Novel Furan-2-yl-1<i>H</i>-pyrazoles Possess Inhibitory Activity against α-Synuclein Aggregation

Ryan, Philip; Xu, Mingming; Jahan, Kousar; Davey, Andrew K.; Bharatam, Prasad V.; Anoopkumar‐Dukie, Shailendra; Kassiou, Michael; Mellick, George D.; Rudrawar, Santosh

doi:10.1021/acschemneuro.0c00252

Cited by 11 publications

(15 citation statements)

References 41 publications

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“…The role of α-syn misfolding in the initiation of PD is well established (Mahul-Mellier et al, 2020). Several studies report on targeting α-syn aggregation and synthesis as a potential therapeutic option in PD (Fields et al, 2019;Chakroun et al, 2020;Gabr and Peccati, 2020;Mahul-Mellier et al, 2020;Ryan et al, 2020). Here, it is important to mention that native α-syn plays a crucial role in releasing the neurotransmitter associated with SV due to its greater curvature, but its over-expression is reported to inhibit the release of neurotransmitters (Sulzer and Edwards, 2019;Cai et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“Janus-Faced” α-Synuclein: Role in Parkinson’s Disease

Ray

Mahalakshmi

Tuladhar

et al. 2021

Front. Cell Dev. Biol.

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Parkinson’s disease (PD) is a pathological condition characterized by the aggregation and the resultant presence of intraneuronal inclusions termed Lewy bodies (LBs) and Lewy neurites which are mainly composed of fibrillar α-synuclein (α-syn) protein. Pathogenic aggregation of α-syn is identified as the major cause of LBs deposition. Several mutations in α-syn showing varied aggregation kinetics in comparison to the wild type (WT) α-syn are reported in PD (A30P, E46K, H 50Q, G51D, A53E, and A53T). Also, the cell-to-cell spread of pathological α-syn plays a significant role in PD development. Interestingly, it has also been suggested that the pathology of PD may begin in the gastrointestinal tract and spread via the vagus nerve (VN) to brain proposing the gut–brain axis of α-syn pathology in PD. Despite multiple efforts, the behavior and functions of this protein in normal and pathological states (specifically in PD) is far from understood. Furthermore, the etiological factors responsible for triggering aggregation of this protein remain elusive. This review is an attempt to collate and present latest information on α-syn in relation to its structure, biochemistry and biophysics of aggregation in PD. Current advances in therapeutic efforts toward clearing the pathogenic α-syn via autophagy/lysosomal flux are also reviewed and reported.

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Section: Introductionmentioning

confidence: 99%

“Janus-Faced” α-Synuclein: Role in Parkinson’s Disease

Ray

Mahalakshmi

Tuladhar

et al. 2021

Front. Cell Dev. Biol.

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“… Chemical structures of furan-2-yl-1H-pyrazoles derivatives 43 , 44 , and 45 and proposed binding scheme of a peptide backbone with a furan-2-yl-1H-pyrazole with highlighted HBD and HBA features (reprinted with permission from [ 130 ]. Copyright 2020 American Chemical Society).…”

Section: Figurementioning

confidence: 99%

Alpha-Synuclein PET Tracer Development—An Overview about Current Efforts

et al. 2021

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Neurodegenerative diseases such as Parkinson’s disease (PD) are manifested by inclusion bodies of alpha-synuclein (α-syn) also called α-synucleinopathies. Detection of these inclusions is thus far only possible by histological examination of postmortem brain tissue. The possibility of non-invasively detecting α-syn will therefore provide valuable insights into the disease progression of α-synucleinopathies. In particular, α-syn imaging can quantify changes in monomeric, oligomeric, and fibrillic α-syn over time and improve early diagnosis of various α-synucleinopathies or monitor treatment progress. Positron emission tomography (PET) is a non-invasive in vivo imaging technique that can quantify target expression and drug occupancies when a suitable tracer exists. As such, novel α-syn PET tracers are highly sought after. The development of an α-syn PET tracer faces several challenges. For example, the low abundance of α-syn within the brain necessitates the development of a high-affinity ligand. Moreover, α-syn depositions are, in contrast to amyloid proteins, predominantly localized intracellularly, limiting their accessibility. Furthermore, another challenge is the ligand selectivity over structurally similar amyloids such as amyloid-beta or tau, which are often co-localized with α-syn pathology. The lack of a defined crystal structure of α-syn has also hindered rational drug and tracer design efforts. Our objective for this review is to provide a comprehensive overview of current efforts in the development of selective α-syn PET tracers.

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“…Unlike the concurrent administration of two medications, molecular hybridization offers pharmacokinetic benefits over single ligands. [4][5][6] The molecular hybrids comprising the pyrazole-furan backbone have exhibited diverse pharmacological properties such as antibacterial, [7][8][9] anti-Alzheimer,, [10,11] anticancer, [12][13][14][15] antiinflammatory (Cox-1 and Cox-2), [16] and anti-Parkinson's disease (α-synuclein aggregation inhibitor), [17] (Figure 1). Hence, proves to be a useful scaffold in drug design and discovery.…”

Section: Introductionmentioning

confidence: 99%

Novel Furan‐Pyrazole Molecular Hybrids as Prospective Anti‐Neuroinflammatory Agents: Design, Synthesis, and In‐Vitro Screening Thereof

Mudimela,

Janardhanan

2023

Asian J Org Chem

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Neuro‐inflammatory responses lead to various neurodegenerative disorders. A small library of 1H‐pyrazole‐1‐carbothioamidoacetamido)‐furan‐3‐carboxamide molecular hybrids were designed and subjected to molecular docking against two neuroinflammatory targets, HMGB1 (2LY4) and Box A (4QR9) proteins. The in‐silico investigations indicated notable binding of 9 c and 9 d against HMGB1(2LY4), while compounds 9 c, 9 h, and 9 g demonstrated high affinity towards HMGB1 Box A (4QR9) proteins. A total of ten compounds, which showed good binding interactions with the target proteins were selected for further synthesis and evaluated for anti‐neuroinflammatory activity. The compounds, 9 a–j were synthesized by reacting pyrazole‐carbothioamides (iii & iv) with furanyl acetamides (7a–e). FTIR, NMR, and mass spectrometric data confirmed all structures. The in‐vitro cytotoxicity was evaluated on microglial cells BV‐2, N‐9, HMO6, leukemic HAP1 and human fibroblast cells. Notable suppression of anti‐inflammatory markers TNF‐α, IL‐1β, IL‐6, and Bcl‐2 was observed by 9 a–d and 9 f. All derivatives were moderate in potency compared to reference doxorubicin and could act as novel anti‐neuroinflammatory agents. The current discoveries could provide insights for developing novel lead compounds that could target neuroinflammation and related diseases.

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Novel Furan-2-yl-1H-pyrazoles Possess Inhibitory Activity against α-Synuclein Aggregation

Cited by 11 publications

References 41 publications

“Janus-Faced” α-Synuclein: Role in Parkinson’s Disease

“Janus-Faced” α-Synuclein: Role in Parkinson’s Disease

Alpha-Synuclein PET Tracer Development—An Overview about Current Efforts

Novel Furan‐Pyrazole Molecular Hybrids as Prospective Anti‐Neuroinflammatory Agents: Design, Synthesis, and In‐Vitro Screening Thereof

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