Multifunctional novel Diallyl disulfide (DADS) derivatives with β-amyloid-reducing, cholinergic, antioxidant and metal chelating properties for the treatment of Alzheimer's disease.
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-m exhibited significant anti-Aβ 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 Aβ aggregation (74% and 71.4%, 25 μM) and metal chelating ability. Furthermore, compounds 7k and 7l disaggregated Aβ fibrils generated by Cu(2+)-induced Aβ 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 μM and 0.121 μM, 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 0.546-5.86Trolox 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.
Bio-Organic Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India.
Apra
A
Manral
Bio-Organic Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India.
Vikas
V
Saini
Bio-Organic Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India.
Poonam
P
Meena
Bio-Organic Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India. Electronic address: mtiwari07@gmail.com.
Manisha
M
Tiwari
D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000498:Allyl Compounds / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000812:Anhydrides / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D000975:Antioxidants / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D002614:Chelating Agents / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D003300:Copper / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
D000498:Allyl Compounds; D016229:Amyloid beta-Peptides; D000812:Anhydrides; D000975:Antioxidants; D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; D004220:Disulfides; C000608970:bis(2-(3, 4-dimethoxy phenyl)ethenyl)dithioperoxyanhydride; C000609169:bis(2-(4-hydroxy,3-methoxy phenyl)-ethenyl)dithioperoxyanhydride; C028009:diallyl disulfide; D003300:Copper; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
AChE inhibitors; Alzheimer’s disease; Antioxidant; Aβ aggregation; Diallyl disulfide derivatives; Metal chelator; Molecular docking