Multifunctional novel Diallyl disulfide (DADS) derivatives with beta-amyloid-reducing, cholinergic, antioxidant and metal chelating properties for the treatment of Alzheimer's disease

作者：Manral Apra; Saini Vikas; Meena Poonam; Tiwari Manisha^*

来源：Bioorganic & Medicinal Chemistry, 2015, 23(19): 6389-6403.

DOI：10.1016/j.bmc.2015.08.024

• Diallyl disulfide derivatives
• Alzheimer's disease
• A beta aggregation
• AChE inhibitors
• Antioxidant
• Metal chelator
• Molecular docking

A series of novel Diallyl disulfide (DADS) derivatives were designed, synthesized and evaluated as chemical agents, which target and modulate multiple facets of Alzheimer's disease (AD). The results showed that the target compounds 5a-l and 7e-mexhibited significant anti-A beta aggregation activity, considerable acetylcholinesterase (AChE) inhibition, high selectivity towards AChE over butyrylcholinesterase (BuChE), potential antioxidant and metal chelating activities. Specifically, compounds 7k and 7l exhibited highest potency towards self-induced A beta aggregation (74% and 71.4%, 25 mu M) and metal chelating ability. Furthermore, compounds 7k and 7l disaggregated A beta fibrils generated by Cu2+-induced A beta aggregation by 80.9% and 78.5%, later confirmed by transmission electron microscope (TEM) analysis. Besides, 7k and 7l had the strongest AChE inhibitory activity with IC50 values of 0.056 mu M and 0.121 mu M, respectively. Furthermore, molecular modelling studies showed that these compounds were capable of binding simultaneously to catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. All the target compounds displayed moderate to excellent antioxidant activity with ORAC-FL values in the range 0.546-5.86 Trolox equivalents. In addition, absorption, distribution, metabolism and excretion (ADME) profile and toxicity prediction (TOPKAT) of best compounds 7k and 7l revealed that they have drug like properties and possess very low toxic effects. Collectively, the results strongly support our assertion that these compounds could provide good templates for developing new multifunctional agents for AD treatment.

• 出版日期2015-10-1