New peptide deformylase inhibitors design, synthesis and pharmacokinetic assessment.
The docking approach for the screening of designed small molecule ligands, led to the identification of a critical arginine residue in peptide deformylase for spiro cyclopropyl PDF inhibitor's extra hydrophobic binding, providing us a useful tool for searching more efficient PDF inhibitors to fight for horrifying antibiotics resistance. Further synthetic modification was undertaken to optimize the potency of amide compounds. To lower metabolic susceptibility and in turn reduce unwanted metabolic toxicity that was observed clinically, while retaining desired antibacterial activity, the use of azoles as amide bioisosteres had also been investigated. After the completion of chemical synthesis, all the compounds were evaluated through in vitro antibacterial activity assay, some of which were further subject to in vivo rat pharmacokinetic assessment. Those findings in this letter showed that spiro cyclopropyl proline N-formyl hydroxylamines, and especially the bioisosteric azoles, can represent a promising class of PDF inhibitors.
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, North Zhongshan Road 3663, Shanghai, China.
Fengping
F
Lv
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, North Zhongshan Road 3663, Shanghai, China.
Chen
C
Chen
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, North Zhongshan Road 3663, Shanghai, China.
Yang
Y
Tang
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, North Zhongshan Road 3663, Shanghai, China.
Jianhai
J
Wei
Department of Physics and State Key Laboratory of Precision Spectroscopy, East China Normal University, North Zhongshan Road 3663, Shanghai 200062, China. Electronic address: tongzhu@chem.ecnu.edu.cn.
Tong
T
Zhu
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, North Zhongshan Road 3663, Shanghai, China. Electronic address: whu@chem.ecnu.edu.cn.
Wenhao
W
Hu
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D000581:Amidohydrolases; C084507:peptide deformylase
Amide bioisosteres; Antibacterial drug; Antibiotics resistance; Docking study; MRSA; PDF inhibitor