Identification of SQ609 as a lead compound from a library of dipiperidines

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 18; pp. 5353 - 5357
• Main Authors: Bogatcheva, Elena, Hanrahan, Colleen, Nikonenko, Boris, de los Santos, Gladys, Reddy, Venkata, Chen, Ping, Barbosa, Francis, Einck, Leo, Nacy, Carol, Protopopova, Marina
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-09-2011; Elsevier
• Subjects: (Piperidin-4-ylmethyl)piperidine; Adamantane - analogs & derivatives; Adamantane - chemical synthesis; Adamantane - chemistry; Adamantane - pharmacology; Animals; Antibacterial agents; antibacterial properties; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Biological and medical sciences; Combinatorial library; Dipiperidine scaffold; Disease Models, Animal; Dose-Response Relationship, Drug; macrophages; Macrophages - drug effects; Macrophages - microbiology; Medical sciences; Mice; Mice, Inbred C3H; microbial growth; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - growth & development; Pharmacology. Drug treatments; piperidines; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Small Molecule Libraries; Structure-Activity Relationship; structure-activity relationships; therapeutics; toxicity; Tuberculosis; weight loss; Weight Loss - drug effects; Dipiperidine scaffold; Tuberculosis; (Piperidin-4-ylmethyl)piperidine; Combinatorial library; Combinatorial chemistry; Mycobacterial infection; Structure activity relation; Chemical compound library; Piperidine derivatives; Bacteria; Antituberculous agent; Aminoalcohol; Rodentia; Oral administration; In vitro; Infection; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mycobacterium tuberculosis; Mouse; Mycobacteriales; Animal; Bacteriosis; Mycobacteriaceae; Actinomycetes; Antibacterial agent
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2011.07.015

We recently reported that compounds created around a dipiperidine scaffold demonstrated activity against Mycobacterium tuberculosis (Mtb) (Bogatcheva, E.; Hanrahan, C.; Chen, P.; Gearhart, J.; Sacksteder, K.; Einck, L.; Nacy, C.; Protopopova, M. Bioorg. Med. Chem. Lett.2010, 20, 201). To optimize the dipiperidine compound series and to select a lead compound to advance into preclinical studies, we evaluated the structure–activity relationship (SAR) of our proprietary libraries. The (piperidin-4-ylmethyl)piperidine scaffold was an essential structural element required for antibacterial activity. Based on SAR, we synthesized a focused library of 313 new dipiperidines to delineate additional structural features responsible for antitubercular activity. Thirty new active compounds with MIC 10–20μg/ml on Mtb were identified, but none was better than the original hits of this series, SQ609, SQ614, and SQ615. In Mtb-infected macrophages in vitro, SQ609 and SQ614 inhibited more than 90% of intracellular bacterial growth at 4μg/ml; SQ615 was toxic to these cells. In mice infected with Mtb, weight loss was completely prevented by SQ609, but not SQ614, and SQ609 had a prolonged therapeutic effect, extended by 10–15days, after cessation of therapy. Based on in vitro and in vivo antitubercular activity, SQ609 was identified as the best-in-class dipiperidine compound in the series.