Flavonols and 4-thioflavonols as potential acetylcholinesterase and butyrylcholinesterase inhibitors: Synthesis, structure-activity relationship and molecular docking studies

Mughal, Ehsan Ullah; Sadiq, Amina; Ashraf, Jamshaid; Zafar, Muhammad; Sumrra, Sajjad Hussain; Tariq, Rubina; Mumtaz, Amara; Javid, Asif; Khan, Bilal Ahmad; Ali, Anser; Chaudhary, Omer Javed

doi:10.1016/j.bioorg.2019.103124

Cited by 30 publications

(20 citation statements)

References 30 publications

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“…In a water-mediated phosphorylative cyclodehydrogenation, flavones and flavanones can be synthesized in the same condition with the product type controlled by dosage of reagent [173]. As the oxidative state of flavones, flavonols can be produced from flavones by the oxidation with 3,3-dimethyldioxirane (DMDO) [174] or Algar-Flynn-Oyamada reaction in the presence of base and hydrogen peroxide [175,176], which may generate by-product of aurone due to the different attacking position of epoxide [177]. Selective synthesis of Scheme 17 Total-synthetic strategies of flavonoids by cyclization of 2'-hydroxychalcones aurone could be achieved through oxidative cyclization of 2'-hydroxychalcones mediated by Hg(OAc) 2 in a good yield [178,179].…”

Section: Total-synthesis Strategies Of Flavonoid Derivativesmentioning

confidence: 99%

Structural derivatization strategies of natural phenols by semi-synthesis and total-synthesis

Ding

Jiang

Zhang

et al. 2022

Nat. Prod. Bioprospect.

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Structural derivatization of natural products has been a continuing and irreplaceable source of novel drug leads. Natural phenols are a broad category of natural products with wide pharmacological activity and have offered plenty of clinical drugs. However, the structural complexity and wide variety of natural phenols leads to the difficulty of structural derivatization. Skeleton analysis indicated most types of natural phenols can be structured by the combination and extension of three common fragments containing phenol, phenylpropanoid and benzoyl. Based on these fragments, the derivatization strategies of natural phenols were unified and comprehensively analyzed in this review. In addition to classical methods, advanced strategies with high selectivity, efficiency and practicality were emphasized. Total synthesis strategies of typical fragments such as stilbenes, chalcones and flavonoids were also covered and analyzed as the supplementary for supporting the diversity-oriented derivatization of natural phenols.

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Section: Total-synthesis Strategies Of Flavonoid Derivativesmentioning

confidence: 99%

Structural derivatization strategies of natural phenols by semi-synthesis and total-synthesis

Ding

Jiang

Zhang

et al. 2022

Nat. Prod. Bioprospect.

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“…In addition, it presented high in vitro inhibitory potency for AChE (PDB#1DX6) as well, which can indicate that these amino acids are essential to promote higher inhibition rates [19]. Mughal and co-workers synthetized a series of 4-thioflavonols that displayed very promising in vitro outputs and studied their interactions with the AChE (PDB#4BDT) active site through molecular docking [20]. Particularly, compound 1 (Figure 2) had the highest affinity and also formed identical interactions with the amino acids of the catalytic site of AChE similar to the observed for donepezil, especially with residues Trp86 and Tyr337 [20].…”

Section: Acetylcholinesterasementioning

confidence: 99%

“…Mughal and co-workers synthetized a series of 4-thioflavonols that displayed very promising in vitro outputs and studied their interactions with the AChE (PDB#4BDT) active site through molecular docking [20]. Particularly, compound 1 (Figure 2) had the highest affinity and also formed identical interactions with the amino acids of the catalytic site of AChE similar to the observed for donepezil, especially with residues Trp86 and Tyr337 [20]. An identical strategy was performed to study other natural products, namely canadine derivatives [21], cinnamic acid derivatives, indolinones and cycloartane triterpenoids [22], phenolic acid derivatives [23], and synthetic compounds, such as arylisoxazole-phenylpiperazine derivatives [24], dipropargyl substituted diphenylpyrimidines [25], quinoline chalcone derivatives [26], and N-(4-methylpyridin-2-yl)thiophene-2-carboxamide analogs [27], as displayed in (Figure 2).…”

