Alzheimer’s disease (AD) is the most common type of dementia and is a serious disruption to normal life. Monoamine oxidase-B (MAO-B) is an important target for the treatment of AD. In this study, machine learning approaches were applied to investigate the identification model of MAO-B inhibitors. The results showed that the identification model for MAO-B inhibitors with K-nearest neighbor(KNN) algorithm had a prediction accuracy of 94.1% and 88.0% for the 10-fold cross-validation test and the independent test set, respectively. Secondly, a quantitative activity prediction model for MAO-B was investigated with the Topomer CoMFA model. Two separate cutting mode approaches were used to predict the activity of MAO-B inhibitors. The results showed that the cut model with q² = 0.612 (cross-validated correlation coefficient) and r² = 0.824 (non-cross-validated correlation coefficient) were determined for the training and test sets, respectively. In addition, molecular docking was employed to analyze the interaction between MAO-B and inhibitors. Finally, based on our proposed prediction model, 1-(4-hydroxyphenyl)-3-(2,4,6-trimethoxyphenyl)propan-1-one (LB) was predicted as a potential MAO-B inhibitor and was validated by a multi-spectroscopic approach including fluorescence spectra and ultraviolet spectrophotometry.

Host -directed therapy (HDT) is a new adjuvant strategy that interfere with host cell factors that are required by a pathogen for replication or persistence. In this study, we assessed the effect of dehydrozaluzanin C -derivative (DHZD), a modified compound from dehydrozaluzanin C (DHZC), as a potential HDT agent for severe infection. LPS-induced septic mouse model and Carbapenem resistant Klebsiella pneumoniae (CRKP) infection mouse model was used for testing in vivo. RAW264.7 cells, mouse primary macrophages, and DCs were used for in vitro experiments. Dexamethasone (DXM) was used as a positive control agent. DHZD ameliorated tissue damage (lung, kidney, and liver) and excessive inflammatory response induced by LPS or CRKP infection in mice. Also, DHZD improved the hypothermic symptoms of acute peritonitis induced by CRKP, inhibited heat -killed CRKP (HKCRKP)-induced inflammatory response in macrophages, and upregulated the proportions of phagocytic cell types in lungs. In vitro data suggested that DHZD decreases LPS-stimulated expression of IL -6, TNF-alpha and MCP -1 via PI3K/Akt/p70S6K signaling pathway in macrophages. Interestingly, the combined treatment group of DXM and DHZD had a higher survival rate and lower level of IL -6 than those of the DXM-treated group; the combination of DHZD and DXM played a synergistic role in decreasing IL -6 secretion in sera. Moreover, the phagocytic receptor CD36 was increased by DHZD in macrophages, which was accompanied by increased bacterial phagocytosis in a clathrin- and actin -dependent manner. This data suggests that DHZD may be a potential drug candidate for treating bacterial infections.

The first palladium-catalyzed Ugi-type multicomponent reaction for the synthesis of N-acyl anthranilamides from isocyanides, 2-iodoanilines and carboxylic acids has been developed. This method provides expeditious and highly efficient access to structurally diverse N-acyl anthranilamides from readily available starting materials with good functional group compatibility. The utility of this method has been demonstrated by the late stage functionalization of two commercial drugs: Flurbiprofen and Loxoprofen.