Discovery of dipiperidines as new antitubercular agents

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 1; pp. 201 - 205
• Main Authors: Bogatcheva, Elena, Hanrahan, Colleen, Chen, Ping, Gearhart, Jacqueline, Sacksteder, Katherine, Einck, Leo, Nacy, Carol, Protopopova, Marina
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.01.2010; Elsevier
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Antitubercular drugs; Biological and medical sciences; Dipiperidines; Drug Discovery; Medical sciences; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Small Molecule Libraries; Structure-Activity Relationship; Tuberculosis; Dipiperidines; Antitubercular drugs; Tuberculosis; Aminoalcohol; Benzene derivatives; In vitro; Diamine; Mycobacterium tuberculosis; Structure activity relation; Mycobacteriales; Chemical compound library; Piperidine derivatives; Mycobacteriaceae; Bacteria; Actinomycetes; Antituberculous agent; Solid phase; Antibacterial agent; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.10.135

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 Mycobacterium tuberculosis. 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 7.8 μM, the ability to induce promoter Rv0341 activated in response to cell wall biosynthesis inhibition, relatively low nonspecific cellular toxicity in the range of 30–162 μM, and log P values less than 4.