79221-45-7Relevant academic research and scientific papers
Synthesis, biological activities and docking studies of pleuromutilin derivatives with piperazinyl urea linkage
Zhang, Yuanyuan,Xie, Chuan,Liu, Yang,Shang, Feng,Shao, Rushiya,Yu, Jing,Wu, Chunxia,Yao, Xinghui,Liu, Dongfang,Wang, Zhouyu
, p. 764 - 775 (2021/03/29)
Antibiotics resistance is becoming increasingly common, involving almost all antibiotics on the market. Diseases caused by drug resistant bacteria, such as MRSA, have high mortality and negatively affect public health. The development of new drugs would be an effective means of solving this problem. Modifications based on bioactive natural products could greatly shorten drug development time and improve success rate. Pleuromutilin, a natural product from the basidiomycete bacterial species, is a promising antibiotic candidate. In this study, a series of novel pleuromutilin derivatives possessing piperazinyl urea linkage were efficiently synthesised, and their antibacterial activities and bactericidal properties were evaluated via MIC, MBC and Time-kill kinetics assays. The results showed that all compounds exhibited potent activities against tested strains, especially MRSA strains with MIC values as low as 0.125 μg/mL; 8 times lower than that of marketed antibiotic Tiamulin. Docking studies indicate substituted piperazinyl urea derivatives could provide hydrogen bonds and initiate π-π stacking between molecules and surrounding residues.
Covalent docking modelling-based discovery of tripeptidyl epoxyketone proteasome inhibitors composed of aliphatic-heterocycles
Dong, Xiao-Wu,Zhang, Jian-Kang,Xu, Lei,Che, Jin-Xin,Cheng, Gang,Hu, Xiao-Bei,Sheng, Li,Gao, An-Hui,Li, Jia,Liu, Tao,Hu, Yong-Zhou,Zhou, Yu-Bo
supporting information, p. 602 - 614 (2019/01/11)
The potential of specific proteasome inhibitors to act as anti-cancer agents has attracted intensive investigations. The proteasome can be covalently inhibited by epoxyketone derivatives via a two-step reaction. Several computational approaches have been developed to mimic the covalent binding event. Compound 1 composed of a six-membered heterocyclic ring was designed by using covalent docking. With a possible different binding mode from the clinical compound Carfilzomib, it occupied the S5 pocket of 20S proteasome and showed favorable inhibitory activity. Subsequently optimization and evaluation were taken place. Among these compounds, 11h demonstrated extraordinary in vitro inhibitory activity and selectivity, and good in vivo proteasome inhibitory activity, a favorable pharmacokinetic profile and xenograft tumor inhibition. The possible binding pattern of compound 11h against proteasome was further fully explored via calculations, providing a theoretical basis for finding potent proteasome inhibitors.
The design and synthesis of novel, potent and orally bioavailable N-aryl piperazine-1-carboxamide CCR2 antagonists with very high hERG selectivity
Cumming, John G.,Bower, Justin F.,Waterson, David,Faull, Alan,Poyser, Philip J.,Turner, Paul,McDermott, Benjamin,Campbell, Andrew D.,Hudson, Julian,James, Michael,Winter, Jon,Wood, Christine
scheme or table, p. 3895 - 3899 (2012/07/03)
A novel N-aryl piperazine-1-carboxamide series of human CCR2 chemokine receptor antagonists was discovered. Early analogues were potent at CCR2 but also inhibited the hERG cardiac ion channel. Structural modifications which decreased lipophilicity and basicity resulted in the identification of a sub-series with an improved margin over hERG. The pharmacological and pharmacokinetic properties of the lead compound from this series, N-(3,4-dichlorophenyl)-4-[(2R)-4-isopropylpiperazine-2-carbonyl] piperazine-1-carboxamide, are described.
