2. Academic Validation
  3. Structure-activity relationships of a novel pyranopyridine series of Gram-negative bacterial efflux pump inhibitors

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.
Son T Nguyen 1,  Steven M Kwasny 2,  Xiaoyuan Ding 3,  Steven C Cardinale 4,  Courtney T McCarthy 5,  Hong-Suk Kim 6,  Hiroshi Nikaido 7,  Norton P Peet 8,  John D Williams 9,  Terry L Bowlin 10,  Timothy J Opperman 11
Affiliations

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.
PMID: 25818767 DOI: 10.1016/j.bmc.2015.03.016
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.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z