Evaluation of chromane derivatives: Promising privileged scaffolds for lead discovery within Alzheimer's disease

The chromane ring system is widely distributed in nature and has proven to be a highly potent pharmacophore in medicinal chemistry, which includes the area of Alzheimer's and Parkinson's diseases. We report on the development of a gem-dimethylchroman-4-ol family that was shown to give good inhibition of equine serum butyrylcholinesterase (eqBuChE) (in the range 2.9 - 7.3 mu M) and in the same range of currently used drugs. We also synthesized a small library of gem-dimethyl-chroman-4-amine compounds, via a simple reductive amination of the corresponding chromanone precursor, that were also selective for eqBuChE presenting inhibitions in the range 7.6 - 67 mu M. Kinetic studies revealed that they were mixed inhibitors. Insights into their mechanism of action were obtained through molecular docking and STD-NMR experiments, and the most active examples showed excellent drug-likeness and pharmacological properties predicted using Swiss-ADME. We also prepared a set of propargyl gem-dimethylchromanamines, for monoamine oxidase (MAO) inhibition but they were only moderately active (the best being 28% inhibition at 1 mu M on MAO-B). Overall, our compounds were found to be best suited as inhibitors for BuChE.

Automated summary

A new gem-dimethylchroman-4-ol family of compounds was developed in this study, showing good inhibition of equine serum butyrylcholinesterase (eqBuChE), making them suitable as inhibitors for BuChE.