Design, synthesis, structure, toxicology and in vitro testing of three novel agents for Alzheimer’s disease

Abstract

This article describes the synthesis of three novel compounds for the treatment of Alzheimer’s disease (AD). The compounds were formed by the reaction of 3-methoxy-2-hydroxybenzaldehyde (1) with dimedone (2) using water as solvent at room temperature. Subsequently, Na₂S or NaCl was added under reflux to obtain (R)-9-mercapto-5-methoxy-3,3-dimethyl-3,4-dihydro-2H-xanthen-1(9H)-one (5) and 9-chloro-3,4-dihydro-5-methoxy-3,3-dimethyl-2H-xanthen-1(9H)-one (6), respectively. The final reaction proceeded under reflux with water only to obtain 3,4-dihydro-9-hydroxy-5-methoxy-3,3-dimethyl-2H-xanthen-1(9H)-one (7). Compounds 5, 6 and 7 were selected due to their structural similarities to tacrine, which is one of the most effective AChE inhibitors for AD. The compounds were studied by nuclear magnetic resonance (NMR) to assign all chemical shifts and determine their three-dimensional structures. A parallel molecular modeling study was conducted to confirm the NMR results and obtain the energy, dipole moment, area, polar surface area (PSA) and volume of each compound. The PSA values indicated that the new compounds should be able to cross the blood–brain barrier. Compounds 5, 6 and 7 were then tested as inhibitors of human acetylcholinesterase (HuAChe) using docking experiments, and in vitro tests of the compounds as HuAChe inhibitors were performed using the Fig-NMR method with tacrine as a reference. The results confirmed that the new compounds are effective agents for the treatment of AD. Toxicity tests carried out using mice indicated very low toxicity. The findings suggest that the new compounds are better agents than tacrine for the treatment of AD.