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Series of synthetic coumarin derivatives (1-16) were tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes linked to the pathology of Alzheimer's disease (AD). Compound 16 was the most active AChE inhibitor with IC 50 32.23±2.91 μM, while the reference (galantamine) had IC 50 =1.85±0.12 μM. Compounds 9 (IC 50 75.14±1.82 μM), 13 (IC 50 =16.14±0.43 μM), were determined to be stronger BChE inhibitors than the reference galantamine (IC 50 =93.53±2.23 μM). The IC 50 value of compound 16 for BChE inhibition (IC 50 =126.56±11.96 μM) was slightly higher than galantamine. The atomic interactions between the ligands and the key amino acids inside the binding cavities were simulated to determine their ligand-binding positions and free energies. The three inhibitory coumarins (9, 13, 16) were next tested for their effects on the genes associated with AD using human neuroblastoma (SH-SY5Y) cell lines. Our data indicate that they could be considered for further evaluation as new anti-Alzheimer drug candidates., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Melanogenesis is simply defined as the production of melanin in melanosomes by melanocytes through a complex process. Melanin, a pigment derived from L-tyrosine, comes into two forms, namely eumelanin (brownish to black) and pheomelanin (red to yellow). Melanin synthesis starts via the hydroxylation of L-tyrosine to L-3,4-Dihydroxyphenylalanine (DOPA) catalyzed by the enzyme known as Tyrosinase (TYR), which triggers further conversion reaction to DOPAquinone and then to DOPAchrome. Additionally, this process is also related to two more proteins, i.e., oxygenase TYR-related Protein 1 (TYRP1), and Dopachrome Tautomerase TYRP2 (or DCT). However, TYR located in the melanosomal membrane still stands as the key enzyme to initiate the whole process of melanogenesis. Due to some deficits, melanogenesis may emerge as hypo- or hyperpigmentation in the skin. High production of melanin in melanocytes leads to hyperpigmentation- related skin disorders, including freckles, melasma, melanoma, etc., that may cause displeasure in personal appearance and reduce quality of life. Consequently, several melanogenesis inhibitors of synthetic and natural origins have been developed up to date, though most of them have been reported with serious side effects. For this reason, extensive research is still going on to find novel and more effective melanogenesis inhibitors with less side effects. In this sense, particularly flavonoids, catechins, and stilbenes from plants have been a hope to discover new inhibitors which gain significant attention from scientists. In this review, promising natural products effective in melanogenesis inhibition will be scrutinized., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Xanthine oxidase (EC 1.17.3.2) (XO) is one of the main enzymatic sources that create reactive oxygen species (ROS) in the living system. It is a dehydrogenase enzyme that performs electron transfer to nicotinamide adenine dinucleotide (NAD+), while oxidizing hypoxanthin, which is an intermediate compound in purine catabolism, first to xanthine and then to uric acid. XO turns into an oxidant enzyme that oxidizes thiol groups under certain stress conditions in the tissue. The last metabolic step, in which hypoxanthin turns into uric acid, is catalyzed by XO. Uric acid, considered a waste product, can cause kidney stones and gouty-type arthritis as it is crystallized, when present in high concentrations. Thus, XO inhibitors are one of the drug classes used against gout, a purine metabolism disease that causes urate crystal storage in the joint and its surroundings caused by hyperuricemia. Urate-lowering therapy includes XO inhibitors that reduce uric acid production as well as uricosuric drugs that increase urea excretion. Current drugs that obstruct uric acid synthesis through XO inhibition are allopurinol, febuxostat, and uricase. However, since the side effects, safety and tolerability problems of some current gout medications still exist, intensive research is ongoing to look for new, effective, and safer XO inhibitors of natural or synthetic origins for the treatment of the disease. In the present review, we aimed to assess in detail XO inhibitory capacities of pure natural compounds along with the extracts from plants and other natural sources via screening Pubmed, Web of Science (WoS), Scopus, and Google Academic. The data pointed out to the fact that natural products, particularly phenolics such as flavonoids (quercetin, apigenin, and scutellarein), tannins (agrimoniin and ellagitannin), chalcones (melanoxethin), triterpenes (ginsenoside Rd and ursolic acid), stilbenes (resveratrol and piceatannol), alkaloids (berberin and palmatin) have a great potential for new XO inhibitors capable of use against gout disease. In addition, not only plants but other biological sources such as microfungi, macrofungi, lichens, insects (silk worms, ants, etc) seem to be the promising sources of novel XO inhibitors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: One of the best methods to treat Alzheimer disease (AD) is through the effective use of cholinesterase inhibitors as vital drugs due to the identification of acetylcholine deficit in the AD patients., Objective: The present study aims the investigation of spiro heterocyclic compounds as potential AD agents supported by their metal chelation capacity, POM analyses and DFT studies, respectively., Methods: The cholinesterase inhibition and metal chelation ability were performed on ELISA microtiter assay. Whereas, the B3LYP method with 6-31+G(d,p) basis set was implemented to study HOMOLUMO energy calculations. The pharmacokinetic properties of the synthesized molecules were studied through Petra, Osiris and Molinspiration (POM)., Results: The six spiro (1-6) skeletons were tested for their inhibitory potential and metal-chelation capacity. Our findings revealed that the tested spiro skeletons exerted none or lower than 50% inhibition against both cholinesterases, while compound 4 proved to be the most active molecule with 57.21±0.89% of inhibition toward BChE. The spiro molecule 3 exhibited the highest metal-chelation capacity (9.12±5.26%). Molecular docking model for the most active molecule exhibited promising bindings with AChE and BChE's active site pertained to hydrophobic hydrogen bonds and positive ionizable interactions. The POM analyses gave the information about the flexibility at the site of coordination of spiro compounds (1-6)., Conclusion: The screening of spirocompounds (1-6) against cholinesterases revealed that some of them show considerable potential to inhibit AChE and BChE. Herein, we propose that the spiro molecules after further derivatization could serve interesting AD inhibitor drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Twelve undescribed triterpenoid pentacyclic glycosides, medicagenic acid (3-O-β-D-glucuronopyranosyl-28-O-{[β-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)]-[α-L-rhamnopyranosyl-(1 → 3)]-4-O-acetyl-β-D-fucopyranosyl-(1→)}-2β,3β-dihydroxyolean-12-ene-23,28-dioic acid, 3-O-β-D-glucuronopyranosyl-28-O-{[α-L-rhamnopyranosyl-(1 → 2)]-[β-D-apiofuranosyl-(1 → 3)]-4-O-acetyl-β-D-fucopyranosyl-(1→)}-2β,3β-dihydroxyolean-12-ene-23,28-dioic acid, 3-O-β-D-glucuronopyranosyl-28-O-{[α-L-rhamnopyranosyl-(1 → 2)]-3,4-O-diacetyl-β-D-fucopyranosyl-(1→)}-2β,3β-dihydroxyolean-12-ene-23,28-dioic acid, 28-O-{[6-O-acetyl-β-D-glucopyranosyl-(1 → 2)]-[2-O-acetyl-α-L-rhamnopyranosyl-(1 → 4)-β-D-glucopyranosyl-(1 → 6)]-β-D-glucopyranosyl-(1→)}-2β,3β-dihydroxyolean-12-ene-23,28-dioic acid, 28-O-{[6-O-acetyl-β-D-glucopyranosyl-(1 → 2)]-[3-O-acetyl-α-L-rhamnopyranosyl-(1 → 4)-β-D-glucopyranosyl-(1 → 6)]-β-D-glucopyranosyl-(1→)}-2β,3β-dihydroxyolean-12-ene-23,28-dioic acid, 28-O-{[6-O-acetyl-β-D-glucopyranosyl-(1 → 2)]-[4-O-acetyl-α-L-rhamnopyranosyl-(1 → 4)-β-D-glucopyranosyl-(1 → 6)]-β-D-glucopyranosyl-(1→)}-2β,3β-dihydroxyolean-12-ene-23,28-dioic acid, 28-O-{[6-O-acetyl-β-D-glucopyranosyl-(1 → 2)]-[β-D-glucopyranosyl-(1 → 6)]-β-D-glucopyranosyl-(1→)}-2β,3β-dihydroxyolean-12-ene-23,28-dioic acid, 28-O-{[β-D-glucopyranosyl-(1 → 2)]-[β-D-glucopyranosyl-(1 → 6)]-β-D-glucopyranosyl-(1→)}-2β,3β-dihydroxyolean-12-ene-23,28-dioic acid), zanhic acid (3-O-β-D-glucuronopyranosyl-28-O-{[β-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)]-[α-L-rhamnopyranosyl-(1 → 3)]-4-O-acetyl-β-D-fucopyranosyl-(1→)}2β,3β,16α-trihydroxyolean-12-ene-23,28-dioic acid, 3-O-β-D-glucuronopyranosyl-28-O-{[β-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)]-β-D-fucopyranosyl-(1→)}-2β,3β,16α-trihydroxyolean-12-ene-23,28-dioic acid), 29-hydroxy-medicagenic acid (3-O-β-D-glucuronopyranosyl-28-O-{[β-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)]-[α-L-rhamnopyranosyl-(1 → 3)]-4-O-acetyl-β-D-fucopyranosyl-(1→)}-2β,3β,29β-trihydroxyolean-12-ene-23,28-dioic acid) and herniaric acid (28-O-{[6-O-acetyl-β-D-glucopyranosyl-(1 → 2)]-[α-L-rhamnopyranosyl-(1 → 4)-β-D-glucopyranosyl-(1 → 6)]-β-D-glucopyranosyl-(1→)}-2β,3β-dihydroxyolean-18-ene-23,28-dioic acid) were isolated from the whole plant extract of Herniaria glabra L. (Caryophyllaceae), wild growing in the