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Azasterols as inhibitors of sterol 24-methyltransferase in Leishmania species and Trypanosoma cruzi.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2003 Oct 23; Vol. 46 (22), pp. 4714-27. - Publication Year :
- 2003
-
Abstract
- 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.
- Subjects :
- Animals
Aza Compounds chemistry
Aza Compounds pharmacology
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Leishmania enzymology
Leishmania ultrastructure
Methyltransferases chemistry
Pregnanediol analogs & derivatives
Pregnanediol chemistry
Pregnanediol pharmacology
Recombinant Proteins chemistry
Species Specificity
Sterols chemistry
Sterols pharmacology
Structure-Activity Relationship
Trypanocidal Agents chemistry
Trypanocidal Agents pharmacology
Trypanosoma enzymology
Trypanosoma ultrastructure
Aza Compounds chemical synthesis
Enzyme Inhibitors chemical synthesis
Leishmania drug effects
Methyltransferases antagonists & inhibitors
Pregnanediol chemical synthesis
Sterols chemical synthesis
Trypanocidal Agents chemical synthesis
Trypanosoma drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 46
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 14561091
- Full Text :
- https://doi.org/10.1021/jm021114j