Inhibition of the M. tuberculosis 3β-hydroxysteroid dehydrogenase by azasteroids.

Abstract

The cholesterol metabolism pathway in Mycobacterium tuberculosis (M. tb) is a potential source of energy as well as secondary metabolite production that is important for survival of M. tb in the host macrophage. Oxidation and isomerization of 3β-hydroxysterols to 4-en-3-ones is requisite for sterol metabolism and the reaction is catalyzed by 3β-hydroxysteroid dehydrogenase (Rv1106c). Three series of 6-azasteroids and 4-azasteroids were employed to define the substrate preferences of M. tb 3β-hydroxysteroid dehydrogenase. 6-Azasteroids with large, hydrophobic side chains at the C17 position are the most effective inhibitors. Substitutions at C1, C2, C4 and N6 were poorly tolerated. Our structure-activity studies indicate that the 6-aza version of cholesterol is the best and tightest binding competitive inhibitor (K(i)=100 nM) of the steroid substrate and are consistent with cholesterol being the preferred substrate of M. tb 3β-hydroxysteroid dehydrogenase.

• Authors: Suzanne T Thomas, Xinxin Yang, Nicole S Sampson
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 8 Pg. 2216-9 (Apr 15 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 21439822 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Azasteroids
• Enzyme Inhibitors
• 3-Hydroxysteroid Dehydrogenases

Topics

• 3-Hydroxysteroid Dehydrogenases (antagonists & inhibitors, metabolism)
• Azasteroids (chemical synthesis, chemistry, pharmacology)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Mycobacterium tuberculosis (drug effects, enzymology)
• Structure-Activity Relationship