Combined molecular modeling and cholinesterase inhibition studies on some natural and semisynthetic O-alkylcoumarin derivatives

Orhan, İlkay Erdoğan; Deniz, Fatma Sezer Şenol; Salmas, Ramin Ekhteiari; Durdağı, Serdar; Epifano, Francesco; Genovese, Salvatore; Fiorito, Serena

doi:10.1016/j.bioorg.2018.11.044

Cited by 20 publications

(16 citation statements)

References 21 publications

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“…Coumarins constitute another important class of cholinesterase inhibitors as seen in some scientific reports [ 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 ]. Compounds 1 – 6 ( Table S3 ) isolated from Angelica archangelica , Caryopteris odorata , and Mutellina purpurea showed low activities, and although with slight structural differences, there is no significant difference in their activities [ 86 , 87 , 88 , 89 ].…”

Section: Discussionmentioning

confidence: 99%

“…Between compounds 6 and 7 , the addition of a prenyl group decreases the percentage inhibition. Compound 9 , Umbelliprenin, isolated from Heptaptera cilicica , shows good activity with IC 50 values of 5.86 ± 0.030 µM and 1.10 ± 0.190 µM on AChE and BChE inhibition [ 90 , 91 ]. By adding hydroxyl (-OH), carboxyl (-COOH), or acetyl substituent to compounds 10 , 11 , and 12 , respectively, the percentage inhibitions increase as compared to compound 7 [ 90 ].…”

Section: Discussionmentioning

confidence: 99%

“…Compound 9 , Umbelliprenin, isolated from Heptaptera cilicica , shows good activity with IC 50 values of 5.86 ± 0.030 µM and 1.10 ± 0.190 µM on AChE and BChE inhibition [ 90 , 91 ]. By adding hydroxyl (-OH), carboxyl (-COOH), or acetyl substituent to compounds 10 , 11 , and 12 , respectively, the percentage inhibitions increase as compared to compound 7 [ 90 ]. Subsequent addition of isoprenyl groups, as seen in compounds 13 and 14 , decreases the percentage cholinesterase inhibition [ 90 ].…”

Section: Discussionmentioning

confidence: 99%

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Non-Alkaloid Cholinesterase Inhibitory Compounds from Natural Sources

et al. 2021

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Alzheimer’s disease (AD) is a severe neurodegenerative disorder of different brain regions accompanied by distresses and affecting more than 25 million people in the world. This progressive brain deterioration affects the central nervous system and has negative impacts on a patient’s daily activities such as memory impairment. The most important challenge concerning AD is the development of new drugs for long-term treatment or prevention, with lesser side effects and greater efficiency as cholinesterases inhibitors and the ability to remove amyloid-beta(Aβ) deposits and other related AD neuropathologies. Natural sources provide promising alternatives to synthetic cholinesterase inhibitors and many have been reported for alkaloids while neglecting other classes with potential cholinesterase inhibition. This review summarizes information about the therapeutic potential of small natural molecules from medicinal herbs, belonging to terpenoids, coumarins, and phenolic compounds, and others, which have gained special attention due to their specific modes of action and their advantages of low toxicity and high efficiency in the treatment of AD. Some show superior drug-like features in comparison to synthetic cholinesterase inhibitors. We expect that the listed phytoconstituents in this review will serve as promising tools and chemical scaffolds for the discovery of new potent therapeutic leads for the amelioration and treatment of Alzheimer’s disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Non-Alkaloid Cholinesterase Inhibitory Compounds from Natural Sources

et al. 2021

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“…Quite a low value to this respect was recorded (11.7% at a concentration of 100 µM). This was confirmed in 2019 by Erdogan Orhan and coworkers (12.5% inhibition at the same concentration value) [33]. However, in the latter investigation, it was found that 7-isopentenyloxycoumarin exerted a potent inhibitory activity on butyrylcholinesterase (86.9%, IC 50 = 11.77 µM), about 3.5-fold higher than galanthamine, which was used as the reference drug (IC 50 = 46.6 µM).…”

Section: Neuroprotective Activitymentioning

confidence: 56%

7-Isopentenyloxycoumarin: What Is New across the Last Decade

et al. 2020

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7-Isopentenyloxycoumarin is among the most widespread naturally occurring prenyloxy umbelliferone derivatives. This secondary metabolite of mixed biosynthetic origin has been typically isolated from plants belonging to several genera of the Rutaceae and Apiaceae families, comprising widely used medicinal plants and in general plants with beneficial effects on human welfare, as well as edible fruits and vegetables. Although known for quite a long time (more than 50 years), only in the last two decades has this natural compound been revealed to exert powerful and promising pharmacological properties, such as active cancer chemopreventive, antibacterial, antiprotozoal, antifungal, anti-inflammatory, neuroprotective, and antioxidant properties, among the activities best outlined in the recent literature. The aim of this comprehensive miniature review article is to detail the novel natural sources and the effects described during the last decade for 7-isopentenyloxycoumarin and what has been reported on the mechanisms of action underlying the observed biological activities of this oxyprenylated secondary metabolite. In view of the herein described data, suggestions on how to address future research on the abovementioned natural product and structurally related derivatives in the best ways according to the authors will be also provided.

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“…List of tested small moleculesSelected molecules were assessed in terms of their therapeutic activities, pharmacokinetic effects and toxicity features by using MetaCore/MetaDrug suite from Clarivate Analytics as we have done previously(14)(15)(16)(17)(18)(19). List of possible metabolites produced by each molecule were determined.…”

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confidence: 99%

Identification of first-in-class plasmodium OTU inhibitors with potent anti-malarial activity

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Akgöl

Durdağı

et al. 2021

Biochemical Journal

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OTU proteases antagonize the cellular defense in the host cells and involve in pathogenesis. Intriguingly, P. falciparum, P. vivax, and P. yoelii have an uncharacterized and highly conserved viral OTU-like proteins. However, their structure, function or inhibitors have not been previously reported. To this end, we have performed structural modeling, small molecule screening, deconjugation assays to characterize and develop first-in-class inhibitors of P. falciparum, P. vivax, and P. yoelii OTU-like proteins. These Plasmodium OTU-like proteins have highly conserved residues in the catalytic and inhibition pockets similar to viral OTU proteins. Plasmodium OTU proteins demonstrated Ubiquitin and ISG15 deconjugation activities as evident by intracellular ubiquitinated protein content analyzed by western blot and flow cytometry. We screened a library of small molecules to determine plasmodium OTU inhibitors with potent anti-malarial activity. Enrichment and correlation studies identified structurally similar molecules. We have identified two small molecules that inhibit P. falciparum, P. vivax, and P. yoelii OTU proteins (IC50 values as low as 30nM) with potent anti-malarial activity (IC50 of 4.1-6.5 μM). We also established enzyme kinetics, druglikeness, ADME, and QSAR model. MD simulations allowed us to resolve how inhibitors interacted with plasmodium OTU proteins. These findings suggest that targeting malarial OTU-like proteases is a plausible strategy to develop new anti-malarial therapies.

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Combined molecular modeling and cholinesterase inhibition studies on some natural and semisynthetic O-alkylcoumarin derivatives

Cited by 20 publications

References 21 publications

Non-Alkaloid Cholinesterase Inhibitory Compounds from Natural Sources

Non-Alkaloid Cholinesterase Inhibitory Compounds from Natural Sources

7-Isopentenyloxycoumarin: What Is New across the Last Decade

Identification of first-in-class plasmodium OTU inhibitors with potent anti-malarial activity

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