•Novel urea derivatives as dual-acting agonists of GK and PPARγ were synthesized.•Several agonists exhibited high enzyme activity and moderate hypoglycemic efficacy.•The discovery may provide an effective approaching for treating T2DM.Motivated by the discovery of a potential ligand that activates both glucokinase (GK) and perioxisome proliferator-activated receptor-γ (PPARγ), this work presents the rational design and synthesis of a series of novel urea derivatives as potent dual-target ligands of GK and PPARγ. The derivatives obtained, particularly compounds 14j, 14m, 15g, 15j, and 15s, showed relatively high enzyme activity and moderate blood glucose-lowering efficacy in normal ICR mice (GK activation fold >1.7, PPARγ activation percentage >38.8%, relative to rosiglitazone). The discovery of a dual-acting agent may provide an effective approach for treating type 2 diabetes mellitus.A novel series of urea derivatives as potent dual-acting agonists of GK and PPARγ were designed and synthesized. The binding model was predicted by molecular docking simulation.

A series of novel sorafenib derivatives have been designed and synthesized. The cytotoxic activities of these compounds were tested in three tumor cell lines. Most of the compounds showed potent antiproliferative activity against the tested cell lines with IC50 = 0–20 μmol/L. Some compounds demonstrated competitive antiproliferative activities to sorafenib against all three cancer cell lines. Among them, compound 5g demonstrated significant inhibitory activity against A549, ACHN and MDA-MB-231 cell lines with IC50 values of 1.29, 1.99, 3.11 μmol/L, respectively.A series of novel sorafenib derivatives have been designed and synthesized. The cytotoxic activities of these compounds were tested in three tumor cell lines. Most of the compounds showed potent antiproliferative activity against the tested cell lines with IC50 = 0–20 μmol/L.

A new series of benzamide derivatives as glucokinase activators (GKAs) were designed and synthesized, and their activation for glucokinase were evaluated by the preliminary glucokinase activity assay. The structure–activity relationship (SAR) is discussed. The result shows that compound 12d and 12h have potent activity reference drug RO-28-1675.

The conformations of γ-butyrolactone ring in solution were deduced on the basis of 1H NMR spectra of geminal protons of the butyrolactone ring. A series of optically pure (Z)-(−)-4-(1′-alkoxyl-1′-carbalkoxy-methylene)-5(R)[(1R)-menthyloxy]-γ-butyrolactones with a stable planar conformation of γ-butyrolactone ring were found.

Clausenamide, isolated from aqueous extract of dry leaves of Clausena lansium, a Chinese folk medicine, was found to have potent activity in enhancing LTP and show nootropic activity in animal tests. In order to discovery more potent stereoisomers and to analyze the relationship of structure–activity, the synthesis of 16 (8 pairs) optically pure stereoisomers of clausenamide with four chiral centers was achieved. The results of LTP assay showed that the nootropic activity of the stereoisomers of clausenamide is closely related to the configuration of stereoisomers.The synthesis and activity in enhancing LTP of 16 (8 pairs) optically pure stereoisomers of clausenamide with four chiral centers are reported.

A series of novel phenyl-urea derivatives which can simultaneously activate glucokinase (GK) and peroxisome proliferator-activated receptor γ (PPARγ) was designed and prepared, and their activation of GK and PPARγ was evaluated. The structure–activity relationships of these compounds are also described. Three compounds showed potent ability to activate both GK and PPARγ. The possible binding mode of one of these compounds with GK and PPARγ were predicted by molecular docking simulation.Graphical abstractA series of novel phenyl-urea derivatives which can simultaneously activate GK and PPARγ was designed, prepared and evaluated.Download full-size image