Mammalian carboxylesterases (CES) are key enzymes that participate in the hydrolytic metabolism of various endogenous and exogenous substrates. Human carboxylesterase 2A (hCES2A), mainly distributed in the small intestine and colon, plays a significant role in the hydrolysis of many drugs. In this study, 3‐arylisoquinolones 3 h [3‐(4‐(benzyloxy)‐3‐methoxyphenyl)‐7,8‐dimethoxyisoquinolin‐1(2H)‐one] and 4 a [3‐(4‐(benzyloxy)‐3‐methoxyphenyl)‐4‐bromo‐7,8‐dimethoxyisoquinolin‐1(2H)‐one] were found to have potent inhibitory effects on hCES2A (IC50=0.68 μΜ, Ki=0.36 μΜ) and excellent specificity (more than 147.05‐fold over hCES1 A). Moreover, 4 a exhibited threefold improved inhibition on intracellular hCES2A in living HepG2 cells relative to 3 h, with an IC50 value of 0.41 μΜ. Results of inhibition kinetics studies and molecular docking simulations demonstrate that both 3 h and 4 a can bind to multiple sites on hCES2A, functioning as mixed inhibitors. Structure−activity relationship analysis revealed that the lactam moiety on the B ring is crucial for specificity towards hCES2A, while a benzyloxy group is optimal for hCES2A inhibitory potency; the introduction of a bromine atom may enhance cell permeability, thereby increasing the intracellular hCES2A inhibitory activity.

The multi-modifications of polyhydroxyl groups and the stereoselective formation of 1,2-cis glycosidic bonds are difficult in glycochemistry. Herein we disclosed a concise synthesis of the oxazoline-fused saccharides (oxazolinoses) from acetyl saccharides and benzonitriles under acidic conditions promoted by the stoichiometric water. The oxazolinoses can be easily converted into 1,2-cis glycosylamines with differentiated modifications at 2,3-positions on the saccharide ring in few steps and the 1-NH2 can further be simply transformed to the 1-OH. Oxazolinoses can also be directly used to synthesize complex chiral molecules such as schisandrins. Saccharides screening have shown that the oxazolinoses could be synthesized from various monosaccharides and oligosaccharides. Accordingly, 1-α- or 1-β-1,2-cis glycosylamines can be obtained from different oxazolinoses which are 1,2-cis stereoselectivity controlled by neighboring group participation. The density functional theory (DFT) calculations have revealed the origin of the stereoselectivity and the key role of water.

Oxazolinoses, which can be converted into 1,2-cis glycosylamines and allowed the access to schisandrin derivatives, are prepared concisely from peracetylated saccharides and benzonitriles under acidic conditions with stoichiometric amounts of water.