Acridone-based acetylcholinesterase inhibitors: synthesis, antioxidant activity and molecular modeling

Abstract

Acridone is a unique naturally occurring alkaloid known to associate with several biological activities. 2,3-dimethoxy-10-methyl-10,8a-dihydroacridin-9(8aH)-one (4) and its precursor 2-((3,4-dimethoxyphenyl)methylamino)benzoic acid (3) were synthesized and investigated for potential antioxidant and inhibitory activity against acetylcholinestrase. The synthetic pathway involves reaction of 2-(methylamino) benzoic acid (1) with 4-chloro-1,2-dimethoxybenzene (2) in presence of CuO and K2CO3 to give the precursor 3. Subsequent, cyclcondensation of 3 with Conc. H2SO4 afforded the anticipated acridone 4. Furthermore, the dimethoxyacridone derivative 4 showed potent antiacetylcholinesterase (ACHE) activity at (100 uM) with IC50 = 9.25 uM that is as potent as the reference drug rivastigmine. Assessment of total antioxidant activity of compounds 3 & 4 in comparison to known standard compounds revealed the following order: α-tocopherol > Acridone 4 > trolox > butylated hydroxyl anisole (BHA) > butylated hydroxyl toluene (BHT) > compound 3. Molecular docking characteristics of 3 & 4 within the active site of AChE (PDB: 1ACJ) co-crystallized with 9-amino-tetrahydroacridine (Tacrine) have been studied. Interestingly, the results revealed comparable binding poses to the co-crystallized ligand and demonstrates good correlation of the binding energy (DG) with the observed IC50-values. This finding suggests that compounds 3 & 4 exhibit good antioxidant effect and inhibition of acetylcholinesterase, which might provide profitable candidates in management of Alzheimer’s disease.