New Cholinesterase Inhibiting Bisbenzylisoquinoline Alkaloids from Cocculus pendulus (original) (raw)

New cholinesterase inhibiting bisbenzylisoquinoline alkaloids from Abuta grandifolia

Fitoterapia, 2012

The phytochemical study of the stem bark and wood of Abuta grandifolia (Mart.) Sandwith led to the identification of four bisbenzylisoquinoline alkaloids (BBIQs), namely (R,S)-2 N-norberbamunine (1), (R,R)-isochondodendrine (2), (S-S)-O4″-methyl, Nb-nor-O6'-demethyl-(+)-curine (3), and (S-S)-O4″-methyl, O6'-demethyl-(+)-curine (4), together with the aporphine alkaloid R-nornuciferine (5), all obtained by countercurrent distribution separation (CCD) and identified on the basis of their spectroscopic data. Alkaloids 3 and 4 were new. All the isolated compounds were tested for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. 1 was the most active against AChE, whereas 3 and 4 were the most potent against BChE. Interestingly, all tested alkaloids are more potent against BChE than against AChE. This selectivity of cholinesterase (ChE) inhibition could be important in order to speculate on their potential therapeutic relevance.

New Cholinesterase-Inhibiting Triterpenoid Alkaloids fromBuxus hyrcana

Chemistry & Biodiversity, 2006

The current phytochemical investigation on Buxus hyrcana Pojark. has resulted in the isolation of the triterpenoid alkaloids 1 -10. The structures of five new alkaloids, hyrcanone (1), hyrcanol (2), hyrcatrienine (3), N b -dimethylcycloxobuxoviricine (4), and hyrcamine (5), were elucidated by means of modern spectroscopic techniques, while the known alkaloids, buxidin , buxandrine , buxabenzacinine (8), buxippine-K (9) and E-buxenone (10), were identified by comparing their spectral data with those reported earlier. Compounds 1 and 3 -9 were found to be acetyl-and butyrylcholinesterase inhibitors. The IC 50 values were estimated to be in the range of 83.0 -468.0 mm against AChE and 1.12 -350.0 mm against BChE. The structure -activity relationship studies suggested that the presence of dimethylamino moieties at C(3) and C(20) is the most important factor influencing the activity of these compounds against the cholinesterase enzymes. All compounds were also evaluated for cytotoxicity on a fibroblast cell line with incubation of 24 h. No cytotoxic effects were exerted by any compound.

Cholinesterase inhibitory alkaloids from the rhizomes of Coptis chinensis

Bioorganic chemistry, 2018

Coptis chinensis has been used as a medicinal herb in traditional oriental medicine. In this study, chemical investigation of a water extract of C. chinensis identified two new quaternary protoberberines (1, 2), a new tricyclic amide (3), together with five known compounds. Their chemical structures were elucidated by analysis with 1D and 2D NMR and high-resolution mass spectroscopy, as well as by comparison with those reported in the literature. Compounds 4, 5, and 7 showed potent inhibition against acetylcholinesterase (AChE) with ICvalues of 1.1, 5.6, and 12.9 μM, respectively. Compounds 2 and 4 showed inhibition of butyrylcholinesterase (BChE) with ICvalues of 11.5 and 27.8 μM, respectively. The kinetic activities were investigated to find out the type of enzyme inhibition involved. The types of AChE inhibition shown by compounds 5 and 7 were noncompetitive; BChE inhibition by compound 2 was also noncompetitive.

