Thiazole‐substituted benzoylpiperazine derivatives as acetylcholinesterase inhibitors

Abstract

Hit, Lead & Candidate Discovery After acetylcholine is released into the synaptic cleft, it is reabsorbed or deactivated by acetylcholinesterase (AChE). Studies on Alzheimer's disease (AD) in the mid‐20th century proved that cognitive dysfunctions are associated with cholinergic neurotransmission. Drugs, such as tacrine, rivastigmine, donepezil, and galantamine are known as acetylcholinesterase inhibitors. However, these drugs have limited use in advanced AD and dementia. Recently, the anticholinesterase activity of various heterocyclic‐framed compounds, including piperazine derivatives, has been investigated, and compounds with similar effects to known drugs have been identified. The aim of this study was to design new donepezil analogs. In this study, 66 original piperazinyl thiazole derivatives were synthesized by the reaction of piperazine N′‐benzoyl thioamides and bromoacetophenones to inhibit AChE. Biological activity was measured by the Ellman method. Compounds 35, 38, 40, 45, 57, and 61 showed a high inhibitory effect among the series (80.36%–83.94% inhibition), and donepezil had a 96.42% inhibitory effect. The IC50 values of compounds 35, 38, and 40, were calculated as 0.9767 μM, 0.9493 μM, and 0.8023 μM, respectively. Compound 45 (IC50 = 1.122), Compound 57 (IC50 = 1.2130) and 61 (IC50 = 0.9193) also exhibited good activity on AChE. Molecular modeling studies were in agreement with the predictions. Trp286, Arg296, and Tyr341 were the key amino acids at the active site. Both donepezil and synthesized compounds seemed to interact with these residues.

Identification of two arylimides as cholinesterase inhibitors and testing of propranolol addition on impaired rat memory

“…Hence, medicinal chemists have made great effort to develop new AChE‐Is (Gao et al, ; Nygaard, ; Sahin et al, ). These efforts have ranged from slight structural modifications of the endogenous substrate of AChE (Bermúdez‐Lugo, Rosales‐Hernández, Deeb, Trujillo‐Ferrara, & Correa‐Basurto, ; Zemek et al, ) to the design and study of more complicated molecular structures.…”

“…Moreover, it has been demonstrated that the activity of this neurotransmitter in the brain is downregulated by the hydrolytic action of cholinesterases, particularly acetylcholinesterase (AChE) and also butyrylcholinesterase. Therefore, one of the main approaches for the palliative treatment of AD is still the use of AChE inhibitors (AChE-Is) (Gao, Tang, Liu, Liu, & Liu, 2019;Greig, Reale, & Tata, 2013;Herrmann, Chau, Kircanski, & Lanctôt, 2011;Hugo & Ganguli, 2014;Nygaard, 2013;Sahin et al, 2018), despite the increasing number of other strategies for treating AD that have led to drug design and development (Herrmann et al, 2011;Hugo & Ganguli, 2014;Nygaard, 2013).…”

Novel thiazole‐piperazine derivatives as potential cholinesterase inhibitors

“…As in our previous study, aryl piperazine derivatives were used as starting materials. First, the selected secondary amines were converted to the corresponding thioureide compounds ( A ) with benzoyl chloride/ammonium thiocyanate and reacted with α‐bromoacetophenone derivatives ( B ) to provide the final 2,4,5‐thiazole compounds ( 1‐44 ).…”

“…The IC 50 values were also calculated as 0.950μM for compound 4 and 2.104μM for compound 37 . When the chemical structures of these compounds were evaluated, the methoxy substituent on the phenyl ring linked to the piperazine structure had attracted attention, and this substituent was revealed in all compounds whose IC 50 value was calculated. Especially, compounds 5 , 16 , 27 , and 38 containing 4‐methoxyphenyl exhibited the highest enzyme inhibitory activity.…”

“…On the basis of the literature data given above and extending our previous study, we were encouraged to design and develop [2‐(4‐(2/3/4‐substituted phenyl)piperazin‐1‐yl)‐4‐phenylthiazol‐5‐yl][3/4‐substituted phenyl]methanone derivatives ( 1‐44 ), considering the benzophenone structure, piperazine, and thiazole rings as pharmacophoric groups for cholinesterase inhibitory activity. We performed molecular modeling studies using Schrödinger Maestro program.…”