Design, synthesis and biological evaluation of monobactams as antibacterial agents against gram-negative bacteria

A series of monobactam derivatives were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative strains, taking Aztreonam and BAL30072 as the leads. Six conjugates (12a–f) bearing PIH-like siderophore moieties were created to enhance the bactericidal...

Full description

Saved in:
Bibliographic Details
Published in:European journal of medicinal chemistry 2016-03, Vol.110, p.151-163
Main Authors: Fu, Hai-Gen, Hu, Xin-Xin, Li, Cong-Ran, Li, Ying-Hong, Wang, Yan-Xiang, Jiang, Jian-Dong, Bi, Chong-Wen, Tang, Sheng, You, Xue-Fu, Song, Dan-Qing
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Antibacterial activity
Aztreonam - analogs & derivatives
Aztreonam - chemical synthesis
Aztreonam - pharmacology
Click chemistry
Drug Design
Escherichia coli - drug effects
Gram-Negative Bacteria - drug effects
Gram-Negative Bacterial Infections - drug therapy
Humans
Klebsiella pneumoniae - drug effects
Microbial Sensitivity Tests
Models, Molecular
Monobactam
Monobactams - chemical synthesis
Monobactams - chemistry
Monobactams - pharmacology
Siderophore
Structure-Activity Relationship
Thiazoles - chemical synthesis
Thiazoles - chemistry
Thiazoles - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:A series of monobactam derivatives were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative strains, taking Aztreonam and BAL30072 as the leads. Six conjugates (12a–f) bearing PIH-like siderophore moieties were created to enhance the bactericidal activities against Gram-negative bacteria based on Trojan Horse strategy, and all of them displayed potencies against susceptible Gram-negative strains with MIC ≤ 8 μg/mL. SAR revealed that the polar substituents on the oxime side chain were beneficial for activities against resistant Gram-negative bacteria. Compounds 19c and 33a–b exhibited the promising potencies against ESBLs-producing E. coli and Klebsiella pneumoniae with MICs ranging from 2 μg/mL to 8 μg/mL. These results offered powerful information for further strategic optimization in search of the antibacterial candidates against MDR Gram-negative bacteria. [Display omitted] •Fourteen monobactams were designed and synthesized.•Click Chemistry was first applied for the synthesis of monolactams.•Representative compounds exhibited potency against Gram-negative bacteria.•Lower ClogP might be a powerful strategy in designing antibacterial agents.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2016.01.024