Pregnane-Type Steroidal Alkaloids ofSarcococca saligna: a New Class of Cholinesterase Inhibitors

Helvetica Chimica Acta, 2002

Phytochemical investigation of Sarcococca saligna by extensive bioassay-guided fractionation resulted in the isolation of the pregnane-type steroidal alkaloids 1 ± 15, i.e. of the five new compounds 1 ± 5 and the ten known alkaloids 6 ± 15. The structures of the new alkaloids salignenamide C (1), salignenamide D (2), 2bhydroxyepipachysamine D (3), salignenamide E (4), and salignenamide F (5) were elucidated with the help of modern spectroscopic techniques, while the known alkaloids axillarine C (6), axillarine F (7), sarcorine (8), N 3demethylsaracodine (9), saligcinnamide (10), salignenamide A (11), vaganine A (12), axillaridine A (13), sarsalignone (14), and sarsalignenone (15) were identified by comparing their spectral data with those reported earlier. Inhibition of electric-eel acetylcholinesterase (EC 3.1.1.7) and horse-serum butyrylcholinesterase (EC 3.1.1.8) by alkaloids 1 ± 15 were investigated. These new cholinesterase inhibitors may act as potential leads in the discovery of clinically useful inhibitors for nervous-system disorders, particularly by reducing memory deficiency in Alzheimer×s disease patients by potentiating and effecting the cholinergic transmission process. These compounds were found to inhibit both enzymes in a concentration-dependent fashion with the IC 50 values ranging from 5.21 ± 227.92 mm against acetylcholinesterase and 2.18 ± 38.36 mm against butyrylcholinesterase.

New pregnane-type steroidal alkaloids from Sarcococca saligna and their cholinesterase inhibitory activity

Steroids, 2004

Five new steroidal alkaloids, 5,14-dehydro-Na-demethylsaracodine [3β-Na-methyl-20S-Nb-acetyl-Nb-methylamino-pregn-5,14-diene] (1), 14-dehydro-Na-demethylsaracodine [3β-Na-methyl-20S-Nb-acetyl-Nb-methylamino-5α-pregn-14-ene] (2), 16-dehydrosarcorine [(20S)-20-(N,N-dimethylamino)-3β-(Na-acetylamido)-5α-pregn-16-ene] (3), 2,3-dehydrosarsalignone [(20S)-20-(N,N-dimethylamino)-3β-(tigloylamino)-pregn-2,5-diene-4-one] (4), and 14,15-dehydrosarcovagine-D [(20S)-20-(N,N-dimethylamino)-3β-(tigloylamino)-5α-pregn-2,14-diene-4-one] (5), were isolated from the ethanolic extract of Sarcococca saligna, along with two known bases, sarcovagenine-C (6) and salignarine-C (7). Their structures were elucidated on the basis of spectroscopic methods. All seven compounds were found to possess cholinesterase inhibitory potential in a concentration-dependent manner with the IC50 values ranging from 12.5 to 200 μM against acetylcholinesterase and from 1.25 to 32.2 μM against butyrylcholinesterase.

Kinetics and structure–activity relationship studies on pregnane-type steroidal alkaloids that inhibit cholinesterases

Bioorganic & Medicinal Chemistry, 2004

The mechanism of inhibition of acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8) enzymes by 23 pregnane-type alkaloids isolated from the Sarcococca saligna was investigated. Lineweaver–Burk and Dixon plots and their secondary replots showed that the majority of these compounds, that is 1, 4, 5, 6, 9, 10, 12, 13, 15–19, and 21 were found to be noncompetitive inhibitors of both enzymes. Compounds 8, 20, 22, and 23 were determined to be uncompetitive inhibitors of BChE, while compounds 11 and 14 were found to be uncompetitive and linear mixed inhibitors of AChE, respectively. Ki values were found to be in the range of 2.65–250.0 μM against AChE and 1.63–30.0 μM against BChE. The structure–activity relationship (SAR) studies suggested that the major interaction of the enzyme–inhibitor complexes are due to hydrophobic and cation–π interactions inside the aromatic gorge of these cholinesterases. The effects of various substituents on the activity of these compounds are also discussed in details.The mechanism of inhibition of acetyl-cholinesterase and butyrylcholinesterase enzymes by natural pregnane-type steroidal alkaloids isolated from Sarcococca saligna are discussed.

