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

Elena Bogatcheva, Colleen Hanrahan, Boris Nikonenko, Gladys De Los Santos, Venkata Reddy, Ping Chen, Francis Barbosa, Leo Einck, Carol Nacy, Marina Protopopova

Research output: Contribution to journalArticle

Abstract

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 10-20 μg/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 4 μg/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 10-15 days, 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.

Original languageEnglish (US)
Pages (from-to)5353-5357
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number18
DOIs
StatePublished - Sep 15 2011

Keywords

  • (Piperidin-4-ylmethyl)piperidine
  • Combinatorial library
  • Dipiperidine scaffold
  • Tuberculosis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Bogatcheva, E., Hanrahan, C., Nikonenko, B., De Los Santos, G., Reddy, V., Chen, P., Barbosa, F., Einck, L., Nacy, C., & Protopopova, M. (2011). Identification of SQ609 as a lead compound from a library of dipiperidines. Bioorganic and Medicinal Chemistry Letters, 21(18), 5353-5357. https://doi.org/10.1016/j.bmcl.2011.07.015