Novel 6,7-dimethoxyquinazolin-4(3H)-one derivatives as promising compounds for the therapy of alzheimer's disease

Relevance. Alzheimer's disease is one of the most common forms of dementia with a high mortality and disability rate. Some quinazolinone derivatives having methoxy groups in the quinazolinone scaffold may be potentially effective agents for the treatment of Alzheimer's disease.

The aim of the study. To evaluate the effect of new derivatives of 6,7-dimethoxyquinazoline-4(3H)-one on the activity of acetylcholinesterase and the aggregation of amyloid particles process under experimental conditions

Materials and methods. The studied derivatives of 6,7-dimethoxyquinazoline-4(3H)-one with amino acid and dipeptides residues were obtained by replacing the oxygen heteroatom in the benzoxazinone core by boiling the initial compound with the corresponding amino acid. The anticholinesterase activity of the studied compounds was evaluated using an Ellman reagent with spectrophotometric detection of degradation products of 5.5'-dithiobis-2-nitrobenzoic acid. The antiamyloid activity of 6,7-dimethoxyquinazoline-4(3H)-oh derivatives was determined by a change in the intensity of aggregation of β-amyloid particles (fragment 1-42) with congo red. All tests were performed three times.

Results. As a result of the study, it was found that derivatives of 6,7-dimethoxyquinazoline-4(3H)-oh inhibit the activity of acetylcholinesterase in vitro with IC₅₀ values in the range of 1.8±0.36 mg/ml to 4.2±0.96 mg/ml, which corresponded to the indicators of the referent - donepezil (IC₅₀ = 2.4±0.06). It is also worth noting the presence of moderate antiamyloid properties of the studied substances, which reduced the aggregation of β-amyloid particles by more than 50%, which, however, was lower than the indicators of the referent - GV-791 (p<0.05). Among the studied substances, the highest level of activity was characterized by substances containing glycylglycine and glycylleucine residues in the structure, surpassing donepezil (p<0.05) in the ability to inhibit acetylcholinesterase.

Conclusion. The study showed that derivatives of 6,7-dimethoxyquinazoline-4(3H)-one with amino acid and dipeptides residues, in particular with fragments of glycylglycine and glycylleucine, can be promising objects for further development of drugs for the treatment of Alzheimer's disease with a predominant effect on acetylcholine metabolism.