title: A novel quinoline derivative that inhibits mycobacterial FtsZ.
abstract: High throughput phenotypic screening of large commercially available libraries through two NIH programs has produced thousands of potentially interesting hits for further development as antitubercular agents. Unfortunately, these screens do not supply target information, and further follow up target identification is required to allow optimal rational design and development of highly active and selective clinical candidates. Cheminformatic analysis of the quinoline and quinazoline hits from these HTS screens suggested a hypothesis that certain compounds in these two classes may target the mycobacterial tubulin homolog, FtsZ. In this brief communication, activity of a lead quinoline against the target FtsZ from Mycobacterium tuberculosis (Mtb) is confirmed as well as good in vitro whole cell antibacterial activity against Mtb H37Rv. The identification of a putative target of this highly tractable pharmacophore should help medicinal chemists interested in targeting FtsZ and cell division develop a rational design program to optimize this activity toward a novel drug candidate.
authors: Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA. mathew@southernresearch.org
authors: Bini
authors: B
authors: Mathew
authors: Larry
authors: L
authors: Ross
authors: Robert C
authors: RC
authors: Reynolds
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors*; D015195:Drug Design; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D058990:Molecular Targeted Therapy / Q000379:methods; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D011804:Quinolines; C037219:quinoline
references: J Med Chem. 1968 Nov;11(6):1216-8
references: 5680040
references: Tuberculosis (Edinb). 2009 Sep;89(5):354-63
references: 19783214
references: Med Chem. 2006 Sep;2(5):505-10
references: 17017990
references: Bioorg Med Chem. 2011 Dec 1;19(23):7120-8
references: 22024272
references: J Med Chem. 2008 Aug 14;51(15):4771-9
references: 18651728
references: Tuberculosis (Edinb). 2009 Sep;89(5):331-3
references: 19716767
references: ChemMedChem. 2007 Nov;2(11):1624-30
references: 17680579
references: PLoS One. 2012;7(3):e33886
references: 22479467
references: Bioorg Med Chem Lett. 2010 Apr 1;20(7):2330-4
references: 20188546
references: Cell. 1995 Feb 10;80(3):367-70
references: 7859278
references: Bioorg Med Chem Lett. 2004 Jun 21;14(12):3161-4
references: 15149666
references: J Antimicrob Chemother. 2002 Jul;50(1):111-4
references: 12096015
references: Org Lett. 2005 Dec 8;7(25):5609-12
references: 16321003
references: Future Med Chem. 2010 Aug;2(8):1305-23
references: 21339840
references: Nat Rev Drug Discov. 2007 Jan;6(1):29-40
references: 17159923
references: Antimicrob Agents Chemother. 2013 Jan;57(1):317-25
references: 23114779
references: Science. 2008 Sep 19;321(5896):1673-5
references: 18801997
references: ChemMedChem. 2006 Jun;1(6):593-7
references: 16892398
references: Science. 2005 Jan 14;307(5707):223-7
references: 15591164
references: Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11821-6
references: 15289600
references: J Med Chem. 2009 Apr 9;52(7):2109-18
references: 19271749
references: ChemMedChem. 2012 Jul;7(7):1161-72
references: 22639193
references: Tuberculosis (Edinb). 2012 Jan;92(1):72-83
references: 21708485
references: Nature. 2011 Jan 27;469(7331):483-90
references: 21270886
references: J Biol Chem. 2003 Nov 7;278(45):44424-8
references: 12952956
references: J Med Chem. 2011 Jan 13;54(1):374-81
references: 21126020
references: J Med Chem. 2009 Apr 23;52(8):2341-51
references: 19296653
references: Tuberculosis (Edinb). 2009 Sep;89(5):334-53
references: 19758845