Design, synthesis, and structure-activity relationship studies of conformationally restricted mutilin 14-carbamates.
We report herein the design, synthesis, and structure-activity relationship studies of conformationally restricted mutilin 14-carbamates based on the structure of SB-222734. The antibacterial activities of these newly synthesized compounds were also evaluated and compared with linezolid and retapamulin. Results showed that most of the target compounds exhibit good potency in inhibiting the growth of Gram-positive bacteria including Methicillin-susceptible Staphylococcus aureus MSSA (MIC: 0.0625-2μg/mL), Methicillin-resistant S. aureus MRSA (MIC: 0.0625-2μg/mL), Methicillin-susceptible Staphylococcus epidermidis MSSE (MIC: 0.0625-2μg/mL), Methicillin-resistant S. epidermidis MRSE (MIC: 0.0625-2μg/mL), and Streptococcus pneumonia (MIC: 0.0625-4μg/mL). In particular, three remarkable compounds of this series (12l, 12m, and 21l) exhibited comparable in vitro antibacterial profiles to that of retapamulin.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
Liqiang
L
Fu
Xin
X
Liu
Chenyu
C
Ling
Jianjun
J
Cheng
Xingsheng
X
Guo
Huili
H
He
Shi
S
Ding
Yushe
Y
Yang
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D015394:Molecular Structure; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D013212:Staphylococcus epidermidis / Q000187:drug effects* / Q000254:growth & development; D013237:Stereoisomerism; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D002219:Carbamates; C434329:mutilin 14-(N-(4-methoxybenzoyl))-carbamate