1. Academic Validation
  2. Synthesis and antibacterial evaluation of new, unsymmetrical triaryl bisamidine compounds

Synthesis and antibacterial evaluation of new, unsymmetrical triaryl bisamidine compounds

  • Bioorg Med Chem Lett. 2014 Aug 1;24(15):3366-72. doi: 10.1016/j.bmcl.2014.05.094.
Son T Nguyen 1 John D Williams 2 Michelle M Butler 2 Xiaoyuan Ding 2 Debra M Mills 2 Tommy F Tashjian 2 Rekha G Panchal 3 Susan K Weir 4 Chaeho Moon 5 Hwa-Ok Kim 5 Jeremiah A Marsden 6 Norton P Peet 2 Terry L Bowlin 2
Affiliations

Affiliations

  • 1 Microbiotix, Inc., 1 Innovation Drive, Worcester, MA 01604, USA. Electronic address: snguyen@microbiotix.com.
  • 2 Microbiotix, Inc., 1 Innovation Drive, Worcester, MA 01604, USA.
  • 3 United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD 21702, USA.
  • 4 Department of Medicine, Boston University School of Medicine, 88 E. Newton Street, Boston, MA 02118, USA.
  • 5 CreaGen Biosciences, Inc., 23 Rainin Road, Woburn, MA 01801, USA.
  • 6 Organic Consultants, Inc., 132 E. Broadway, Suite 107, Eugene, OR 97401, USA.
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.

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