Design, synthesis and anti-MRSA activities of cycloberberine derivatives with a novel chemical scaffold
10.16438/j.0513-4870.2018-0141
- VernacularTitle:新型环化小檗碱衍生物的设计合成及抗MRSA活性研究
- Author:
Tian-yun FAN
1
;
Xin-xin HU
1
;
Yan-xiang WANG
1
;
Sheng TANG
1
;
Xue-fu YOU
1
;
Dan-qing SONG
1
Author Information
1. Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Publication Type:SPECIAL REPORTS
- Keywords:
cycloberberine;
chelerythrine;
antibacterial;
MRSA;
drug resistance;
structure-activity relationship
- From:
Acta Pharmaceutica Sinica
2018;53(6):887-894
- CountryChina
- Language:Chinese
-
Abstract:
9-Acetoxycycloberberine (1) with a unique skeleton was first identified to display a potent antimicrobial profile against methicillin-resistant Staphylococcus aureus (MRSA) with MIC values of 1-16 μg·mL-1. Taking the compound as a lead, 14 target cycloberberine analogues with diverse structures, such as berberine and chelerythrine derivatives, were synthesized and evaluated for their anti-bacterial activities. Analysis of the structure-activity relationship revealed that:① ring E was essential for the activity; ② the removing of ring B decreased the activity against MRSA. However, the antimicrobial activity against vancomycin-resistant Enterococcus faecium (VRE) was improved; ③ the introduction of a suitable rigid substituent at the 9-position was beneficial for the activity. Among them, compound 9a showed the most potential activity against methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA isolates with MIC values of 0.5-1 μg·mL-1, suggesting a different mechanism from clinical drugs. It displayed higher stability in blood. Therefore, we consider 9a worthy of further investigation. The results provide key scientific evidence for development of such compounds into a new type of anti-MRSA candidates.
