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Antimicrobial Agents and Chemotherapy, November 2007, p. 4049-4061, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00205-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Quinuclidine Derivatives as Potential Antiparasitics{triangledown}

Simon B. Cammerer,1 Carmen Jimenez,2 Simon Jones,1 Ludovic Gros,3 Silvia Orenes Lorente,1 Carlos Rodrigues,4 Juliany C. F. Rodrigues,5 Aura Caldera,4 Luis Miguel Ruiz Perez,2 Wanderley da Souza,5 Marcel Kaiser,6 Reto Brun,6 Julio A. Urbina,4 Dolores Gonzalez Pacanowska,2 and Ian H. Gilbert1,3*

Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, United Kingdom,1 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,2 School of Life Sciences, University of Dundee, MSI/WTB/CIR Complex, Dow Street, Dundee DD1 5EH, United Kingdom,3 Laboratorio de Química Biológica, Centro de Biofisica y Bioquímica, Instituto Venezolano de Investigaciones Cientificas, Altos de Pipe, Km. 11, Carretera Panamericana, Caracas 1020, Venezuela,4 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,5 Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland6

Received 12 February 2007/ Returned for modification 15 April 2007/ Accepted 28 July 2007

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.

* Corresponding author. Mailing address: School of Life Sciences, University of Dundee, MSI/WTB/CIR Complex, Dow Street, Dundee DD1 5EH, United Kingdom. Phone: 44 1382 386 240. Fax: 44 1382 386 373. E-mail: i.h.gilbert{at}dundee.ac.uk

{triangledown} Published ahead of print on 20 August 2007.

Antimicrobial Agents and Chemotherapy, November 2007, p. 4049-4061, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00205-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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