Design, synthesis and evaluation of dihydropyranoindole derivatives as potential cholinesterase inhibitors against Alzheimer's disease

Abstract

A series of novel dihydropyranoindole derivatives containing sulphonamide group were designed, synthesized and evaluated for in-vitro anti-cholinesterase activity. The result showed that all the compounds exhibited potent acetylcholinesterase (AChE) activity (IC₅₀ = 0.41-8.79 µM) while demonstrated moderate to good activity for butyrylcholinesterase (BuChE) (IC₅₀ = 1.17-30.17 µM). The tested compounds exhibited selectivity towards AChE over BuChE. Compound 5o was most potent towards both AChE (IC₅₀ = 0.41 µM) and BuChE (IC₅₀ = 1.17 µM) when compared to standard galantamine and rivastigmine. Enzyme kinetics and molecular docking studies revealed that compound 5o shows mixed type inhibition and binds to peripheral anionic site (PAS) and the catalytic sites (CAS) of both the enzymes. Furthermore, cell viability studies were also performed against N2a cells along with neuroprotection studies against H₂O₂ in the same cell line. Antioxidant studies using DPPH radical and H₂O₂ were also performed which revealed that all compounds possessed some antioxidant activity. Also, DNA damage protection assay for compound 5o was performed implying that compound 5o was protective in nature. ADME studies were also performed which demonstrated good pharmacokinetics. These findings indicated that dihydropyranoindole derivatives could be possible drug lead in the search for new multifunctional AD drugs.

Keywords: Antioxidant; Cell viability; Cholinesterase inhibitor; DNA damage; Molecular docking.