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• Insecticidal activity of 47 macroalgae mostly from Mediterranean Sea was examined. • Cholinesterase and tyrosinase inhibitory effect of the alga extracts was investigated. • D. dichotoma var. intricata was the only one exhibiting BChE inhibition over 50%. • BChE inhibition by four diterpenes in DDI was investigated in silico. • The macroalgae and their metabolites might be new sources of novel insecticides. Ethanolic extracts prepared from forty-seven macroalgae species collected from the Mediterranean Sea, Aegean Sea, and Sea of Marmara were tested at 200 μg/mL against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and tyrosinase (TYR), crucial for insect vivacity. Only one alga extract, e.g. Dictyota dichotoma var. intricata (C.Agardh) Greville 1830, had a notable inhibition of BChE (72.0 ± 0.07%), whereas the rest of the macroalgae possessed no or low inhibition of AChE (2.20 ± 0.39% - 14.20 ± 2.16%), BChE (0.62 ± 0.07% - 41.20 ± 3.07%), and TYR (< 10%). Several known diterpenes (isoamijiol, 14-deoxyamijiol, amijidictyol, dictyodial, and 4α-acetoxydictyodial) found earlier in this species were proceeded to molecular docking experiments to figure out its interactions with BChE. Eleven of the 47 macroalgal extracts were selected based on sufficient availability for testing in larvicidal and adulticidal activity assays against female Aedes aegypti "Orlando1952" the mosquito vector of yellow fever and dengue. The selected extracts displayed a high adulticidal activity ranging between 80–100% activity at 5 μg/mosquito. In contrast, only the ethanol extract of Ceramium siliquosum var. elegans showed larvicidal mortality of 93.3 ± 11.5% at 0.5 μg/mL. Our findings show that the macroalgae and their metabolites could be sources of novel insecticidal agents. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • 26 O-alkylcoumarins were synthesized and tested at 100 µM for their in vitro inhibitory potential against cholinesterases. • 12 of them exerted a potent and selective inhibition against BChE. • None of them possessed any potential to inhibit AChE. • MetaCore/MetaDrug analysis and docking simulations were applied the active compounds. Abstract Coumarins of synthetic or natural origins are an important chemical class exerting diverse pharmacological activities. In the present study, 26 novel O-alkylcoumarin derivatives were synthesized and have been tested at 100 µM for their in vitro inhibitory potential against acetylcholinesterase (AChE) and butyrlcholinesterase (BChE) targets which are the key enzymes playing role in the pathogenesis of Alzheimer's disease. Among the tested coumarins, none of them could inhibit AChE, whereas 12 of them exerted a marked and selective inhibition against BChE as compared to the reference (galanthamine, IC 50 = 46.58 ± 0.91 µM). In fact, 10 of the active coumarins showed higher inhibition (IC 50 = 7.01 ± 0.28 µM – 43.31 ± 3.63 µM) than that of galanthamine. The most active ones were revealed to be 7-styryloxycoumarin (IC 50 = 7.01 ± 0.28 µM) and 7-isopentenyloxy-4-methylcoumarin (IC 50 = 8.18 ± 0.74 µM). In addition to the in vitro tests, MetaCore/MetaDrug binary QSAR models and docking simulations were applied to evaluate the active compounds by ligand-based and target-driven approaches. The predicted pharmacokinetic profiles of the compounds suggested that the compounds reveal lipophilic character and permeate blood brain barrier (BBB) and the ADME models predict higher human serum protein binding percentages (>50%) for the compounds. The calculated docking scores indicated that the coumarins showing remarkable BChE inhibition possessed favorable free binding energies in interacting with the ligand-binding domain of the target. Therefore, our results disclose that O-alkylcoumarins are promising selective inhibitors of cholinesterase enzymes, particularly BChE in our case, which definitely deserve further studies. [ABSTRACT FROM AUTHOR]

