Design, synthesis, molecular modeling and neuroprotective effects of a new framework of cholinesterase inhibitors for Alzheimer's disease

In search of a novel class of compounds against Alzheimer's disease (AD), a new series of 7-chloro-aminoquinoline derivatives containing methylene spacers of different sizes between the 7-chloro-4-aminoquinoline nucleus and imino methyl substituted phenolic rings, and also their reduced analogues, were designed, synthesized and evaluated as neuroprotective agents for ADin vitro. In spite of the multifaceted feature of AD, cholinesterases continue to be powerful and substantial targets, as their inhibition increases both the level and duration of the acetylcholine neurotransmitter action. The compounds presented inhibitory activity in the micromolar range against acetylcholinesterase (AChE) (imines and amines) and butyrylcholineterase (BChE) (amines). The SAR study revealed that elongation of the imine side chain improved AChE activity, whereas the reduction of these compounds to amines was crucial for higher activity and indispensable for BChE inhibition. The most promising selective inhibitors were not cytotoxic and did not stimulate pro-inflammatory activity in glial cells. Kinetic and molecular modeling studies indicated that they also show mixed-type inhibition for both enzymes, behaving as dual-site inhibitors, which can interact with both the peripheral anionic site and the catalytic anionic site of AChE. They could therefore restore cholinergic transmission and also may inhibit the aggregation of A beta promoted by AChE. Additionally, one compound showed promising anti-inflammatory activity by reducing the microglial release of NO center dot at a concentration that is equivalent to the IC(50)against BChE (30.32 +/- 0.18 mu M) and 15-fold greater than the IC(50)against AChE (1.97 +/- 0.20 mu M). Communicated by Ramaswamy H. Sarma

Automated summary

A new series of compounds were designed, synthesized, and evaluated as potential neuroprotective agents against Alzheimer's disease. These compounds showed inhibitory activity against AChE and BChE and were found to be selective and non-cytotoxic. Kinetic and molecular modeling studies indicated that they could act as dual-site inhibitors for both enzymes and also exhibited promising anti-inflammatory activity.