Design and synthesis of potent inhibitors of beta-ketoacyl-acyl carrier protein synthase III (FabH) as potential antibacterial agents.
Twenty new Schiff bases were synthesized by reacting 5-fluoro-salicylaldehyde and primary amine as potent inhibitors of FabH. These compounds were assayed for antibacterial activity against Escherichia coli, Pseudomonas fluorescence, Bacillus subtilis and Staphylococcus aureus. Compounds with potent antibacterial activities were tested for their E. coli FabH inhibitory activity. (E)-4-fluoro-2-((4-hydroxyphenethylimino)methyl)phenol (10) showed the most potent antibacterial activity with MIC of 1.56-6.25 microg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC(50) of 2.7 microM. Docking simulation was performed to position compound 10 into the E. coli FabH active site to determine the probable binding conformation.
Shi
Lei
L
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
Fang
Rui-Qin
RQ
Zhu
Zhen-Wei
ZW
Yang
Ying
Y
Cheng
Kui
K
Zhong
Wei-Qing
WQ
Zhu
Hai-Liang
HL
D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000447:Aldehydes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular
D000447:Aldehydes; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; C013243:salicylaldehyde; C077402:3-ketoacyl-acyl carrier protein synthase III; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase