title: Design, synthesis and evaluation of novel 2,5,6-trisubstituted benzimidazoles targeting FtsZ as antitubercular agents.
abstract: Filamenting temperature-sensitive protein Z (FtsZ), an essential cell division protein, is a promising target for the drug discovery of new-generation antibacterial agents against various bacterial pathogens. As a part of SAR studies on benzimidazoles, we have synthesized a library of 376 novel 2,5,6-trisubstituted benzimidazoles, bearing ether or thioether linkage at the 6-position. In a preliminary HTP screening against Mtb H37Rv, 108 compounds were identified as hits at a cut off concentration of 5 μg/mL. Among those hits, 10 compounds exhibited MIC values in the range of 0.63-12.5 μg/mL. Light scattering assay and TEM analysis with the most potent compound 5a clearly indicate that its molecular target is Mtb-FtsZ. Also, the Kd of 5a with Mtb-FtsZ was determined to be 1.32 μM.
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, United States.
authors.forename: Bora
authors.initials: B
authors.lastname: Park
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, United States.
authors.forename: Divya
authors.initials: D
authors.lastname: Awasthi
authors.affiliation: Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, United States.
authors.forename: Soumya R
authors.initials: SR
authors.lastname: Chowdhury
authors.affiliation: Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, United States.
authors.forename: Eduard H
authors.initials: EH
authors.lastname: Melief
authors.affiliation: Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, United States.
authors.forename: Kunal
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-0922, United States.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Knudson
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-0922, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Slayden
authors.affiliation: Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, United States. Electronic address: iwao.ojima@stonybrook.edu.
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D019843:Archaeal Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D019843:Archaeal Proteins; D001562:Benzimidazoles; C119586:FtsZ protein, Methanococcus jannaschii
keywords: Antibacterial; Benzimidazole; FtsZ; Tuberculosis
references.citation: J Comb Chem. 2004 Sep-Oct;6(5):811-21
references.pmid: 15360218
references.citation: Expert Opin Ther Pat. 2011 May;21(5):657-79
references.pmid: 21413908
references.citation: Antimicrob Agents Chemother. 1997 May;41(5):1004-9
references.pmid: 9145860
references.citation: J Med Chem. 2011 Jan 13;54(1):374-81
references.pmid: 21126020
references.citation: Tuberculosis (Edinb). 2008 Sep;88(5):420-9
references.pmid: 18479968
references.citation: J Bacteriol. 1999 Feb;181(3):823-32
references.pmid: 9922245
references.citation: Curr Top Med Chem. 2007;7(5):527-43
references.pmid: 17346197
references.citation: Microbiol Mol Biol Rev. 2003 Mar;67(1):52-65, table of contents
references.pmid: 12626683
references.citation: FEMS Microbiol Lett. 2000 Oct 1;191(1):25-9
references.pmid: 11004395
references.citation: Lancet. 2006 Nov 4;368(9547):1575-80
references.pmid: 17084757
references.citation: Bioorg Med Chem Lett. 2004 Jun 21;14(12):3161-4
references.pmid: 15149666
references.citation: Annu Rev Microbiol. 2003;57:125-54
references.pmid: 14527275
references.citation: J Antimicrob Chemother. 2002 Jul;50(1):111-4
references.pmid: 12096015
references.citation: J Med Chem. 2013 Dec 12;56(23):9756-70
references.pmid: 24266862
references.citation: Microbiology (Reading). 2006 Jun;152(Pt 6):1789-1797
references.pmid: 16735741
references.citation: Nature. 1991 Nov 14;354(6349):161-4
references.pmid: 1944597
references.citation: Future Med Chem. 2010 Aug;2(8):1305-23
references.pmid: 21339840
references.citation: Bioconjug Chem. 2010 May 19;21(5):979-87
references.pmid: 20429547
references.citation: Cell. 2002 Apr 19;109(2):257-66
references.pmid: 12007411
references.citation: J Immunol Methods. 1983 Dec 16;65(1-2):55-63
references.pmid: 6606682
references.citation: Bioorg Med Chem. 2012 Dec 15;20(24):7012-29
references.pmid: 23127490
references.citation: Scott Med J. 2000 Oct;45(5 Suppl):52-5; discussion 56
references.pmid: 11130318
references.citation: J Bacteriol. 2000 Jul;182(14):4028-34
references.pmid: 10869082
references.citation: Curr Opin Microbiol. 2001 Dec;4(6):634-8
references.pmid: 11731313