Structure–activity relationships of a novel pyranopyridine series of Gram-negative bacterial efflux pump inhibitors. Issue 9 (1st May 2015)

• Record Type: Journal Article
• Authors: Nguyen, Son T.; Kwasny, Steven M.; Ding, Xiaoyuan; Cardinale, Steven C.; McCarthy, Courtney T.; Kim, Hong-Suk; Nikaido, Hiroshi; Peet, Norton P.; Williams, John D.; Bowlin, Terry L.; Opperman, Timothy J.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 9(2015)
• Page Start: 2024
• Page End: 2034
• Publication Date: 2015-05-01
• Subjects: Pyranopyridine -- Efflux pump inhibitor -- Enterobacteriaceae -- Adjunctive therapy -- Antibacterial; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.03.016
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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-1 H -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 as22d –f, 22i and22k, are significantly more effective than MBX2319 at potentiating the antibacterial activity of levofloxacin and piperacillin against Escherichia coli .