TY - JOUR
T1 - Evaluation of Anti-Alzheimer's Potential of Azo-Stilbene-Thioflavin-T derived Multifunctional Molecules
T2 - Synthesis, Metal and Aβ Species Binding and Cholinesterase Activity
AU - Rana, Monika
AU - Terpstra, Karna
AU - Gutierrez, Citlali
AU - Xu, Kerui
AU - Arya, Hemant
AU - Bhatt, Tarun K.
AU - Mirica, Liviu M.
AU - Sharma, Anuj K.
N1 - Publisher Copyright:
© 2024 Wiley-VCH GmbH.
PY - 2025/1/9
Y1 - 2025/1/9
N2 - Inhibition of amyloid β (Aβ) aggregation and cholinesterase activity are two major therapeutic targets for Alzheimer's disease (AD). Multifunctional Molecules (MFMs) specifically designed to address other contributing factors, such as metal ion induced abnormalities, oxidative stress, toxic Aβ aggregates etc. are very much required. Several multifunctional molecules have been developed using different molecular scaffolds. Reported herein is a new series of four MFMs based on ThT, Azo-stilbene and metal ion chelating pockets. The synthesis, characterization, and metal chelation ability for [Cu2+ and Zn2+] are presented herein. Furthermore, we explored their multifunctionality w.r.t. to their (i) recognition of Aβ aggregates and monomeric form, (ii) utility in modulating the aggregation pathways of both metal-free and metal-bound amyloid-β, (iii) ex-vivo staining of amyloid plaques in 5xFAD mice brain sections, (iv) ability to scavenge free radicals and (v) ability to inhibit cholinesterase activity. Molecular docking studies were also performed with Aβ peptides and acetylcholinesterase enzyme to understand the observed inhibitory effect on activity. Overall, the studies presented here establish the multifunctional nature of these molecules and qualify them as promising candidates for furthermore investigation in the quest for finding Alzheimer's disease treatment.
AB - Inhibition of amyloid β (Aβ) aggregation and cholinesterase activity are two major therapeutic targets for Alzheimer's disease (AD). Multifunctional Molecules (MFMs) specifically designed to address other contributing factors, such as metal ion induced abnormalities, oxidative stress, toxic Aβ aggregates etc. are very much required. Several multifunctional molecules have been developed using different molecular scaffolds. Reported herein is a new series of four MFMs based on ThT, Azo-stilbene and metal ion chelating pockets. The synthesis, characterization, and metal chelation ability for [Cu2+ and Zn2+] are presented herein. Furthermore, we explored their multifunctionality w.r.t. to their (i) recognition of Aβ aggregates and monomeric form, (ii) utility in modulating the aggregation pathways of both metal-free and metal-bound amyloid-β, (iii) ex-vivo staining of amyloid plaques in 5xFAD mice brain sections, (iv) ability to scavenge free radicals and (v) ability to inhibit cholinesterase activity. Molecular docking studies were also performed with Aβ peptides and acetylcholinesterase enzyme to understand the observed inhibitory effect on activity. Overall, the studies presented here establish the multifunctional nature of these molecules and qualify them as promising candidates for furthermore investigation in the quest for finding Alzheimer's disease treatment.
KW - Acetylcholinesterase Inhibitors
KW - Alzheimer's disease
KW - Amyloid-β aggregation
KW - Metal Chelators
KW - Multifunctional Molecules (MFMs)
UR - http://www.scopus.com/inward/record.url?scp=85209805747&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85209805747&partnerID=8YFLogxK
U2 - 10.1002/chem.202402748
DO - 10.1002/chem.202402748
M3 - Article
C2 - 39476334
AN - SCOPUS:85209805747
SN - 0947-6539
VL - 31
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
IS - 2
M1 - e202402748
ER -