Novel Benzylated (Pyrrolidin-2-one)/(Imidazolidin-2-one) Derivatives as Potential Anti-Alzheimer’s Agents: Synthesis and Pharmacological Investigations

Abstract

A series of N-benzylated (pyrrolidin-2-one)/(imidazolidin-2-one) derivatives were synthesized and evaluated for anti-Alzheimer's activity. The analogs were designed and synthesized on the basis of lead compound donepezil, which is currently prescribed as a major drug for the management of mild to severe Alzheimer's disease. Considering the structure activity relationship (SAR) of the lead compound, we first replaced the 5,6-dimethoxy-1-indanone moiety with N-benzylated (pyrrolidin-2-one)/(imidazolidin-2-one) (head) without depriving the key functionality interactions like carbonyl and dimethoxyphenyl and second substituted the spacer linkage (tail) in donepezil. The newly synthesized compounds were characterized by structural conformity and purity using various techniques. The compounds were then subjected to in vivo (behavioral studies) and in vitro (biochemical assays) evaluation using appropriate animal models against the standard drug. Compounds 3-(4-(4-fluorobenzoyl)-piperidin-1-yl)-1-(4-methoxybenzyl)-pyrrolidin-2-one (10b) and 1-(3,4-dimethoxybenzyl)-3-((1-(2-(trifluoromethyl)-benzyl)-piperidin-4-yl)-methyl)-imidazolidin-2-one (18c) displayed an excellent anti-Alzheimer's profile, while the rest of the compounds showed satisfactory results in comparison to donepezil.

Design, Synthesis, and Biological Evaluation of Piperazine and N-Benzylpiperidine Hybrids of 5-Phenyl-1,3,4-oxadiazol-2-thiol as Potential Multitargeted Ligands for Alzheimer’s Disease Therapy

“…There remains an urgent unmet medical need for novel therapeutic approaches and modalities. The main impediment to developing a novel therapeutic approach is the AD etiology, which remains mysterious . Despite the progress in treatment, AD remains an incurable and inexorable disease .…”

“…The main impediment to developing a novel therapeutic approach is the AD etiology, which remains mysterious. 5 Despite the progress in treatment, AD remains an incurable and inexorable disease. 6 The exact causes of AD are unknown, but some hypotheses suggest that cholinergic dysfunction (decline in acetylcholine (ACh) level), formation of amyloid-β (Aβ) plaques, formation of neurofibrillary tangles (NFTs), N-methyl-D-aspartate receptor (NMDAR) activation, neuroinflammation, oxidative stress, mitochondrial dysfunction, as well as hyperactivation of monoamine oxidase (MAO), are key contributors in developing AD pathogenesis.…”

The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α1-Adrenolytic Properties

“…Many studies on pyrrolidine-2-one derivatives prove their diverse pharmacological effects, such as procognitive [ 23 ], anticonvulsant [ 24 ], antidepressant [ 25 , 26 ], sleep-promoting [ 27 ], anti-inflammatory [ 28 ], anticancer [ 29 , 30 ], antifungal [ 31 ], antimalarial [ 32 ], hypotensive, and antiarrhythmic activity [ 33 ]. Furthermore, scientists have discovered that the compounds containing pyrrolidine-2-one fragment often exhibit α-adrenolytic properties [ 20 , 34 ].…”

The recent development of donepezil structure-based hybrids as potential multifunctional anti-Alzheimer's agents: highlights from 2010 to 2020

“…29). 60 Wang et al focused on modifying the benzyl group of donepezil using several disparate fragments, including quinolone, pyridine, and hydroxyquinoline, for better interaction with dual binding sites of AChE. Based on the screening results, all the compounds demonstrated a potent AChE inhibition with values of IC 50 in the nanomolar range, satisfactory antioxidant activities, Ab interaction, and BBB penetration.…”