Azasterols as inhibitors of sterol 24-methyltransferase in leishmania species and Trypanosoma cruzi

Filippo Magaraci, Carmen Jimenez, Carlos Rodrigues, Juliany C. F. Rodrigues, Marina Vianna Braga, Vanessa Yardley, Kate de Luca-Fradley, Simon L. Croft, Wanderley de Souza, Luis M. Ruiz-Perez, Julio Urbina, Dolores Gonzalez Pacanowska, Ian H. Gilbert

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    Abstract

    This paper describes the synthesis of some novel azasterols based on (20R,22xi)-5alpha-pregnan-20-(piperidin-2-yl)-3ß,20-diol. These compounds are potential inhibitors of the enzyme sterol 24-methyltransferase (24-SMT), which is a vital enzyme in the biosynthesis of ergosterol and related 24-alkyl sterols. Structure-activity studies were undertaken to understand the important features for activity against the enzyme, with the aim of increasing activity and selectivity. The compounds were evaluated for inhibition of recombinant Leishmania major 24-SMT and the effect of compounds on sterol composition and parasite proliferation. Essentially, compounds which showed good activity against the recombinant enzyme had a significant effect on the sterol composition and growth of parasites. The activity of compounds was found to be related to the basicity and stereochemical location of the nitrogen. Also, presence of an unprotected 3ß-OH seemed to be important for activity. However, some azasterols which were not good inhibitors of 24-SMT also showed antiproliferative activity, suggesting that there may be other modes of actions of these compounds.

    Original languageEnglish
    Pages (from-to)4714-4727
    Number of pages14
    JournalJournal of Medicinal Chemistry
    Volume46
    Issue number22
    DOIs
    Publication statusPublished - 23 Oct 2003

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