Evolution and Antibacterial Evaluation of 8-Hydroxy-cycloberberine Derivatives as a Novel Family of Antibacterial Agents Against MRSA

Autor: Xinxin Hu, Jing Pang, Dan-Qing Song, Sheng Tang, Yuan-Shuai Yang, Wei Wei, Tian-Yun Fan, Xuefu You, Yan-Xiang Wang
Jazyk: angličtina
Rok vydání: 2019
Předmět:
DNA Topoisomerase IV
Methicillin-Resistant Staphylococcus aureus
Models
Molecular
structure–activity relationship
Berberine
cycloberberine
Topoisomerase IV
Molecular Conformation
Pharmaceutical Science
Microbial Sensitivity Tests
Anti mrsa
medicine.disease_cause
01 natural sciences
Article
Analytical Chemistry
Microbiology
lcsh:QD241-441
03 medical and health sciences
Structure-Activity Relationship
lcsh:Organic chemistry
Drug Stability
anti-MRSA
Drug Discovery
topoisomerase IV
medicine
Structure–activity relationship
Physical and Theoretical Chemistry
Liver microsomes
030304 developmental biology
Whole blood
0303 health sciences
biology
Dose-Response Relationship
Drug
Molecular Structure
010405 organic chemistry
Chemistry
Organic Chemistry
biochemical phenomena
metabolism
and nutrition
biology.organism_classification
bacterial infections and mycoses
0104 chemical sciences
Anti-Bacterial Agents
Chemistry (miscellaneous)
Staphylococcus aureus
biology.protein
Molecular Medicine
Intravenous route
Bacteria
Zdroj: Molecules
Volume 24
Issue 5
Molecules, Vol 24, Iss 5, p 984 (2019)
ISSN: 1420-3049
DOI: 10.3390/molecules24050984
Popis: Twenty-five new derivatives of 8-hydroxycycloberberine (1) were synthesized and evaluated for their activities against Gram-positive bacteria, taking 1 as the lead. Part of them displayed satisfactory antibacterial activities against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-intermediate Staphylococcus aureus (VISA). Especially, compound 15a displayed an excellent anti-MRSA activity with MICs (minimum inhibitory concentrations) of 0.25&ndash
0.5 &mu
g/mL, better than that of 1. It also displayed high stability in liver microsomes and whole blood, and the LD50 value of over 65.6 mg·
kg&minus
1 in mice via intravenous route, suggesting a good druglike feature. The mode of action showed that 15a could effectively suppress topo IV-mediated decatenation activity at the concentration of 7.5 &mu
g/mL, through binding a different active pocket of bacterial topo IV from quinolones. Taken together, the derivatives of 1 constituted a promising kind of anti-MRSA agents with a unique chemical scaffold and a specific biological mechanism, and compound 15a has been chosen for the next investigation.
Databáze: OpenAIRE
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