Synthesis, Molecular Modeling, and Evaluation of Novel Sulfonylhydrazones as Acetylcholinesterase Inhibitors for Alzheimer's Disease

Abstract

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 IC 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 IC (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.

Preparation of a steroid-oxazole-1,2′-[1,3]oxazete] derivative: biological and theoretical evaluation of its interaction with a kinase protein (CK2)

“…Some physicochemical parameters of compounds 2-4 were determined to determine the oral availability of the drug and its pharmacokinetic properties using Swis-sADME, Spartan and ACD/Chem Sketch softwars [23][24][25].…”

Synthesis, structural elucidation and biological activities of some novel sulfonyl hydrazones as antibacterial agents

“…In this present work, new sulfonyl hydrazone derivatives (3a-h) were synthesized for the first time. At first, 4-nitrobenzenesulfonohydrazide (2) was obtained by stirring p-nitrobenzenesulfonyl chloride (1) with hydrazine hydrate in tetrahydrofuran [18]. The reaction of 2 with different aldehydes furnished the corresponding 4-nitro-N′-(substituted arylmethylidene)benzenesulfonohydrazides (3a-h) (Scheme 1) [10,19].…”

Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases

“…Biological results disclosed that among fifteen of these hybrids, twelve showed IC 50 values in the range of 0.64 µM to 51.09 µM. A SAR analysis suggested that the methylcatechol moiety and arylsulfonyl substituents were responsible for the best AChE inhibition than both the benzodioxole and alkylsulfonyl chains [ 78 ].…”

“…In silico studies evidenced that, in fact, the most potent AChEI 31a could interact with the PAS of AChE in a similar manner of donepezil. Furthermore, compound 31a showed antioxidant activity, with no significant toxicity on LL24 cells and adequate predicted oral absorption and brain penetration, which was considered a promising profile for further development against AD [ 78 ].…”