Chalcones and Five-Membered Heterocyclic Isosteres Bind to Alpha Synuclein Fibrils in Vitro

Hsieh, Chia-Ju; Xu, Kuiying; Lee, Iljung; Graham, Thomas J. A.; Dhavale, Dhruva; Kotzbauer, Paul T.; Mach, Robert H.

doi:10.1021/acsomega.7b01897

Cited by 33 publications

(36 citation statements)

References 24 publications

(80 reference statements)

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“…43,61 Compounds 6a, 6c, 6d, and 6f, with LC 50 values of 8.03, 6.66, 9.09, and 10.80 mg L −1 , respectively, and LC 90 values of 11.9, 9.97, 13.58, and 18.21 mg L −1 , respectively, fall in this category. Analysis of structure-activity relationships has guided the synthesis of substituted chalcone derivatives to obtain molecules with other biological properties, such as antimicrobials, 62 compounds for immunodiagnosis of Parkinson's disease, 63 and antioxidants. 64 The presence of a free hydroxyl group in the aromatic ring of chalcones increases the A-ring lipophilicity 64 and is an important structural feature for the antimicrobial activity against methicillin-resistant Staphylococcus aureus.…”

Section: Discussionmentioning

confidence: 99%

Larvicidal activity of substituted chalcones against Aedes aegypti (Diptera: Culicidae) and non‐target organisms

Targanski

Sousa

Pádua

et al. 2020

Pest Management Science

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BACKGROUND: The expansion of Aedes aegypti (Diptera: Culicidae) population has increased the number of cases of arboviruses, in part due to the inefficiency and toxicity of the chemical control methods available to control this vector. We synthesized 19 chalcone derivatives and examined their activity against Ae. aegypti larvae in order to select larvicidal compounds that are non-toxic to other organisms. RESULTS: Seven chalcone derivatives (3a, 3e, 3f, 6a, 6c, 6d, and 6f) had lethal concentrations of substituted chalcones capable of killing 50% (LC 50) values lower than 100 mg mL −1 at 24 h post-treatment, which is the dose that the World Health Organization recommends for the selection of promising larvicides. The type of substituent added to (E)-1,3-diphenylprop-2-en-1-one (3a) markedly affected the larvicidal activity. Addition of chlorine, bromine and methoxy groups to the aromatic rings reduced the larvicidal activity, while replacement of the Bring (phenyl) by a furan ring significantly increased the larvicidal activity. The furan-chalcone (E)-3-(4-bromophenyl)-1-(furan-2-yl)prop-2-en-1-one (6c) killed Ae. aegypti larvae (LC 50 = 6.66 mg mL −1 ; LC 90 = 9.97 mg mL −1) more effectively than the non-substituted chalcone (3a) (LC 50 = 14.43 mg mL −1 ; LC 90 = 20.96 mg mL −1), and was not toxic to the insect Galleria mellonella, to the protozoan Tetrahymena pyriformis, and to the algae Chorella vulgaris. CONCLUSIONS: The substitution pattern of chalcones influenced their larvicidal activity. In the set of compounds tested, (E)-3-(4-bromophenyl)-1-(furan-2-yl)prop-2-en-1-one (6c) was the most effective larvicide against Ae. aegypti, with no clear signs of toxicity to other animal models. Its mechanism of action and effectiveness under field conditions remain to be determined.

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Section: Discussionmentioning

confidence: 99%

Larvicidal activity of substituted chalcones against Aedes aegypti (Diptera: Culicidae) and non‐target organisms

Targanski

Sousa

Pádua

et al. 2020

Pest Management Science

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“…Notably, the identified framework is present in some of the already reported Tau-based drug candidates currently undergoing clinical trials (e.g., xalsalate and curcumin) ( Figure S3 ) [ 69 , 70 ], as well as in the natural compounds xanthohumol and licochalcone A that act as Tau aggregation inhibitors [ 70 , 71 ] ( Figure S3 ). The latter chemotype is currently under evaluation on several targets related to neurodegenerative diseases, including monoaminoxidase B, αβ-amyloid and α-sinuclein [ 72 , 73 , 74 ]. These findings further strengthen the potential use of molecular fragment combinations based on this framework as starting points for the development of novel Tau aggregation inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Chemoinformatics Analyses of Tau Ligands Reveal Key Molecular Requirements for the Identification of Potential Drug Candidates against Tauopathies

