Quinuclidine derivatives as potential antiparasitics.
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.
Cammerer
Simon B
SB
Welsh School of Pharmacy, Cardiff University, United Kingdom.
Jimenez
Carmen
C
Jones
Simon
S
Gros
Ludovic
L
Lorente
Silvia Orenes
SO
Rodrigues
Carlos
C
Rodrigues
Juliany C F
JC
Caldera
Aura
A
Ruiz Perez
Luis Miguel
LM
da Souza
Wanderley
W
Kaiser
Marcel
M
Brun
Reto
R
Urbina
Julio A
JA
Gonzalez Pacanowska
Dolores
D
Gilbert
Ian H
IH
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
D000977:Antiparasitic Agents; D011812:Quinuclidines; D011994:Recombinant Proteins; D013261:Sterols; D013186:Farnesyl-Diphosphate Farnesyltransferase
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