Cholinesterase Inhibition and Molecular Docking Studies of Sesquiterpene Coumarin Ethers from Heptaptera cilicica

Records of Natural Products, 2017

Five sesquiterpene coumarin ethers: umbelliprenin, umbelliprenin-10',11'-monoepoxide, conferone, mogoltacin and feselol were isolated from the fruits of Heptaptera cilicica. Their structures were identified by means of spectroscopic methods. AChE and BuChE inhibitory activities of the compounds were determined by molecular docking method which were confirmed by in vitro experiments. According to molecular docking results, total score of feselol and umbelliprenin were 5.69 and 3.23 kcal/mol against acetylcholinesterase, respectively. Total score for butyrylcholinesterase inhibitory effect of them were 2.76 and 4.99 kcal/mol, respectively. Feselol and umbelliprenin exhibited significantly high inhibitory potency against acetylcholinesterase (IC 50 = 1.26 ± 0.01 and 5.86 ± 0.03 μM, respectively) and butyrylcholinesterase (IC 50 = 9.98 ± 0.24 and 1.10 ± 0.19 μM, respectively). This is the first report of isolation of natural bioactives obtained from the chloroform extract of Heptaptera cilicica fruits with anticholinesterase activity.

Article Anti-Cholinesterase Activity of Lycopodium Alkaloids from

2014

A series of Lycopodium alkaloids, namely lycosquarosine A (1), acetylaposerratinine (2), huperzine A (3), huperzine B (4), 8α-hydrophlemariurine B (5), and huperzinine (6), has been isolated from Vietnamese Huperzia squarrosa. Among them, lycosquarosine A (1) is the new metabolite of the natural source. Lycosquarosine A completely inhibited AChE activity in a dose dependent manner with an IC50 value of 54.3 μg/mL, while acetylaposerratinine (2) showed stronger inhibitory activity than 1 with an IC50 value of 15.2 µg/mL. This result indicates that these alkaloids may be a potent source of AChE inhibitors.

Inhibition of cholinesterase activity by extracts, fractions and compounds from Calceolaria talcana and C. integrifolia (Calceolariaceae: Scrophulariaceae)

Food and Chemical Toxicology, 2013

Extracts, fractions and compounds from Calceolaria talcana and C. integrifolia exhibited strong inhibitory effects of the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes using the in vitro Ellmańs method. The most active samples were from the ethyl acetate extract, which caused a mixed-type inhibition against AChE (69.8% and 79.5% at 100 and 200 μg/ml, respectively) and against BChE (98.5% and 99.8% at 100 and 200 μg/ml, respectively) and its major components verbascoside 8 (50.9 and 70.0% at 200 μg/ml, against AChE and BChE, respectively), martynoside 9, and fraction F-7 (which corresponds to a mixture of 8, 9, and other phenylethanoids and phenolics that remain unidentified) (80.2 and 85.3% at 100 and 200 μg/ml, against AChE, respectively and 99.1 and 99.7% at 100 and 200 μg/ml, against BChE, respectively) inhibited the acetylcholinesterase enzyme competitively. The most polar fraction F-5 from n-hexane extract (a mixture of naphthoquinones: 2-hydroxy-3-(1,1-dimethylallyl-1,4-naphthoquinone) 6, α-dunnione 7 and other polar compounds that remain unidentified) showed a mixed-type inhibition (71.5 and 72.1% against AChE and BChE at 200 μg/ml, respectively). Finally, the methanol-soluble residue presented a complex, mixed-type inhibition (39.9 and 67.9% against AChE and BChE at 200 μg/ml, respectively). The mixture F-3 with diterpenes was obtained from the n-hexane extract: (1,10-cyclopropyl-9-epi-ent-isopimarol) 1, 19-α-hydroxy-abietatriene 2, and F-4 a mixture of triterpenes α-lupeol 3, β-sitosterol 4, ursolic acid 5 together with a complex mixture of terpenes that did not show activity. In summary, extracts and natural compounds from C. talcana and C. integrifolia were isolated, identified and characterized as cholinesterase inhibitors.