Structure-activity relationships of a novel pyranopyridine series of Gram-negative bacterial efflux pump inhibitors

Son T Nguyen; Steven M Kwasny; Xiaoyuan Ding; Steven C Cardinale; Courtney T McCarthy; Hong-Suk Kim; Hiroshi Nikaido; Norton P Peet; John D Williams; Terry L Bowlin; Timothy J Opperman

doi:10.1016/j.bmc.2015.03.016

Structure-activity relationships of a novel pyranopyridine series of Gram-negative bacterial efflux pump inhibitors

Bioorg Med Chem. 2015 May 1;23(9):2024-34. doi: 10.1016/j.bmc.2015.03.016. Epub 2015 Mar 13.

Authors

Affiliations

¹ Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: snguyen@microbiotix.com.
² Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: skwasny@microbiotix.com.
³ Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: xding@microbiotix.com.
⁴ Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: scardinale@microbiotix.com.
⁵ Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: cmccarthy@microbiotix.com.
⁶ Department of Molecular and Cell Biology, University of California Berkeley, 16 Barker Hall # 3202, Berkeley, CA 94720-3202, USA. Electronic address: hskim1604@hanmail.net.
⁷ Department of Molecular and Cell Biology, University of California Berkeley, 16 Barker Hall # 3202, Berkeley, CA 94720-3202, USA. Electronic address: nhiroshi@berkeley.edu.
⁸ Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: nppeet@gmail.com.
⁹ Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: jwilliams@microbiotix.com.
¹⁰ Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: tbowlin@microbiotix.com.
¹¹ Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: topperman@microbiotix.com.

Abstract

Recently we described a novel pyranopyridine inhibitor (MBX2319) of RND-type efflux pumps of the Enterobacteriaceae. MBX2319 (3,3-dimethyl-5-cyano-8-morpholino-6-(phenethylthio)-3,4-dihydro-1H-pyrano[3,4-c]pyridine) is structurally distinct from other known Gram-negative efflux pump inhibitors (EPIs), such as 1-(1-naphthylmethyl)-piperazine (NMP), phenylalanylarginine-β-naphthylamide (PAβN), D13-9001, and the pyridopyrimidine derivatives. Here, we report the synthesis and biological evaluation of 60 new analogs of MBX2319 that were designed to probe the structure activity relationships (SARs) of the pyranopyridine scaffold. The results of these studies produced a molecular activity map of the scaffold, which identifies regions that are critical to efflux inhibitory activities and those that can be modified to improve potency, metabolic stability and solubility. Several compounds, such as 22d-f, 22i and 22k, are significantly more effective than MBX2319 at potentiating the antibacterial activity of levofloxacin and piperacillin against Escherichia coli.

Keywords: Adjunctive therapy; Antibacterial; Efflux pump inhibitor; Enterobacteriaceae; Pyranopyridine.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / metabolism
Dose-Response Relationship, Drug
Enterobacteriaceae / drug effects*
Enterobacteriaceae / metabolism
Escherichia coli / drug effects
Escherichia coli / metabolism
Microbial Sensitivity Tests
Molecular Structure
Pyrans / chemical synthesis
Pyrans / chemistry
Pyrans / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Bacterial Proteins
MBX2319
Pyrans
Pyridines

Abstract

Publication types

MeSH terms

Substances

Grants and funding