Discovery of dipiperidines as new antitubercular agents.
As part of our ongoing research effort to develop new therapeutics for treatment of tuberculosis (TB), we synthesized a combinatorial library of 10,358 compounds on solid support using a pool-and-split technique and tested the resulting compounds for activity against Mycobacteriumtuberculosis. Structure-activity relationship (SAR) evaluation identified new compounds with antitubercular activity, including a novel hit series that is structurally unrelated to any existing antitubercular drugs, dipiperidines. Dipiperidine representatives exhibited MIC values as low as 7.8microM, the ability to induce promoter Rv0341 activated in response to cell wall biosynthesis inhibition, relatively low nonspecific cellular toxicity in the range of 30-162microM, and logP values less than 4.
Bogatcheva
Elena
E
Sequella, Inc., 9610 Medical center Drive, Suite 200, Rockville, MD 20850, USA. elenabogatcheva@sequella.com
Hanrahan
Colleen
C
Chen
Ping
P
Gearhart
Jacqueline
J
Sacksteder
Katherine
K
Einck
Leo
L
Nacy
Carol
C
Protopopova
Marina
M
D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D055808:Drug Discovery; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
D000995:Antitubercular Agents; D010880:Piperidines; D054852:Small Molecule Libraries