Synthesis, Molecular Modeling, and Evaluation of Novel Sulfonylhydrazones as Acetylcholinesterase Inhibitors for Alzheimer's Disease.
Alzheimer's disease (AD) is the most common type of dementia and related to the degeneration of hippocampal cholinergic neurons, which dramatically affects cognitive ability. Acetylcholinesterase (AChE) inhibitors are employed as drugs for AD therapy. Three series of sulfonylhydrazone compounds were designed, and their ability to inhibit AChE was evaluated. Fifteen compounds were synthesized and twelve of them had IC50 values of 0.64-51.09 μM. The preliminary structure-activity relationships indicated that the methylcatechol moiety and arylsulfonyl substituents generated better compounds than both the benzodioxole and alkylsulfonyl chains. Molecular dynamics studies of compound 6d showed that the interaction with the peripheral binding site of AChE was similar to donepezil, which may explain its low IC50 (0.64 μM). Furthermore, the drug-likeness of 6d suggests that the compound may have appropriate oral absorption and brain penetration. Compound 6d also presented antiradical activity and was not cytotoxic to LL24 cells, suggesting that this compound might be considered safe. Our findings indicate that arylsulfonylhydrazones may be a promising scaffold for the design of new drug candidates for the treatment of AD.
['Fernandes|Thais B|TB|http://orcid.org/0000-0003-1232-5737', 'Cunha|Micael R|MR|', 'Sakata|Renata P|RP|', 'Candido|Thalita M|TM|', 'Baby|André R|AR|', 'Tavares|Maurício T|MT|', 'Barbosa|Euzébio G|EG|', 'Almeida|Wanda P|WP|', 'Parise-Filho|Roberto|R|']
D000110:Acetylcholinesterase D000544:Alzheimer Disease D001665:Binding Sites D002800:Cholinesterase Inhibitors D000077265:Donepezil D015195:Drug Design D006801:Humans D006835:Hydrazones D007189:Indans D020128:Inhibitory Concentration 50 D008958:Models, Molecular D010880:Piperidines D013329:Structure-Activity Relationship
Molecular modeling Sulfonylhydrazone Acetylcholinesterase Alzheimer's disease Drug design