzyme in sterol biosynthesis, squalene synthase (SQS). A number of compounds that were inhibitors of the recombinant Leishmania major SQS at submicromolar concentrations were discovered. Some of these compounds were also selective for the parasite enzyme rather than the homologous human enzyme. The compounds inhibited the growth of and sterol biosynthesis in Leishmania parasites. In addition, we identified other quinuclidine derivatives that inhibit the growth of Trypanosoma brucei (the causative organism of human African trypanosomiasis) and Plasmodium falciparum (a causative agent of malaria), but through an unknown mode(s) of action.
authors: Welsh School of Pharmacy, Cardiff University, United Kingdom.
authors: Simon B
authors: SB
authors: Cammerer
authors: Carmen
authors: C
authors: Jimenez
authors: Simon
authors: S
authors: Jones
authors: Ludovic
authors: L
authors: Gros
authors: Silvia Orenes
authors: SO
authors: Lorente
authors: Carlos
authors: C
authors: Rodrigues
authors: Juliany C F
authors: JC
authors: Rodrigues
authors: Aura
authors: A
authors: Caldera
authors: Luis Miguel
authors: LM
authors: Ruiz Perez
authors: Wanderley
authors: W
authors: da Souza
authors: Marcel
authors: M
authors: Kaiser
authors: Reto
authors: R
authors: Brun
authors: Julio A
authors: JA
authors: Urbina
authors: Dolores
authors: D
authors: Gonzalez Pacanowska
authors: Ian H
authors: IH
authors: Gilbert
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018320:Leishmania major / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism; D011812:Quinuclidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013261:Sterols / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000378:metabolism
chemical_list: D000977:Antiparasitic Agents; D011812:Quinuclidines; D011994:Recombinant Proteins; D013261:Sterols; D013186:Farnesyl-Diphosphate Farnesyltransferase
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