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Structure-activity relationships of a novel pyranopyridine series of Gram-negative bacterial efflux pump inhibitors.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2015 May 01; Vol. 23 (9), pp. 2024-34. Date of Electronic Publication: 2015 Mar 13. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Subjects :
- Anti-Bacterial Agents chemical synthesis
Anti-Bacterial Agents chemistry
Bacterial Proteins metabolism
Dose-Response Relationship, Drug
Enterobacteriaceae metabolism
Escherichia coli drug effects
Escherichia coli metabolism
Microbial Sensitivity Tests
Molecular Structure
Pyrans chemical synthesis
Pyrans chemistry
Pyridines chemical synthesis
Pyridines chemistry
Structure-Activity Relationship
Anti-Bacterial Agents pharmacology
Bacterial Proteins antagonists & inhibitors
Enterobacteriaceae drug effects
Pyrans pharmacology
Pyridines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 23
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25818767
- Full Text :
- https://doi.org/10.1016/j.bmc.2015.03.016