Ukraine. In addition, five known triterpenoid saponins; i.e. herniariasaponins 1, 4, 5, 6, and 7 were also isolated. Their structures were elucidated by HRESIMS, 1D and 2D NMR spectroscopy, as well as by comparison with the literature data. Twelve herniariasaponins, the purified crude extract, and the saponin fraction were evaluated in vitro for their xanthine oxidase, collagenase, elastase, and tyrosinase inhibitory activity. Moreover, herniariasaponins 4, 5, and 7 were screened for their cholinesterase inhibitory potential. As a result, no or low inhibition towards the mentioned enzymes was observed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The ethyl acetate fraction of the methanolic extract of Yucca schidigera Roezl ex Ortgies bark exhibited moderate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity (IC 50 47.44 and 47.40 µg mL -1 , respectively). Gel filtration on Sephadex LH-20 and further RP-C 18 preparative HPLC of EtOAc fraction afforded 15 known and 3 new compounds, stereoisomers of larixinol. The structures of the isolated spirobiflavonoids 15 , 26 , and 29 were elucidated using 1D and 2D NMR and MS spectroscopic techniques. The relative configuration of isolated compounds was assigned based on coupling constants and ROESY (rotating-frame Overhauser spectroscopy) correlations along with applying the DP4+ probability method in case of ambiguous chiral centers. Determination of absolute configuration was performed by comparing calculated electronic circular dichroism (ECD) spectra with experimental ones. Compounds 26 and 29 , obtained in sufficient amounts, were evaluated for activities against AChE and BChE, and they showed a weak inhibition only towards AChE (IC 50 294.18 µM for 26 , and 655.18 µM for 29 ). Furthermore, molecular docking simulations were performed to investigate the possible binding modes of 26 and 29 with AChE., Competing Interests: The authors declare no conflicts of interest.

Background: Medicinal plants are a proven source of drug-like small molecules with activity towards targets relevant for diseases of the central nervous system (CNS). Plant species of the Apiaceae family have to date yielded a number of neuroactive metabolites, such as coumarin derivatives with acetylcholinesterase inhibitory activity or anti-seizure activity., Purpose: To accelerate the discovery of neuroactive phytochemicals with potential as CNS drug leads, we sought to rapidly isolate furanocoumarins, primary constituents of the dichloromethane (DCM) extract of the fruits of Peucedanum alsaticum L. (Apiaceae), using high-performance counter-current chromatography (HPCCC) and to evaluate their neuroactivity using both in vitro and in vivo microscale bioassays based on cholinesterase ELISAs and zebrafish epilepsy models., Research Methods and Procedure: In this study the DCM extract was subjected to HPCCC for the efficient separation (60 min) and isolation of furanocoumarins. Isolated compounds were identified with TOF-ESI-MS and NMR techniques and examined as inhibitors of AChE and BChE using ELISA microtiter assays. Anti-seizure properties of the extract and of the isolated compounds were evaluated using a zebrafish epilepsy model based on the GABA A antagonist pentylenetetrazol (PTZ), which induces increased locomotor activity and seizure-like behavior., Results: The solvent system, composed of n-heptane, ethyl acetate, methanol and water (3:1:3:1, v/v/v/v), enabled the isolation of 2.63 mg lucidafuranocoumarin A (purity 98%) and 8.82 mg bergamottin (purity 96%) from 1.6 g crude DCM extract. The crude extract, at a concentration of 100 µg/ml, exhibited a weak inhibitory activity against acetylcholinesterase (AChE) (9.63 ± 1.59%) and a moderate inhibitory activity against butyrylcholinestrase (BChE) (49.41 ± 2.19%). Lucidafuranocoumarin A (100 µg/ml) was inactive against AChE but showed moderate inhibition towards BChE (40.66 ± 1.25%). The DCM extract of P. alsaticum fruits (0.62-1.75 µg/ml) and bergamottin (2-10 µm) exhibited weak anti-seizure activity, while lucidafuranocoumarin A (10-16 µm) was found to significantly inhibit PTZ-induced seizures. The percentage of seizure inhibition for the isolated compounds, at their most bioactive concentration, was 26% for bergamottin and 69% for lucidafuranocoumarin A., Conclusion: Our findings underscore the utility of HPCCC for the rapid isolation of rare coumarin derivatives, and the potential of microscale in vivo bioassays based on zebrafish disease models for the rapid assessment of neuroactivity of these drug-like natural products., (Copyright © 2018. Published by Elsevier GmbH.)