Quercetagetin 3,7 dimethyl ether polymorphs as multi-targeted anti-amyloid agents: Target to cognitive impairment in Alzheimer's disease

Abstract

The extraction of biologically active natural products from plants and the assessment of their medicinal properties play a crucial role in drug development. Taking that into consideration, the current research work was designed. Bioassay-guided isolation from Parthenium hysterophorus led to the isolation of two antioxidant compounds: polymorphs A (1) and B (2) of Quercetagetin 3,7-dimethyl ether which demonstrated IC50 values 13.00 ± 0.63 μM and 16.56 ± 0.82 μM, respectively in the DPPH assay. These polymorphs were further evaluated for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. In silico studies, including molecular docking, and molecular dynamic simulations were conducted using β-secretase, γ-secretase, AChE, and BChE enzymes. Interestingly, compound 1 demonstrated excellent antioxidant activity and showed the better binding affinities -9.0 kcal/mol (BChE), −8.5 kcal/mol (β-secretase), -8.2 kcal/mol (γ-secretase) and -7.7 kcal/mol (AChE) as compared to compound 2. Due to these promising results, compound 1 was selected for molecular dynamic simulations to further evaluate the stability and flexibility of its complexes. Overall, both in silico and in vitro results confirmed that compound 1 and compound 2 exhibit distinct behavior, making them promising candidates as antioxidants and inhibitors of AChE, BChE, and secretases, potentially targeting cognitive impairment in Alzheimer's disease (AD).