2021

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Tau is a highly soluble protein mainly localized at a cytoplasmic level in the neuronal cells, which plays a crucial role in the regulation of microtubule dynamic stability. Recent studies have demonstrated that several factors, such as hyperphosphorylation or alterations of Tau metabolism, may contribute to the pathological accumulation of protein aggregates, which can result in neuronal death and the onset of a number of neurological disorders called Tauopathies. At present, there are no available therapeutic remedies able to reduce Tau aggregation, nor are there any structural clues or guidelines for the rational identification of compounds preventing the accumulation of protein aggregates. To help identify the structural properties required for anti-Tau aggregation activity, we performed extensive chemoinformatics analyses on a dataset of Tau ligands reported in ChEMBL. The performed analyses allowed us to identify a set of molecular properties that are in common between known active ligands. Moreover, extensive analyses of the fragment composition of reported ligands led to the identification of chemical moieties and fragment combinations prevalent in the more active compounds. Interestingly, many of these fragments were arranged in recurring frameworks, some of which were clearly present in compounds currently under clinical investigation. This work represents the first in-depth chemoinformatics study of the molecular properties, constituting fragments and similarity profiles, of known Tau aggregation inhibitors. The datasets of compounds employed for the analyses, the identified molecular fragments and their combinations are made publicly available as supplementary material.

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“…The results of a competition in vitro binding studies with Th-T led to the identification of a compound *11a,b (37 a,b) ( Figure 7), isoxazole derivatives with a modest affinity in comparison to [ 18 F]46a (36) for α-syn at K i 18.5 nM over Aβ and tau fibrils with 5-fold and over 54-fold less affinity respectively (Table 4). Although the compounds described in their report have modest affinity to serve as a PET radiotracer for in vivo imaging studies, they could, however could be used for further SAR studies [214].…”

Section: Chalcone Derivatives and Structural Cogenersmentioning

confidence: 99%

PET Radiopharmaceuticals for Alzheimer’s Disease and Parkinson’s Disease Diagnosis, the Current and Future Landscape

2020

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Ironically, population aging which is considered a public health success has been accompanied by a myriad of new health challenges, which include neurodegenerative disorders (NDDs), the incidence of which increases proportionally to age. Among them, Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common, with the misfolding and the aggregation of proteins being common and causal in the pathogenesis of both diseases. AD is characterized by the presence of hyperphosphorylated τ protein (tau), which is the main component of neurofibrillary tangles (NFTs), and senile plaques the main component of which is β-amyloid peptide aggregates (Aβ). The neuropathological hallmark of PD is α-synuclein aggregates (α-syn), which are present as insoluble fibrils, the primary structural component of Lewy body (LB) and neurites (LN). An increasing number of non-invasive PET examinations have been used for AD, to monitor the pathological progress (hallmarks) of disease. Notwithstanding, still the need for the development of novel detection tools for other proteinopathies still remains. This review, although not exhaustively, looks at the timeline of the development of existing tracers used in the imaging of Aβ and important moments that led to the development of these tracers.

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Chalcones and Five-Membered Heterocyclic Isosteres Bind to Alpha Synuclein Fibrils in Vitro

Cited by 33 publications

References 24 publications

Larvicidal activity of substituted chalcones against Aedes aegypti (Diptera: Culicidae) and non‐target organisms

Larvicidal activity of substituted chalcones against Aedes aegypti (Diptera: Culicidae) and non‐target organisms

Chemoinformatics Analyses of Tau Ligands Reveal Key Molecular Requirements for the Identification of Potential Drug Candidates against Tauopathies

PET Radiopharmaceuticals for Alzheimer’s Disease and Parkinson’s Disease Diagnosis, the Current and Future Landscape

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