لخّصلي

Since the discovery of the first AchE inhibitor, physostigmine (30), a large number of studies have been performed to identify more effective inhibitors.According to structure-activity relationship studies, the design of novel potent multi-target inhibitors should have the following characteristics: i) The presence of a nitrogen atom with a positive charge (91); ii) the size of the alkyl chain attached to the nitrogen atom should be small, such as a methyl group (92); iii) the presence of an oxygen atom able to form hydrogen bonds, such as an ester (93); iv) the presence of electron-donating groups such as hydroxyl and methoxy groups (83); and v) the presence of a two-carbon unit between nitrogen and oxygen atoms (91).These inhibitors cause milder side effects than traditional drugs and may have improved properties, such as better BBB permeability and increased effectiveness (11,67).Other inhibitors include analogues of the traditional inhibitors, derivatives of natural compounds and hybrids of synthetic inhibitors.protein, metal dyshomeostasis and oxidative stress.

Since the discovery of the first AchE inhibitor, physostigmine (30), a large number of studies have been performed to identify more effective inhibitors. Traditional inhibitors are naturally-derived agents. Other inhibitors include analogues of the traditional inhibitors, derivatives of natural compounds and hybrids of synthetic inhibitors. These inhibitors cause milder side effects than traditional drugs and may have improved properties, such as better BBB permeability and increased effectiveness (11,67). In addition, these compounds are able to limit the progression of AD. Recent reports investigated AChE inhibition (80,88,90), but only a few novel drugs have been tested in humans (18,60–62,78). Most of these inhibitors have been studied in animal models, or using in vitro and in silico models. Therefore, further studies in humans to investigate the safety, efficacy and toxicity of these drugs are required.

AChE inhibitors are not able to completely stop the progression of AD, and various single-target drugs that have reached clinical trials were not able to effectively treat AD. Therefore, there is a need to develop multi-functional drugs that are able to target all symptoms of AD, including the decreased levels of ACh, protein misfolding and associated Aβ aggregation, hyperphosphorylation of τ protein, metal dyshomeostasis and oxidative stress. However, only a limited number of studies have focused on the development of multi-target drugs (79,81,89).

According to structure-activity relationship studies, the design of novel potent multi-target inhibitors should have the following characteristics: i) The presence of a nitrogen atom with a positive charge (91); ii) the size of the alkyl chain attached to the nitrogen atom should be small, such as a methyl group (92); iii) the presence of an oxygen atom able to form hydrogen bonds, such as an ester (93); iv) the presence of electron-donating groups such as hydroxyl and methoxy groups (83); and v) the presence of a two-carbon unit between nitrogen and oxygen atoms (91). Notably, the overall size of the molecule should be small, since large molecules can exhibit decreased activity (94).