Discovery, synthesis, and biological evaluation of piperidinol analogs with anti-tuberculosis activity.

Dianqing Sun, Michael S Scherman, Victoria Jones, Julian G Hurdle, Lisa K Woolhiser, Susan E Knudson, Anne J Lenaerts, Richard A Slayden, Michael R McNeil, Richard E Lee

Index: Bioorg. Med. Chem. 17 , 3588-3594, (2009)

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Abstract

Direct anti-tuberculosis screening of commercially available compound libraries identified a novel piperidinol with interesting anti-tuberculosis activity and drug like characteristics. To generate a structure activity relationship about this hit a 22 member optimization library was generated using parallel synthesis. Products of this library 1-((R)-3-(4-chlorophenoxy)-2-hydroxypropyl)-4-(4-chloro-3-(trifluoromethyl) phenyl)piperidin-4-ol and 1-((S)-3-(4-(trifluoromethyl) phenoxy)-2-hydroxypropyl)-4-(4-chloro-3-(trifluoromethyl) phenyl) piperidin-4-ol demonstrated good anti-tuberculosis activity. Unfortunately, side effects were observed upon in vivo anti-tuberculosis testing of these compounds precluding their further advancement, which may be in part due to the secondary pharmacology associated with the aryl piperidinol core.