Novel Potent and Selective Acetylcholinesterase Inhibitors as Potential Drugs for the Treatment of Alzheimer's Disease: Synthesis, Pharmacological Evaluation, and Molecular Modeling of Amino-Alkyl-Substituted Fluoro-Chalcones Derivatives.

A new series of-fluoro chalcones-substituted amino-alkyl derivatives (3a˜3l) were designed, synthesized, characterized and evaluated for the inhibitory activity against acetylcholinesterase and butyrylcholinesterase. The results showed that the alteration of fluorine atom position and amino-alkyl groups markedly influenced the activity and the selectivity of chalcone derivates in inhibiting acetylcholinesterase and butyrylcholinesterase. Among them, compound 3l possesses the most potent inhibitory against acetylcholinesterase (IC50  = 0.21 ± 0.03 µmol/L), and the highest selectivity for acetylcholinesterase over butyrylcholinesterase (IC50 (BuChE)/IC50 (AChE) = 65.0). Molecular modeling and enzyme kinetic study on compound 3l supported its dual acetylcholinesterase inhibitory profile, simultaneously binding at the catalytic active and peripheral anionic site of the enzyme.

Design, synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors.

A novel series of chalcone derivatives (4a-8d) were designed, synthesized, and evaluated for the inhibition activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The logP values of the compounds were shown to range from 1.49 to 2.19, which suggested that they were possible to pass blood brain barriers in vivo. The most promising compound 4a (IC50: 4.68 µmol/L) was 2-fold more potent than Rivastigmine against AChE (IC50: 10.54 µmol/L) and showed a high selectivity for AChE over BuChE (ratio: 4.35). Enzyme kinetic study suggested that the inhibition mechanism of compound 4a was a mixed-type inhibition. Meanwhile, the result of molecular docking showed its potent inhibition of AChE and high selectivity for AChE over BuChE.

Synthesis and acetylcholinesterase inhibitory activity of Mannich base derivatives flavokawain B.

A novel series of flavokawain B derivatives, chalcone Mannich bases (4-10) were designed, synthesized, characterized, and evaluated for the inhibition activity against acetylcholinesterase (AChE). Biological results revealed that four compounds displayed potent activities against AChE with IC50 values below 20µM. Moreover, the most promising compound 8 was 2-fold more active than rivastigmine, a well-known AChE inhibitor. The logP values of 4-10 were around 2 which indicated that they were sufficiently lipophilic to pass blood brain barriers in vivo. Enzyme kinetic study suggested that the inhibition mechanism of compound 8 was a mixed-type inhibition. Meanwhile, the molecular docking showed that this compound can both bind with the catalytic site and the periphery of AChE.

Synthesis and biological activity of nitric oxide-releasing derivatives of ferulic acid as potential agents for the treatment of chronic kidney diseases.

In order to search for novel potential agents for the treatment of chronic kidney diseases (CKD), nitric oxide (NO)-releasing derivatives (5a-c) of ferulic acid were synthesized and characterized by MS, 1H NMR, and elementary analysis. They showed different NO-releasing rate in the absence or presence of L-cysteine in vitro. In the adenine induced CKD rats, these compounds revealed reno-protective effect via lowering blood urea nitrogen (BUN), creatinine (Cr) in serum and malondialdehyde (MDA) in kidney, increasing NO and superoxide dismutase (SOD) level in kidney. Among them, 3-methoxy-4-(nitrooxy)ethoxy cinnamic acid (5a) was confirmed to have a higher NO-releasing rate in vitro and better effect in ameliorating adenine-induced kidney damage in rats.