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

Magaraci, F; Jimenez, CJ; Rodrigues, C; Rodrigues, JCF; Braga, MV; Yardley, V; de Luca-Fradley, K; Croft, SL; de Souza, W; Ruiz-Perez, LM; Urbina, J; Pacanowska, DG; Gilbert, IH; (2003) Azasterols as inhibitors of sterol 24-methyltransferase in leishmania species and Trypanosoma cruzi. Journal of medicinal chemistry, 46 (22). pp. 4714-4727. ISSN 0022-2623 DOI:

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This paper describes the synthesis of some novel azasterols based on (20R,22xi)-5alpha-pregnan-20-(piperidin-2-yl)- 3beta,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 3beta-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.

Item Type: Article
Keywords: methyl transferase inhibitors, schizotrypanum cruzi, in-vitro, ultrastructural alterations, ketoconazole, donovani, growth, biosynthesis, combinations, mechanism, Animal, Aza Compounds, chemical synthesis, chemistry, pharmacology, Enzyme Inhibitors, chemical synthesis, chemistry, pharmacology, Leishmania, drug effects, enzymology, ultrastructure, Methyltransferases, antagonists & inhibitors, chemistry, Pregnanediol, analogs & derivatives, chemical synthesis, chemistry, pharmacology, Recombinant Proteins, chemistry, Species Specificity, Sterols, chemical synthesis, chemistry, pharmacology, Structure-Activity Relationship, Support, Non-U.S. Gov't, Trypanocidal Agents, chemical synthesis, chemistry, pharmacology, Trypanosoma, drug effects, enzymology, ultrastructure
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Research Centre: Leishmaniasis Group
Malaria Centre
Neglected Tropical Diseases Network
PubMed ID: 14561091
Web of Science ID: 185991100012


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