Pteryxin is a dihydropyranocoumarin derivative found in Apiaceae family. In this study, pteryxin, which was previously isolated from the fruits of Mutellina purpurea , was investigated for its inhibitory potential against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which are the key enzymes in the pathology of Alzheimer's disease (AD). The compound was tested in vitro using ELISA microplate reader at 100 μg/ml and found to cause 9.30 ± 1.86% and 91.62 ± 1.53% inhibition against AChE and BChE, respectively. According to our results, pteryxin (IC 50 = 12.96 ± 0.70 μg/ml) was found to be a more active inhibitor of BChE than galanthamine (IC 50 = 22.16 ± 0.91 μg/ml; 81.93± 2.52% of inhibition at 100 μg/ml). Further study on pteryxin using molecular docking experiments revealed different possible binding modes with both polar and hydrophobic interactions inside the binding pocket of BChE. Top docking solution points out to the formation of two hydrogen bonds with the catalytic residues S198 and H438 of BChE as well as a strong π - π stacking with W231. Therefore, pteryxin as a natural coumarin seems to be a strong BChE inhibitor, which could be considered as a lead compound to develop novel BChE inhibitors for AD treatment. [ABSTRACT FROM AUTHOR]

Abstract: In the current study, neuroprotective effect of the essential oil and aromatic waters of rose was investigated by in vitro and in silico methods. The samples were tested for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Since oxidative damage is associated with neurodegeneration, antioxidant activity of the samples was determined by DPPH radical scavenging, metal-chelation, and ferric-reducing antioxidant power (FRAP) assays. Their chemical composition was elucidated by GC–MS. Anti-cholinesterase effects of the main components (citronellol, geraniol, nerol, and phenylethyl alcohol) were also examined. The rose oil showed a noteworthy inhibition against AChE (60.86±1.99%) and BChE (51.08±1.70%) at 1000μg/mL and low activity in DPPH radical scavenging and FRAP tests. Phenylethyl alcohol exerted higher cholinesterase inhibition than other components and applied further to molecular docking simulations. Docking and binding energies supporting experimental results show that the compound is more selective towards BChE than AChE. [Copyright &y& Elsevier]

The EtOH extracts of the leaves of two new cultivars (Uysal-SFU and Turgut-SFT) of Salvia fruticosa Mill. was tested against acetylcholinesterase (IC50: 30.62 ± 3.27 and 32.97 ± 2.33 µg/mL for SFU and SFT, respectively) and butyrylcholinesterase (IC50: 69.91 ± 1.08 µg/mL and 86.55 ± 1.26 µg/mL), respectively, relevant to Alzheimer's disease. The essential oils showed a stumpy inhibition against AChE and no inhibition against BChE. DPPH radical scavenging activity of the extracts (86.70 ± 0.17% and 86.14 ± 1.13% for SFU and SFT, respectively) was stronger than that of quercetin (85.51 ± 0.17%): Their (1.24 ± 0.05 and 1.04 ± 0.16 for SFU and SFT, respectively) ferric-reducing antioxidant power were close to that of the reference (e.g. quercetin, 1.42 ± 0.14). Molecular docking simulations were performed on their major monoterpenes. Our findings revealed that the leaf EtOH extracts of two cultivars are promising inhibitors of both AChE and BChE. [ABSTRACT FROM AUTHOR]

Cholinesterase (ChE) inhibition is an important treatment strategy for Alzheimer's disease (AD) as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are involved in the pathology of AD. In the current work, ChE inhibitory potential of twenty-four natural products from different chemical classes (i.e., diosgenin, hecogenin, rockogenin, smilagenin, tigogenin, astrasieversianins II and X, astragalosides I, IV, and VI, cyclocanthosides E and G, macrophyllosaponins A-D, kokusaginin, lamiide, forsythoside B, verbascoside, alyssonoside, ipolamide, methyl rosmarinate, and luteolin-7-O-glucuronide) was examined using ELISA microtiter assay. Among them, only smilagenin and kokusaginine displayed inhibitory action against AChE (IC50 = 43.29 ± 1.38 and 70.24 ± 2.87 µg/mL, respectively). BChE was inhibited by only methyl rosmarinate and kokusaginine (IC50 = 41.46 ± 2.83 and 61.40 ± 3.67 µg/mL, respectively). IC50 values for galantamine as the reference drug were 1.33 ± 0.11 µg/mL for AChE and 52.31 ± 3.04 µg/mL for BChE. Molecular docking experiments showed that the orientation of smilagenin and kokusaginine was mainly driven by the interactions with the peripheral anionic site (PAS) comprising residues of hAChE, while kokusaginine and methyl rosmarinate were able to access deeper into the active gorge in hBChE. Our data indicate that similagenin, kokusaginine, and methyl rosmarinate could be hit compounds for designing novel anti-Alzheimer agents. [ABSTRACT FROM AUTHOR]

