Chemical Modification of the Multitarget Neuroprotective Compound Fisetin

Chiruta, Chandramouli; Schubert, David; Dargusch, Richard; Maher, Pamela

doi:10.1021/jm2012563

Cited by 86 publications

(52 citation statements)

References 38 publications

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“…In this program, a chemical library of new flavonoid molecules was synthesized based upon the parent compound fisetin(80, 81). To ensure the development of compounds superior to that of fisetin, the baseline pharmacological properties of fisetin were characterized.…”

Section: Resultsmentioning

confidence: 99%

Drug-Like Property Profiling of Novel Neuroprotective Compounds to Treat Acute Ischemic Stroke: Guidelines to Develop Pleiotropic Molecules

Lapchak

2012

Transl. Stroke Res.

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The development of novel neuroprotective compounds to treat acute ischemic stroke (AIS) has been problematic and quite complicated, since many candidates that have been tested clinically lacked significant pleiotropic activity, were unable to effectively cross the blood brain barrier (BBB), had poor bioavailability or were toxic. Moreover, the compounds did not confer significant neuroprotection or clinical efficacy measured using standard behavioral endpoints, when studied in clinical trials in a heterogeneous population of stroke patients. To circumvent some of the drug development problems describe above, we have used a rational funnel approach to identify and develop promising candidates. Using a step-wise approach, we have identified a series of compounds based upon two different neuroprotection assays. We have then taken the candidates and determined their “drug-like” properties. This guidelines article details in vitro screening assays used to show pleiotropic activity of a series of novel compounds; including enhanced neuroprotective activity compared to the parent compound fisetin. Moreover, for preliminary drug de-risking or risk reduction during development, we used compound assessment in the CeeTox assay, ADME toxicity using the AMES test for genotoxicity and interaction with Cytochrome P450 using CYP450 inhibition analysis against a spectrum of CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) as a measure of drug interaction. Moreover, the compounds have been studied using a transfected Madin Darby canine kidney (MDCK) cell assay to assess blood brain barrier penetration (BBB). Using this series of assays, we have identified 4 novel molecules to be developed as an AIS treatment.

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Section: Resultsmentioning

confidence: 99%

Drug-Like Property Profiling of Novel Neuroprotective Compounds to Treat Acute Ischemic Stroke: Guidelines to Develop Pleiotropic Molecules

Lapchak

2012

Transl. Stroke Res.

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“…Some biological activities attributed to chromone derivatives are antitumor [4], antimicrobial [5], antioxidant [6], antiallergic [7], anti-inflammatory [8], antiplaque [9], and neuroprotection [10]. Chalcones are the precursors of chromones, and are significant pharmacophores exhibiting a variety of biological activities, such as antimalarial [11], antimicrobial [12], antifilarial [13], antioxidant [14], anti-inflammatory [15], and antiproliferation [16].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, antimicrobial evaluation, and molecular docking studies of novel chromone based 1,2,3-triazoles

et al. 2016

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In Search of novel antimicrobial agents with improved potency, we designed and synthesized a series of 3-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-2-(4-fluorophenyl)-4H-chromen-4-ones 5a-f using click chemistry. The structures of synthesized compounds were found using IR, 1 H NMR, 13 C NMR, and MS. All the synthesized compounds were assayed for their in vitro antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa and antifungal activity against Candida albicans, Candida glabrata, and Candida tropicalis by micro broth dilution method. The antimicrobial data suggested that from the series, compounds 3e, 4e, 5e, and 5f shows pronounced antimicrobial activity against the tested strain with low MIC value. Molecular docking study was used to rationalize binding interaction at the active site and the results showed good binding interaction.Electronic supplementary material The online version of this article (

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“…Low bioavailbility of flavonoids drives medicinal chemistry efforts to design their structural analogs of higher bioavailability with uncompromised biological activity in specific in vitro models [50]. Despite the known low bioavailability and stability, quercetin in 25-75 mg/kg dose twice a day for 4 days was shown to be neuroprotective in the rotenone-induced hemiparkinsonian rats [51].…”

Section: Discussionmentioning

confidence: 99%

Bioactive Flavonoids and Catechols as Hif1 and Nrf2 Protein Stabilizers - Implications for Parkinson’s Disease

Smirnova¹,

Kaidery²,

Hushpulian³

et al. 2016

Aging and disease

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Flavonoids are known to trigger the intrinsic genetic adaptive programs to hypoxic or oxidative stress via estrogen receptor engagement or upstream kinase activation. To reveal specific structural requirements for direct stabilization of the transcription factors responsible for triggering the antihypoxic and antioxidant programs, we studied flavones, isoflavones and catechols including dihydroxybenzoate, didox, levodopa, and nordihydroguaiaretic acid (NDGA), using novel luciferase-based reporters specific for the first step in HIF1 or Nrf2 protein stabilization. Distinct structural requirements for either transcription factor stabilization have been found: as expected, these requirements for activation of HIF ODD-luc reporter correlate with in silico binding to HIF prolyl hydroxylase. By contrast, stabilization of Nrf2 requires the presence of 3,4-dihydroxy- (catechol) groups. Thus, only some but not all flavonoids are direct activators of the hypoxic and antioxidant genetic programs. NDGA from the Creosote bush resembles the best flavonoids in their ability to directly stabilize HIF1 and Nrf2 and is superior with respect to LOX inhibition thus favoring this compound over others. Given much higher bioavailability and stability of NDGA than any flavonoid, NDGA has been tested in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-animal model of Parkinson’s Disease and demonstrated neuroprotective effects.

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Chemical Modification of the Multitarget Neuroprotective Compound Fisetin

Cited by 86 publications

References 38 publications

Drug-Like Property Profiling of Novel Neuroprotective Compounds to Treat Acute Ischemic Stroke: Guidelines to Develop Pleiotropic Molecules

Drug-Like Property Profiling of Novel Neuroprotective Compounds to Treat Acute Ischemic Stroke: Guidelines to Develop Pleiotropic Molecules

Synthesis, antimicrobial evaluation, and molecular docking studies of novel chromone based 1,2,3-triazoles

Bioactive Flavonoids and Catechols as Hif1 and Nrf2 Protein Stabilizers - Implications for Parkinson’s Disease

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