Discovery, synthesis, and biological evaluation of piperidinol analogs with anti-tuberculosis activity.
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.
Sun
Dianqing
D
Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Scherman
Michael S
MS
Jones
Victoria
V
Hurdle
Julian G
JG
Woolhiser
Lisa K
LK
Knudson
Susan E
SE
Lenaerts
Anne J
AJ
Slayden
Richard A
RA
McNeil
Michael R
MR
Lee
Richard E
RE
D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D002522:Chlorocebus aethiops; D055808:Drug Discovery; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014709:Vero Cells
D000995:Antitubercular Agents; D010880:Piperidines; D054852:Small Molecule Libraries