• Four compounds were isolated from the plant with activity-guided fractionation. • All the ligands can be regarded as inhibitor candidates with fair binding energies. • Methyl gallate and astragalin were predicted as non-mutagenic. • Cotinus coggygria would be a suitable raw herbal material for cosmetic products. Cotinus coggygria Scop. (Anacardiaceae, syn: Rhus cotinus L.) is known as "boyacı sumağı, sarı boya, duman ağacı" in Turkish and "smoke tree" in English. It is commonly grown in Southern Europe and Anatolia. The leaves have been used due to its antiseptic, hemostatic, antipyretic, and wound healing effects as a 5% infusion in traditional medicine. It has also been reported to be used against skin disorders in Russia. Based on this information, the ethanol extracts prepared from the pedicels and leaves of C. coggygria were investigated for their elastase, collagenase, and tyrosinase inhibitory effects, which are enzymes related to anti-aging, using ELISA microtiter assays. Based on our results, the ethanol extracts prepared from the leaves and pedicels of C. coggygria had low elastase (28.16% ± 2.91 and 25.76% ± 1.71, respectively), moderate collagenase (47.78% ± 4.90 and 46.51% ± 3.15, respectively), and tyrosinase (57.94% ± 0.67 and 46.20% ± 0.92, respectively) inhibition at final concentration (666 µg/mL). The ethanol extract prepared from the pedicels of C. coggygria was subjected to bioactivity-guided fractionation, which led to isolation of methyl gallate, astragalin, isoquercetin, and hyperoside from the active fractions. In addition to the enzyme assays, in order to understand the inhibition mechanisms of the compounds inside the ligand-binding domains, the interactions were simulated and the key amino acids contributing to the hydrogen bonds and non-polar interactions with the ligands were reported. [ABSTRACT FROM AUTHOR]

The absolute configurations of the known but unusual spiro-flavostilbenoids found in the bark of Yucca schidigera Roezl ex Ortgies, were determined by applying time-dependent density functional theory simulation of electronic circular dichroism spectra. The absolute configurations obtained were as follows: (2 S ,3 R) for yuccaol A, yuccaol D and yuccalide A; (2 S ,3 S) for yuccaol B, yuccaol C and yuccaol E; (2 S ,3 S ,2′ S ,3′ S) for gloriosaol A; (2 S ,3 R ,2′ S ,3′ R) for gloriosaol C; (2 S ,3 S ,2′ S ,3′ R) for gloriosaol D; (2 S ,3 R ,2′ S ,3′ S) for gloriosaol E. These findings indicate that the compounds are all biosynthetic derivatives either of (2 R)-naringenin and trans -resveratrol or of trans -3,3 ′ ,5,5 ′ -tetrahydroxy-4′-methoxystilbene. In contrast, gloriosaols are direct derivatives of yuccaols (note that substituting by stilbenoid changes the absolute configuration of C-2 naringenin carbon to 2 S). A putative mechanism for their biosynthesis is proposed taking into account key aspects of regio- and stereoselectivity. Yuccaol B and gloriosaol A showed in vitro moderate inhibitory effects against acetyl-/butyrylcholinesterases (AChE/BChE) with IC 50 values of 43/81 and 45/65 μM respectively. The selectivity index values calculated from the IC 50 values of BChE and AChE were 1.9 and 1.4. Molecular docking simulations showed their interaction with the peripheral anionic site of human AChE and the catalytic site of the human BChE. [Display omitted] • The absolute configurations of spiro-flavostilbenoids from Y. schidigera were elucidated. • Their biosynthetic origin from unusual (2 R)-naringenin was proposed. • Yuccaol B and gloriosaol A showed moderate in vitro AChE/BChE inhibitory activities. • Molecular docking of yuccaol B and gloriosaol A to hAChE/hBChE was performed. [ABSTRACT FROM AUTHOR]

