A method for the synthesis of 1-dialkylaminoalkyl-2-phenyl-4-arylidene-5-imidazolones from N-benzoyl-α,β-dehydroamino acid dialkylaminoalkylamides using trimethylchlorosilane and hexamethyldisilazane as dehydrating agents was proposed. The synthesized imidazolones were converted into the corresponding ammonium salts by reacting with various alkyl halides and acids. The anticholinesterase properties of 1-dialkylaminoalkyl-2-phenyl-4-arylidene-5-imidazolones and their quaternary ammonium salts were studied. It was found that the studied substances have anticholinesterase activity and are mainly specific for BuChE.

Store-operated calcium entry (SOCE) constitutes a fine-tuning mechanism responsible for the replenishment of intracellular stores. Hippocampal SOCE is regulated by store-operated channels (SOC) organized in tripartite complex TRPC6/ORAI2/STIM2. It is suggested that in neurons, SOCE maintains intracellular homeostatic Ca2+ concentration at resting conditions and is needed to support the structure of dendritic spines. Recent evidence suggests that positive modulators of SOC are prospective drug candidates to treat Alzheimer’s disease (AD) at early stages. Although STIM2 and ORAI2 are definitely involved in the regulation of nSOC amplitude and a play major role in AD pathogenesis, growing evidence suggest that it is not easy to target these proteins pharmacologically. Existing positive modulators of TRPC6 are unsuitable for drug development due to either bad pharmacokinetics or side effects. Thus, we concentrate the review on perspectives to develop specific nSOC modulators based on available 3D structures of TRPC6, ORAI2, and STIM2. We shortly describe the structural features of existing models and the methods used to prepare them. We provide commonly used steps applied for drug design based on 3D structures of target proteins that might be used to develop novel AD preventing therapy.

The reaction of 2-phenyl-4-(4-benzoyloxyarylidene)-5(4H)-oxazolones the corresponding amino acids with hydrochlorides of methyl esters afforded N,O-dibenzoyl-α,β-dehydrotyrosylpeptides methyl esters. From the latter, O-benzoyl protecting group was removed with 3-(dimethylamino)-1-propylamine. Antiradical and anticholinesterase activity of the synthesized α,β-dehydrotyrosylpeptides were studied.

The one-pot synthesis of N-substituted α,β-dehydrotyrosyl dipeptides was carried out by the azlactone method. The target dipeptides were obtained in good yields (53–79%). From the latter, 2,3,5-trisubstituted 4-imidazolones were obtained using 1,1,1,3,3,3-hexamethyldisilazane as a dehydrating agent. It was found that in the case of β-alanine-containing peptides, abstraction of the methyl ester of acrylic acid and the formation of 2,5-disubstituted 4-imidazoline were observed. Antiradical and anticholinesterase properties of the synthesized compounds were studied. Docking analysis was carried out for both some dipeptides and imidazole-4-ones.

The use of O-benzoyl protection in the synthesis of N-benzoyl-α,β-dehydrotyrosine benzylamide, and the corresponding 4-imidazolone was studied. The reaction of 4-(4-benzoyloxybenzylidene)oxazol-5(4H)-one with benzylamine proceeds with the retention of the O-benzoyl protecting group. The latter is removed with 2-(dimethylamino)-1-ethylamine or 3-(dimethylamino)-1-propylamine. In the case of the cyclization of N,O-dibenzoyl-α,β-dehydrotyrosine benzylamide with 1,1,1,3,3,3-hexamethyldisilazane into (Z)-3-benzyl-5-(4-hydroxybenzylidene)-2-phenyl-3,5-dihydro-4H-imidazol-4-one leads to elimination of the O-benzoyl protection. The antiradical and anticholinesterase properties of the synthesized compounds were studied.

The piperazine derivative N-(2,6-difluorophenyl)-2-(4-phenylpiperazin-1-yl)propanamide (cmp2) has emerged as a potential transient receptor potential cation channel, subfamily C, member 6 (TRPC6) modulator, offering a promising pathway for Alzheimer’s disease (AD) therapy. Our recent findings identify cmp2 as a novel compound with synaptoprotective effects in primary hippocampal cultures and effective blood–brain barrier (BBB) penetration. In vivo studies demonstrate that cmp2 (10 mg/kg, intraperitoneally) restores synaptic plasticity deficits in 5xFAD mice. This study further shows cmp2’s selectivity towards tetrameric TRPC6 channel in silico. Acute administration of cmp2 is non-toxic, with no indications of chronic toxicity, and Ames testing confirms its lack of mutagenicity. Behavioral assays reveal that cmp2 improves cognitive functions in 5xFAD mice, including increased novel object recognition, better passing of the Morris water maze, and improved fear memory, as well as upregulation of motor function in beam walking tests. These findings suggest that cmp2 holds promise as a candidate for AD treatment.