Section: Acetylcholinesterasementioning

confidence: 99%

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches

et al. 2021

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Neurodegenerative diseases (ND), including Alzheimer’s (AD) and Parkinson’s Disease (PD), are becoming increasingly more common and are recognized as a social problem in modern societies. These disorders are characterized by a progressive neurodegeneration and are considered one of the main causes of disability and mortality worldwide. Currently, there is no existing cure for AD nor PD and the clinically used drugs aim only at symptomatic relief, and are not capable of stopping neurodegeneration. Over the last years, several drug candidates reached clinical trials phases, but they were suspended, mainly because of the unsatisfactory pharmacological benefits. Recently, the number of compounds developed using in silico approaches has been increasing at a promising rate, mainly evaluating the affinity for several macromolecular targets and applying filters to exclude compounds with potentially unfavorable pharmacokinetics. Thus, in this review, an overview of the current therapeutics in use for these two ND, the main targets in drug development, and the primary studies published in the last five years that used in silico approaches to design novel drug candidates for AD and PD treatment will be presented. In addition, future perspectives for the treatment of these ND will also be briefly discussed.

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“…The syntheses of flavonoid derivatives presented in this article have been published elsewhere (Mughal et al, 2017(Mughal et al, , 2018(Mughal et al, , 2019. The synthesis of 1,2-benzisothiazol-3(2H)-ones (BITs) was accomplished via a simple reported method (Viani et al, 2017).…”

Section: Synthesis Of Compoundmentioning

confidence: 99%

“…In present research work, we have screened several synthetic flavonoids with diverse structures (Mughal et al, 2017(Mughal et al, , 2018(Mughal et al, , 2019 and BIT-analogs (Viani et al, 2017), and explored the in silico inhibition of M pro of SAR-CoV-2 by 3-hydroxyflavones, 4thioflavonols, 3-O-flavonol glucosides, 3-benzyloxyflavones, 3oxoaurones, 3-thioaurones, and 1,2-benzisothiazol-3(2H)-ones. The virtual ADME/T properties were employed to assess druglikeness and to filter molecules with unfavorable pharmacokinetics and medicinal properties, leading to identification of thioflavonols as potent inhibitors of the M pro .…”

Section: Introductionmentioning

confidence: 99%

Synthetic flavonoids as potential antiviral agents against SARS-CoV-2 main protease

Batool

Mughal

Zia

et al. 2020

Journal of Biomolecular Structure and Dynamics

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The COVID-19 pandemic has claimed more than a million lives worldwide within a short time span. Due to the unavailability of specific antiviral drugs or vaccine, the infections are causing panic both in general public and among healthcare providers. Therefore, an urgent discovery and development of effective antiviral drug for the treatment of COVID-19 is highly desired. Targeting the main protease (M pro) of the causative agent, SARS-CoV-2 has great potential for drug discovery and drug repurposing efforts. Published crystal structures of SARS-CoV-2 M pro further facilitated in silico investigations for discovering new inhibitors against M pro. The present study aimed to screen several libraries of synthetic flavonoids and benzisothiazolinones as potential SARS-CoV-2 M pro inhibitors using in silico methods. The short-listed compounds after virtual screening were filtered through SwissADME modeling tool to remove molecules with unfavorable pharmacokinetics and medicinal properties. The drug-like molecules were further subjected to iterative docking for the identification of top binders of SARS-CoV-2 M pro. Finally, molecular dynamic (MD) simulations and binding free energy calculations were performed for the evaluation of the dynamic behavior, stability of protein-ligand complex, and binding affinity, resulting in the identification of thioflavonol, TF-9 as a potential inhibitor of M pro. The computational studies further revealed the binding of TF-9 close to catalytic dyad and interactions with conserved residues in the S1 subsite of the substrate binding site. Our in-silico study demonstrated that synthetic analogs of flavonoids, particularly thioflavonols, have a strong tendency to inhibit the main protease M pro , and thereby inhibit the reproduction of SARS-CoV-2.

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Flavonols and 4-thioflavonols as potential acetylcholinesterase and butyrylcholinesterase inhibitors: Synthesis, structure-activity relationship and molecular docking studies

Cited by 30 publications

References 30 publications

Structural derivatization strategies of natural phenols by semi-synthesis and total-synthesis

Structural derivatization strategies of natural phenols by semi-synthesis and total-synthesis

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches

Synthetic flavonoids as potential antiviral agents against SARS-CoV-2 main protease

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