Quinuclidine Derivatives as Potential Antiparasitics

Cammerer, Simon B.; Jimenez, Carmen; Jones, Simon; Gros, Ludovic; Lorente, Silvia Orenes; Rodrigues, Carlos; Rodrigues, Juliany C. F.; Caldera, Aura; Ruiz Perez, Luis Miguel; da Souza, Wanderley; Kaiser, Marcel; Brun, Reto; Urbina, Julio A.; Gonzalez Pacanowska, Dolores; Gilbert, Ian H.

doi:10.1128/aac.00205-07

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Journal article

Quinuclidine Derivatives as Potential Antiparasitics

Cammerer, Simon B. Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, United Kingdom
Jimenez, Carmen Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Avda. del Conocimiento s/n, Parque Tecnológico de Ciencias de la Salud, 18100-Armilla, Granada, Spain
Jones, Simon Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, United Kingdom
Gros, Ludovic School of Life Sciences, University of Dundee, MSI/WTB/CIR Complex, Dow Street, Dundee DD1 5EH, United Kingdom
Lorente, Silvia Orenes Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, United Kingdom
Rodrigues, Carlos Laboratorio de Química Biológica, Centro de Biofisica y Bioquímica, Instituto Venezolano de Investigaciones Cientificas, Altos de Pipe, Km. 11, Carretera Panamericana, Caracas 1020, Venezuela
Rodrigues, Juliany C. F. Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Bloco G, Ilha do Fundão, 21949-900 Rio de Janeiro, Brazil
Caldera, Aura Laboratorio de Química Biológica, Centro de Biofisica y Bioquímica, Instituto Venezolano de Investigaciones Cientificas, Altos de Pipe, Km. 11, Carretera Panamericana, Caracas 1020, Venezuela
Ruiz Perez, Luis Miguel Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Avda. del Conocimiento s/n, Parque Tecnológico de Ciencias de la Salud, 18100-Armilla, Granada, Spain
da Souza, Wanderley Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Bloco G, Ilha do Fundão, 21949-900 Rio de Janeiro, Brazil
Kaiser, Marcel Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland
Brun, Reto Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland
Urbina, Julio A. Laboratorio de Química Biológica, Centro de Biofisica y Bioquímica, Instituto Venezolano de Investigaciones Cientificas, Altos de Pipe, Km. 11, Carretera Panamericana, Caracas 1020, Venezuela
Gonzalez Pacanowska, Dolores Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Avda. del Conocimiento s/n, Parque Tecnológico de Ciencias de la Salud, 18100-Armilla, Granada, Spain
Gilbert, Ian H. School of Life Sciences, University of Dundee, MSI/WTB/CIR Complex, Dow Street, Dundee DD1 5EH, United Kingdom

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Antimicrobial Agents and Chemotherapy. - American Society for Microbiology. - 2007, vol. 51, no. 11, p. 4049-4061

English 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.

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