Discovery and modification of sulfur-containing heterocyclic pyrazoline derivatives as potential novel class of β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors.
A series of sulfur-containing heterocyclic pyrazoline derivatives (C1-C18; D1-D9) have been synthesized and purified (all are new except one) to be screened for FabH inhibitory activity. Compound C14 showed the most potent biological activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis (MIC values: 1.56-3.13 μg/mL), being comparable with the positive control, while D6 performed the best in the thiazolidinone series (MIC values: 3.13-6.25 μg/mL). They also demonstrated strong broad-spectrum antimicrobial activity. Compounds C14 and D6 exhibited the most potent E. coli FabH inhibitory activity with IC(50) of 4.6 and 8.4 μM, respectively, comparable with the positive control DDCP (IC(50)=2.8 μM). Docking simulation was performed to position compound C14 and D6 into the E. coli FabH structure active site to determine the probable binding model. The structurally modification of previous compounds and the attempt in innovative target have brought a positive progress.
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
Yu-Shun
YS
Yang
Fei
F
Zhang
Chao
C
Gao
Yan-Bin
YB
Zhang
Xiao-Liang
XL
Wang
Jian-Feng
JF
Tang
Jian
J
Sun
Hai-Bin
HB
Gong
Hai-Liang
HL
Zhu
D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D050296:Microbial Viability / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013457:Sulfur Compounds / Q000737:chemistry* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D011720:Pyrazoles; D013457:Sulfur Compounds; C077402:3-ketoacyl-acyl carrier protein synthase III; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase