Aryldiazoquinoline based multifunctional small molecules for modulating Aβ<sub>42</sub>aggregation and cholinesterase activity related to Alzheimer's disease

Rana, Monika; Pareek, Abhishek; Bhardwaj, Shivani; Arya, Geeta; Nimesh, Surendra; Arya, Hemant; Bhatt, Tarun Kumar; Yaragorla, Srinivasarao; Sharma, A.

doi:10.1039/d0ra05172a

Cited by 12 publications

(17 citation statements)

References 78 publications

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“…The azo group is inspired from Congo red, which is a gold standard in the staining agents for amyloids. 45,51,52 Metal-chelating arms have been developed by linking tridentate (N,N,O) and tetradenate ligands (N,N,N,O), which are known to effectively bind metals (Scheme 1). 41 Furthermore, since the phenolic functionality is known to induce antioxidant properties, these molecules are anticipated to have antioxidant properties.…”

Section: Resultsmentioning

confidence: 99%

“…69 The active site of TcAChE is almost identical to that of hAChE, and the detailed information is given in the literature. 52 Structurally, AChE possesses a catalytic active site (CAS) and a peripheral anionic site (PAS), the two commonly understood binding sites. The active site is primarily responsible for hydrolysis of the ester bond of acetylcholine involving Ser200, His440, and Glu327 with the anionic site consisting of Trp84 and Phe330 aromatic residues.…”

Section: Inhibition Of Aβ 42 Aggregation Studied By Transmission Elec...mentioning

confidence: 99%

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Azo-Stilbene and Pyridine–Amine Hybrid Multifunctional Molecules to Target Metal-Mediated Neurotoxicity and Amyloid-β Aggregation in Alzheimer’s Disease

et al. 2022

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Neurodegenerative diseases such as Alzheimer’s disease (AD) are associated with progressive neuronal cell death, and they are commonly correlated with aberrant protein misfolding and aggregation of Aβ peptides. Transition metal ions (Cu, Fe, and Zn) have been shown to promote aggregation and oxidative stress through formation of Aβ–metal complexes. In this context, integrating molecular scaffolds rationally is used here to generate multifunctional molecules as modulators for metal-induced abnormalities. This work encompasses two azo-stilbene (AS)-derived compounds (AS-HL1 and AS-HL2), the rationale behind the design, their synthesis, characterization, and metal chelation ability [Cu(II) and Zn(II)]. The molecular frameworks of the designed compounds consist of stilbene as an Aβ-interacting moiety, whereas N,N,O and N,N,N,O donor atoms are linked to generate the metal chelation moiety. Furthermore, we went on exploring their multifunctionality with respect to (w.r.t.) (i) their metal chelating capacities and (ii) their utility to modulate the aggregation pathways of both metal-free and metal-bound amyloid-β, (iii) scavenge free radicals, and (iv) inhibit the activity of acetylcholinesterase and (v) cytotoxicity. Moreover, the compounds were able to sequester Cu2+ from the Aβ–Cu complex as studied by the UV–visible spectroscopic assay. Molecular docking studies were also performed with Aβ and acetylcholinesterase enzyme. Overall, the studies presented here qualify these molecules as promising candidates for further investigation in the quest for finding a treatment for Alzheimer’s disease.

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Section: Resultsmentioning

confidence: 99%

Section: Inhibition Of Aβ 42 Aggregation Studied By Transmission Elec...mentioning

confidence: 99%

Azo-Stilbene and Pyridine–Amine Hybrid Multifunctional Molecules to Target Metal-Mediated Neurotoxicity and Amyloid-β Aggregation in Alzheimer’s Disease

et al. 2022

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“…Azo group is inspired from Congo-red, which is a gold standard as the staining agent for amyloids. 31,[36][37] Metal chelating arms have been developed by linking tridentate (N,N,O) and tetradenate ligand (N,N,N,O), which are known to effectively bind metals (Scheme 1). 38 Further, phenolic functionality is known to exhibit anti-oxidant properties, the newly designed molecules are anticipated to have anti-oxidant potential and reduction of ROS generation.…”

Section: Design Rationalementioning

confidence: 99%

“…63 The active site of TcAChE is almost identical to the hAChE and the detailed information is given in literature. 37 Structurally, AChE possesses a catalytic active site (CAS) and a peripheral anionic site (PAS), the commonly understood two binding sites. Active site is primarily responsible for hydrolysis of ester bond of acetylcholine involves Ser200, His440 and Glu327 and anionic site consisting of Trp84 and Phe330 aromatic residues.…”

Section: Molecular Docking With Achementioning

confidence: 99%

“…Therefore, inhibitors with dual interactions with both PAS and CAS simultaneously appears to be a better therapeutic strategy as these can combat cognitive dysfunctions as well as prevent complications related to Aβ aggregation. 37,61,64 Molecular docking studies were performed with Maestro v11.9 of Schrödinger software. The Xray crystal structure of torpedo AChE (TcAChE) in complex with tacrine (PDB ID: 1ACJ) was downloaded from Protein Data Bank (PDB) and docked with the designed compounds.…”

Section: Molecular Docking With Achementioning

confidence: 99%

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Novel Azo-Stilbene and Pyridine-Amine Hybrid Multifunctional Molecules to Target Metal Mediated Neurotoxicity and Amyloid-β Aggregation in Alzheimer’s disease

Rana¹,

Cho²,

Arya³

et al. 2022

Preprint

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Neurodegenerative diseases such as Alzheimer’s diseases (AD) are associated with progressive neuronal cell death and a common correlation is aberrant protein misfolding and aggregation of the Aβ peptide. Transition metal ions (Cu, Fe and Zn) have been shown to promote aggregation and oxidative stress through formation of Aβ-metal complexes. In this context, integrating molecular scaffolds rationally is used here to generate multifunctional molecules as modulators for metal-induced abnormalities. This work encompasses two novel compounds (HL1 and HL2), the rationale behind the design, their synthesis, characterization and metal chelation ability [Cu(II) and Zn(II)]. The molecular frameworks of the designed compounds consist of stilbene as an Aβ interacting moiety; whereas N,N,O and N,N,N,O donor atoms are linked to generate the metal chelation moiety. Further, we went on exploring their multifunctionality w.r.t. to (i) their metal chelating capacities (ii) their utility to modulate the aggregation pathways of both metal-free and metal-bound amyloid-β, (iii) scavenge free radicals, (iv) inhibit the activity of acetylcholinesterase and (v) cytotoxicity. Moreover, the compounds were able to sequester Cu2+ from the Aβ-Cu complex and thus disrupt the redox cycle. Molecular docking studies were also performed with Aβ and acetylcholinesterase enzyme. Overall, the studies presented here qualify these molecules as promising anti-Alzheimer’s candidates.

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Evaluation of Anti‐Alzheimer's Potential of Azo‐Stilbene‐Thioflavin‐T derived Multifunctional Molecules: Synthesis, Metal and Aβ Species Binding and Cholinesterase Activity

Rana,

Terpstra,

Gutierrez

et al. 2024

Chemistry A European J

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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 Ab 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 [Cu(II) and Zn(II)] 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.

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Aryldiazoquinoline based multifunctional small molecules for modulating Aβ₄₂aggregation and cholinesterase activity related to Alzheimer's disease

Abstract: Novel series of aryldiazoquinoline multifunctional molecules controls amyloid formation and neuro-protective role by inhibiting esterase enzymes.

Cited by 12 publications

References 78 publications

Azo-Stilbene and Pyridine–Amine Hybrid Multifunctional Molecules to Target Metal-Mediated Neurotoxicity and Amyloid-β Aggregation in Alzheimer’s Disease

Azo-Stilbene and Pyridine–Amine Hybrid Multifunctional Molecules to Target Metal-Mediated Neurotoxicity and Amyloid-β Aggregation in Alzheimer’s Disease

Novel Azo-Stilbene and Pyridine-Amine Hybrid Multifunctional Molecules to Target Metal Mediated Neurotoxicity and Amyloid-β Aggregation in Alzheimer’s disease

Evaluation of Anti‐Alzheimer's Potential of Azo‐Stilbene‐Thioflavin‐T derived Multifunctional Molecules: Synthesis, Metal and Aβ Species Binding and Cholinesterase Activity

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Aryldiazoquinoline based multifunctional small molecules for modulating Aβ42aggregation and cholinesterase activity related to Alzheimer's disease

Abstract: Novel series of aryldiazoquinoline multifunctional molecules controls amyloid formation and neuro-protective role by inhibiting esterase enzymes.

Cited by 12 publications

References 78 publications

Azo-Stilbene and Pyridine–Amine Hybrid Multifunctional Molecules to Target Metal-Mediated Neurotoxicity and Amyloid-β Aggregation in Alzheimer’s Disease

Azo-Stilbene and Pyridine–Amine Hybrid Multifunctional Molecules to Target Metal-Mediated Neurotoxicity and Amyloid-β Aggregation in Alzheimer’s Disease

Novel Azo-Stilbene and Pyridine-Amine Hybrid Multifunctional Molecules to Target Metal Mediated Neurotoxicity and Amyloid-β Aggregation in Alzheimer’s disease

Evaluation of Anti‐Alzheimer's Potential of Azo‐Stilbene‐Thioflavin‐T derived Multifunctional Molecules: Synthesis, Metal and Aβ Species Binding and Cholinesterase Activity

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Aryldiazoquinoline based multifunctional small molecules for modulating Aβ₄₂aggregation and cholinesterase activity related to Alzheimer's disease