356531-56-1Relevant articles and documents
Binding Mode Characterization and Early in Vivo Evaluation of Fragment-Like Thiols as Inhibitors of the Virulence Factor LasB from Pseudomonas aeruginosa
Kany, Andreas M.,Sikandar, Asfandyar,Haupenthal, J?rg,Yahiaoui, Samir,Maurer, Christine K.,Proschak, Ewgenij,K?hnke, Jesko,Hartmann, Rolf W.
, p. 988 - 997 (2018/06/14)
The increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Pseudomonas aeruginosa and therefore represents an attractive antivirulence target. Mercaptoacetamide-based thiols have been reported to inhibit LasB as well as collagenases from clostridia and bacillus species. The present work provides an insight into the structure-activity relationship (SAR) of these fragment-like LasB inhibitors, demonstrating an inverse activity profile compared to similar inhibitors of clostridial collagenase H (ColH). An X-ray cocrystal structure is presented, revealing distinct binding of two compounds to the active site of LasB, which unexpectedly maintains an open conformation. We further demonstrate in vivo efficacy in a Galleria mellonella infection model and high selectivity of the LasB inhibitors toward human matrix metalloproteinases (MMPs).
Synthesis of novel β-propanamides to inhibit cholesteryl ester transfer protein (CETP)
Xie, Hong-Lei,Liu, Chun-Chi,Li, Yi-Qun,Bai, Chang-Lin,Hao, Chen-Zhou,Guo, Jing,Luo, Chang-Qun,Zhao, Dong-Mei,Cheng, Mao-Sheng
, p. 260 - 263 (2017/01/25)
A novel series of β-propanamide derivatives as inhibitors of cholesteryl ester transfer protein (CETP) were synthesized. Previously, H3 (IC502?μmol/L) was observed to inhibit CETP moderately (Xie et al., 2016). Structural modifications based on H3 led to discovery of the successful CETP inhibitor, known as 1-methyl-4-arylpyrazole. Using a similar approach, compound Q08 was identified as a highly potent CETP inhibitor with an IC50of 490?nmol/L in vitro.
Discovery of novel N,N-3-phenyl-3-benzylaminopropionanilides as potent inhibitors of cholesteryl ester transfer protein in vivo
Xie, Honglei,Li, Yiqun,Bai, Changlin,Wang, Ruifeng,Liu, Chunchi,Hao, Chenzhou,Lin, Bin,Cheng, Maosheng,Zhao, Dongmei
, p. 1811 - 1818 (2016/04/05)
Epidemiological studies have identified that the risk of cardiovascular events increases due to the decreased levels of high density lipoprotein-cholesterol and the elevated levels of low density lipoprotein-cholesterol. Herein, we report a novel series of N,N-3-phenyl-3-benzylaminopropionanilide derivatives, which were identified as potent cholesteryl ester transfer protein (CETP) inhibitor. The initial lead compound L10 (IC50 8.06 μM) was found by pharmacophore-based virtual screening (Dong-Mei Zhao et al., Chin. Chem. Lett. 2014, 25, 299). After systematic structure variation and biological testing against CETP, two different series were identified as scaffolds for potent CETP inhibitors. One is N,N-3-phenyl-3-benzylaminopropanamide derivatives, which were investigated in our previous paper (Bioorg. Med. Chem. 2015, doi: http://dx.doi.org/10.1016/j.bmc.2015.12.010). The most potent compound HL16 in that series has the IC50 of 0.69 μM. The other series is N,N-3-phenyl-3-benzylaminopropionanilide derivatives, which was investigated in current study. Further optimization of the structure-activity relationship (SAR) resulted in H16 (IC50 0.15 μM), which was discovered as a potent CETP inhibitor in vitro by BODIPY-CE fluorescence assay. In addition, the results of pharmacodynamics studies showed that H16 exhibited both favorable HDL-C enhancement and LDL-C reduction in vivo by hamster. It also has an excellent stability in rat liver microsomal.
