Evaluation of chromane derivatives: Promising privileged scaffolds for lead discovery within Alzheimer's disease. (15th August 2022)

• Record Type: Journal Article
• Authors: Moutayakine, Amina; Marques, Carolina; López, Óscar; Bagetta, Donatella; Leitzbach, Luisa; Hagenow, Stefanie; Carreiro, Elisabete P.; Stark, Holger; Alcaro, Stefano; Fernández-Bolaños, José G.; Burke, Anthony J.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 68(2022)
• Publication Date: 2022-08-15
• Subjects: Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116807
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 ( eq BuChE) (in the range 2.9 – 7.3 μM) and in the same range of currently used drugs. We also synthesized a small library of gem -dimethylchroman-4-amine compounds, via a simple reductive amination of the corresponding chromanone precursor, that were also selective for eq BuChE presenting inhibitions in the range 7.6 – 67 μM. 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 µM on MAO-B). Overall, our compounds were found to be best suited as inhibitors for BuChE.