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Antimicrobial Agents and Chemotherapy, August 2004, p. 2937-2950, Vol. 48, No. 8
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.8.2937-2950.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Novel Azasterols as Potential Agents for Treatment of Leishmaniasis and Trypanosomiasis

Welsh School of Pharmacy, Cardiff University, Cardiff, CF10 3XF,¹ Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom,⁵ Laboratorio de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Ilha do Fundão 21949-900, Rio de Janeiro, Brazil,² Instituto de Parasitología y Biomedicina "López-Neyra," 18001 Granada, Spain,³ Laboratorio de Química Biológica, Centro de Bioquímica y Biofísica, Instituto Venezolano de Investigaciones Científicas, Carretera Panamericana, Caracas 1020, Venezuela⁴

Received 9 October 2003/ Returned for modification 29 December 2003/ Accepted 29 March 2004

This paper describes the design and evaluation of novel azasterols as potential compounds for the treatment of leishmaniasis and other diseases caused by trypanosomatid parasites. Azasterols are a known class of (S)-adenosyl-L-methionine: ²⁴-sterol methyltransferase(24-SMT) inhibitors in fungi, plants, and some parasitic protozoa. The compounds prepared showed activity at micromolar and nanomolar concentrations when tested against Leishmania spp. and Trypanosoma spp. The enzymatic and sterol composition studies indicated that the most active compounds acted by inhibiting 24-SMT. The role of the free hydroxyl group at position 3 of the sterol nucleus was also probed. When an acetate was attached to the 3ß-OH, the compounds did not inhibit the enzyme but had an effect on parasite growth and the levels of sterols in the parasite, suggesting that the acetate group was removed in the organism. Thus, an acetate group on the 3ß-OH may have application as a prodrug. However, there may be an additional mode(s) of action for these acetate derivatives. These compounds were shown to have ultrastructural effects on Leishmania amazonensis promastigote membranes, including the plasma membrane, the mitochondrial membrane, and the endoplasmic reticulum. The compounds were also found to be active against the bloodstream form (trypomastigotes) of Trypanosoma brucei rhodesiense, a causative agent of African trypanosomiasis.

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