title: Synthesis and antibacterial evaluation of new, unsymmetrical triaryl bisamidine compounds.
abstract: Herein we describe the synthesis and antibacterial evaluation of a new, unsymmetrical triaryl bisamidine compound series, [Am]-[indole]-[linker]-[HetAr/Ar]-[Am], in which [Am] is an amidine or amino group, [linker] is a benzene, thiophene or pyridine ring, and [HetAr/Ar] is a benzimidazole, imidazopyridine, benzofuran, benzothiophene, pyrimidine or benzene ring. When the [HetAr/Ar] unit is a 5,6-bicyclic heterocycle, it is oriented such that the 5-membered ring portion is connected to the [linker] unit and the 6-membered ring portion is connected to the [Am] unit. Among the 34 compounds in this series, compounds with benzofuran as the [HetAr/Ar] unit showed the highest potencies. Introduction of a fluorine atom or a methyl group to the triaryl core led to the more potent analogs. Bisamidines are more active toward bacteria while the monoamidines are more active toward mammalian cells (as indicated by low CC50 values). Importantly, we identified compound P12a (MBX 1887) with a relatively narrow spectrum against bacteria and a very high CC50 value. Compound P12a has been scaled up and is currently undergoing further evaluations for therapeutic applications.
authors: Microbiotix, Inc., 1 Innovation Drive, Worcester, MA 01604, USA. Electronic address: snguyen@microbiotix.com.
authors: Son T
authors: ST
authors: Nguyen
authors: Microbiotix, Inc., 1 Innovation Drive, Worcester, MA 01604, USA.
authors: John D
authors: JD
authors: Williams
authors: Microbiotix, Inc., 1 Innovation Drive, Worcester, MA 01604, USA.
authors: Michelle M
authors: MM
authors: Butler
authors: Microbiotix, Inc., 1 Innovation Drive, Worcester, MA 01604, USA.
authors: Xiaoyuan
authors: X
authors: Ding
authors: Microbiotix, Inc., 1 Innovation Drive, Worcester, MA 01604, USA.
authors: Debra M
authors: DM
authors: Mills
authors: Microbiotix, Inc., 1 Innovation Drive, Worcester, MA 01604, USA.
authors: Tommy F
authors: TF
authors: Tashjian
authors: United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD 21702, USA.
authors: Rekha G
authors: RG
authors: Panchal
authors: Department of Medicine, Boston University School of Medicine, 88 E. Newton Street, Boston, MA 02118, USA.
authors: Susan K
authors: SK
authors: Weir
authors: CreaGen Biosciences, Inc., 23 Rainin Road, Woburn, MA 01801, USA.
authors: Chaeho
authors: C
authors: Moon
authors: CreaGen Biosciences, Inc., 23 Rainin Road, Woburn, MA 01801, USA.
authors: Hwa-Ok
authors: HO
authors: Kim
authors: Organic Consultants, Inc., 132 E. Broadway, Suite 107, Eugene, OR 97401, USA.
authors: Jeremiah A
authors: JA
authors: Marsden
authors: Microbiotix, Inc., 1 Innovation Drive, Worcester, MA 01604, USA.
authors: Norton P
authors: NP
authors: Peet
authors: Microbiotix, Inc., 1 Innovation Drive, Worcester, MA 01604, USA.
authors: Terry L
authors: TL
authors: Bowlin
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D005663:Furans; C469777:bisamidine