title: Structure-activity relationships of a novel pyranopyridine series of Gram-negative bacterial efflux pump inhibitors.
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.
authors.affiliation: Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: snguyen@microbiotix.com.
authors.forename: Son T
authors.initials: ST
authors.lastname: Nguyen
authors.affiliation: Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: skwasny@microbiotix.com.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kwasny
authors.affiliation: Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: xding@microbiotix.com.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Ding
authors.affiliation: Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: scardinale@microbiotix.com.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Cardinale
authors.affiliation: Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: cmccarthy@microbiotix.com.
authors.forename: Courtney T
authors.initials: CT
authors.lastname: McCarthy
authors.affiliation: Department of Molecular and Cell Biology, University of California Berkeley, 16 Barker Hall # 3202, Berkeley, CA 94720-3202, USA. Electronic address: hskim1604@hanmail.net.
authors.forename: Hong-Suk
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Molecular and Cell Biology, University of California Berkeley, 16 Barker Hall # 3202, Berkeley, CA 94720-3202, USA. Electronic address: nhiroshi@berkeley.edu.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nikaido
authors.affiliation: Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: nppeet@gmail.com.
authors.forename: Norton P
authors.initials: NP
authors.lastname: Peet
authors.affiliation: Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: jwilliams@microbiotix.com.
authors.forename: John D
authors.initials: JD
authors.lastname: Williams
authors.affiliation: Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: tbowlin@microbiotix.com.
authors.forename: Terry L
authors.initials: TL
authors.lastname: Bowlin
authors.affiliation: Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, USA. Electronic address: topperman@microbiotix.com.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Opperman
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C000591634:MBX2319; D011714:Pyrans; D011725:Pyridines
keywords: Adjunctive therapy; Antibacterial; Efflux pump inhibitor; Enterobacteriaceae; Pyranopyridine
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