A series of tacrine-methoxybenzene hybrids (5a-5i) were designed, synthesized and evaluated as inhibitors of cholinesterases (ChEs). All the compounds had better ChEs inhibitory activities than tacrine with IC50 values at the nanomolar range. Compound 5h exhibited the strongest inhibition on acetylcholinesterase (AChE) with an IC50 value of 6.74 nmol x L(-1) and compound 5f showed the most potent inhibition on butyrylcholinesterase with IC50 value of 3.83 nmol x L(-1). Kinetic and molecular modeling studies showed that these hybrids targeted both the catalytic active site and the peripheral anionic site of AChE.

A novel series of bis-nicotine derivatives (3a-3i) were designed, synthesized and evaluated as bivalent anti-Alzheimer's disease agents. The pharmacological results indicated that compounds 3e-3i inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the micromolar range (IC50, 2.28-117.86 micromol x L(-1) for AChE and 1.67-125 micromol x L(-1) for BChE), which was at the same potency as rivastigmine. A Lineweaver-Burk plot and molecular modeling study showed that these derivatives targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds could significantly inhibit the self-induced Abeta aggregation with inhibition activity (11.85%-62.14%) at the concentration of 20 micromol x L(-1).

Objective:To examine differences in metabolic characteristics and metabolites between elderly overweight patients with metabolic syndrome and healthy elderly people, and to identify related factors.Methods:A group of 36 MS patients(the MS group)admitted to The Fourth Central Hospital of Tianjin from April to August 2018 and 43 elderly people(the control group)who underwent physical examination during the same period were included in this prospective study.Serum samples of the patients with metabolic syndrome and elderly healthy controls were collected, and ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF/MS)based non-targeted metabolomics was used to search for differences in metabolites between the serum samples of the two groups.The Pearson correlation statistical method was used to find related clinical factors.Results:Comparison of baseline data of the enrolled participants showed that there were statistically significant differences between the two groups in body mass index[(26.9±2.0)kg/m 2vs.(21.7±1.4)kg/m 2], waist circumference, systolic blood pressure, fasting blood glucose, triglycerides and high-density lipoprotein cholesterol( P<0.01). Metabolomics results showed that there were differences in 65 serum metabolites between elderly overweight patients with metabolic syndrome and elderly normal controls, and these differences were enriched in 21 pathways.Correlation analysis showed that waist circumference had the largest number of differential metabolites, followed by body mass index.The major differential metabolites were monosaccharides such as mannose, lyxose and glucose, linolenic acid and its derivatives, and pyroglutamate. Conclusions:Compared with normal elderly people, elderly patients with overweight metabolic syndrome have a variety of differential metabolites, and these metabolites are highly correlated with clinical indicators related to overweight, such as body mass index and waist circumference, and they include monosaccharides, linolenic acid derivatives and amino acids.