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a key enzyme involved in cholesterol biosynthesis and one of the most important targets for the treatment of hypercholesterolemia. A limited number of studies on the HMG-CoA reductase inhibitory potential of natural products are available. Thus, in the current study, we aimed to test the HMG-CoA reductase inhibitory capacity of extracts from the roots and aerial parts of Salvia multicaulis Vahl., through activity-guided isolation. Our findings revealed that the root extract prepared with dichloromethane–acetone (1:1) showed the highest inhibition (71.97 ± 0.37%) at 100 µg/mL. The extract was then initially fractionated by column chromatography and the obtained fractions were monitored by thin layer chromatography. Fractions which were similar to each other were combined and a total of 15 fractions were obtained. Further conventional chromatographic studies were carried out on the active fractions. Based on these fractions, 10 known compounds, comprising 9 terpenes and 1 steroid derivative in total, were isolated and their structures were verified by a combination of IT-TOF-MS, and 1D and 2D NMR techniques. According to the enzyme inhibition data of the identified compounds, 7-acetoxyhorminone exerted the highest inhibition (84.15 ± 0.10%, IC50 = 63.6 ± 1.21 µg/mL). The molecular docking experiments on 7-acetoxyhorminone and horminone indicated that both compounds strongly bind to the active site of the enzyme. [ABSTRACT FROM AUTHOR]

• Annual phytochemical profile of 5 Origanum species was established. • Cholinesterase inhibition and antioxidant effects of 60 extracts were tested. • The links between the phytochemical fingerprints and activities were revealed. • Aromadendrin showed good correlation with AChE, BChE, and FRAP activities. • Caffeoylarbutin had the lowest binding energy against both enzymes. The ethanol extracts of five Origanum species : O. majorana L., O. onites L., O. syriacum L., O. vulgare subsp. hirtum (Link) Ietsw., and O. vulgare subsp. viride (Boiss.) Hayek, collected annually (each month), were investigated for their cholinesterase inhibition and antioxidant effects. The phytochemical composition of a total of 60 extracts was assessed by HPLC-DAD-ESI/HRMS, revealing the presence of a total of 73 compounds. Possible correlation between the bioactivity and metabolite profiles during 12 months was monitored. Acetylcholinesterase (AChE) inhibitory activity was found to be the highest between April and November (50.29–75.95%, 200 μg/mL), while the highest inhibition towards butyrylcholinesterase (BChE) was observed for the extracts between April and October (71.68–88.97%). Aromadendrin showed good correlation with anti-AChE, anti-BChE and reducing power activities. Furthermore, molecular docking data with aromadendrin, caffeoylarbutin and eriodictyol indicated that caffeoylarbutin had the lowest binding energy against both enzymes. [ABSTRACT FROM AUTHOR]

• Novel [3-substitue-6-oxopyridazin-1(6 H)-yl]methyl carbamate derivatives were synthesized. • Compounds 7c , 14c , and 16c showed significant inhibitory activity against eqBuChE. • Compound 7c displayed a competitive inhibition while 14c and 16c showed a mixed-type inhibition. • Molecular docking study was performed for the selected compounds. In the current study, forty-four new [3-(2/3/4-methoxyphenyl)-6-oxopyridazin-1(6 H)-yl]methyl carbamate derivatives were synthesized and evaluated for their ability to inhibit electric eel acetylcholinesterase (Ee AChE) and equine butyrylcholinesterase (eqBuChE) enzymes. According to the inhibitory activity results, [3-(2-methoxyphenyl)-6-oxopyridazin-1(6 H)-yl]methyl heptylcarbamate (16c , eqBuChE, IC 50 = 12.8 μM; Ee AChE, no inhibition at 100 μM) was the most potent eqBuChE inhibitor among the synthesized compounds and was found to be a moderate inhibitor compared to donepezil (eqBuChE, IC 50 = 3.25 μM; Ee AChE, IC 50 = 0.11 μM). Kinetic and molecular docking studies indicated that compounds 16c and 14c (hexylcarbamate derivative, eqBuChE, IC 50 = 35 μM; Ee AChE, no inhibition at 100 μM) were mixed-type inhibitors which accommodated within the catalytic active site (CAS) and peripheral anionic site (PAS) of hBuChE through stable hydrogen bonding and π-π stacking. Furthermore, it was determined that [3-(2-methoxyphenyl)-6-oxopyridazin-1(6 H)-yl]methyl (4-methylphenyl)carbamate 7c (eqBuChE, IC 50 = 34.5 μM; Ee AChE, 38.9% inhibition at 100 μM) was the most active derivative against Ee AChE and a competitive inhibitor binding to the CAS of hBuChE. As a result, 6-(2-methoxyphenyl)pyridazin-3(2 H)-one scaffold is important for the inhibitory activity and compounds 7c , 14c and 16c might be considered as promising lead candidates for the design and development of selective BuChE inhibitors for Alzheimer's disease treatment. [ABSTRACT FROM AUTHOR]