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

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2216-9. doi: 10.1016/j.bmcl.2011.03.004. Epub 2011 Mar 6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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


  • Azasteroids
  • Enzyme Inhibitors
  • 3-Hydroxysteroid Dehydrogenases