4-N-苯胺基喹啉衍生物的合成及胆碱酯酶抑制活性

设计合成了一系列4-N-苯胺基喹啉类衍生物,采用Ellman法测定了目标化合物对乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BChE)的抑制活性.结果表明,当喹啉环上连有伸长的吡啶季铵盐片段时,可显著提高目标化合物的胆碱酯酶抑制作用.化合物16对AChE和BChE具有明显的双重抑制作用,其IC_(50)值分别为0.92和14.20μmol/L,抑制效果强于阳性对照药加兰他敏.     

Biotransformation of physalin H and leishmanicidal activity of its transformed products

The transformation of physalin H (1) with Rhizopus stolonifer and Cunninghamella elegans has afforded two new physalins, 6,7-dehydrophysalin H (2) and 6-deoxyphysalin H (3), along with a known isophysalin B (4). Their structures were elucidated by spectroscopic analysis. All of these compounds have shown potent leishmanicidal activity with IC50 values in the range of 6.03-13.80 microM.     

A new labdane diterpene from the flowers of Solidago canadensis

A new labdane diterpene, 9alpha,16xi-dihydroxy-6-oxo-7,13-labdadien-15,16-olide (solicanolide, 1) and six known compounds identified as quercetin (2), 3-O-caffeoylquinic acid (3, neochlorogenic acid), 5-O-caffeoylquinic acid (4, chlorogenic acid), 4,5-di-O-caffeoylquinic acid (5), 3,5-di-O-caffeoylquinic acid (6) and 3,4-di-O-caffeoylquinic acid (7) were isolated from the flowers of Solidago canadensis. To our knowledge, compound 7 was isolated for the first time in S. canadensis. This work describes the isolation of compounds 1-7 and the structure elucidation of a new compound identified as compound 1. Solicanolide (1) showed cytotoxic activity against A549 (IC(50): 13+/-2 microM), DLD-1 (IC(50): 26+/-2 microM) and WS1 (IC(50): 17+/-1 microM) cell lines.     

Chemical constituents of the new endophytic fungus Mycosphaerella sp. nov. and their anti-parasitic activity

Chemical investigation of a new endophytic fungus, Mycosphaerella sp. nov. strain F2140, associated with the foliage of the plant Psychotria horizontalis (Rubiaceae) in Panama, resulted in the isolation of cercosporin (1) and a new cercosporin analog (3) as the major components. The structures of minor compounds in the extract were elucidated by detailed spectroscopic analysis as 2-(2-butyl)-6-ethyl-3-hydroxy-6-methylcyclohex-2-ene-1,5-dione (4), 3-(2-butyl)-6-ethyl-5-hydroxy-2-methoxy-6-methyl-cyclohex-2-enone (5), and an isomer of 5 (6). To study the influence of the hydroxy groups on the anti-parasitic activity of cercosporin, compound 1 was acetylated to obtain derivative 2. The isolated compounds 1- 6 were tested in vitro to determine their anti-parasitic activity against the causal agents of malaria (Plasmodium falciparum), leishmaniasis (Leishmania donovani), and Chagas disease (Trypanosoma cruzi). Cytotoxicity and potential anticancer activity of these compounds were evaluated using mammalian Vero cells and MCF7 cancer cell lines, respectively. Compounds 1 and 2 displayed high potency against L. donovani (IC50 0.46 and 0.64 microM), T. cruzi (IC50 1.08 and 0.78 microM), P. falciparum (IC50 1.03 and 2.99 microM), and MCF7 cancer cell lines (IC50 4.68 and 3.56 microM). Compounds 3-6 were not active in these assays at a concentration of 10 microg/mL.     

High-performance liquid chromatography-mass spectrometry-based acetylcholinesterase assay for the screening of inhibitors in natural extracts

The present paper describes a High-performance liquid chromatography-mass spectrometry (LC-MS) methodology for the screening of acetylcholinesterase (AChE) inhibitors in natural extracts. AChE activity of sample components is monitored by a post-column biochemical assay that is based on the separate, sequential mixing of AChE and acetylcholine, respectively, with the HPLC eluate. AChE inhibitors are detected by measuring a decrease of product formation using electrospray MS. Ammonium bicarbonate was used as buffer in order to achieve optimum compatibility between biochemical assay and MS detection conditions. The assay is robust and stable for over 13 h and compares favourably with other AChE assays in terms of stability and sensitivity. IC(50) values of 9-aminoacridine, galanthamine, gallamine, (-)-huperzine A and thioflavin T were determined to be 0.12, 0.38, 6.4, 0.46 and 3.2 microM, respectively. The assay was used to effectively identify an AChE inhibitor present in a crude extract of Narcissus c.v. "Bridal Crown".     

Phenolic constituents from the heartwood of Artocapus altilis and their tyrosinase inhibitory activity

From the MeOH extract of the heartwood of Artocapus altilis, thirteen phenolic compounds have been isolated, namely curcumin (1), desmethoxycurcumin (2), retrodihydrochalcone (3), apigenin (4), tangeretin (5), nobiletin (6), O-methyldehydrodieugenol (7), dehydrodieugenol (8), beta-hydroxypropiovanillone (9), p-coumaric acid (10), p-hydroxybenzaldehyde (11), vanillin (12), and vanillic acid (13). This is the first report on the presence of these compounds in the heartwood of A. altilis. Compounds 1, 2, and 10 showed more potent tyrosinase inhibitory activities, with IC50 values ranging from 2.3 to 42.0 microM, than the positive control kojic acid (IC50, 44.6 microM). The most active compound, p-coumaric acid (10) (IC50, 2.3 microM), was 22 times more active in tyrosinase inhibitory activity than kojic acid.     

Inhibition on HIV-1 integrase activity and nitric oxide production of compounds from Ficus glomerata

An ethanol Ficus glomerata wood extract and its purified components were investigated for their HIV-1 integrase (IN) and nitric oxide (NO) inhibitory activities. From bioassay-guided isolation, five compounds: beta-sitosterol-D-glucoside (1), aloe-emodin (2), genistein (3), 1,3,6-trihydroxy-8-methyl-anthraquinone (4) and 3-(1-C-beta-D-glucopyranosyl)-2,6-dihydroxy-5-methoxybenzoic acid (5) were isolated. Among the tested samples, at concentrations of 100 microM; compound 2 showed 31.9% inhibition of HIV-1 IN, followed by 4 (19.5%), whereas other compounds were inactive. With regard to the inhibitory effect on NO production, 3 possessed the highest activity with an IC50 value of 27.5 microM, followed by 4 (IC50 = 34.7 microM) and 2 (IC50 = 41.8 microM), respectively. This is the first time that compounds 2-5 have been isolated from Ficus glomerata.     

Synthesis,Biological Evaluation,and In Silico Studies of New Acetylcholinesterase Inhibitors Based on Quinoxaline Scaffold

A quinoxaline scaffold exhibits various bioactivities in pharmacotherapeutic interests. In this research, twelve quinoxaline derivatives were synthesized and evaluated as new acetylcholinesterase inhibitors. We found all compounds showed potent inhibitory activity against acetylcholinesterase (AChE) with IC₅₀ values of 0.077 to 50.080 µM, along with promising predicted drug-likeness and blood–brain barrier (BBB) permeation. In addition, potent butyrylcholinesterase (BChE) inhibitory activity with IC₅₀ values of 14.91 to 60.95 µM was observed in some compounds. Enzyme kinetic study revealed the most potent compound (6c) as a mixed-type AChE inhibitor. No cytotoxicity from the quinoxaline derivatives was noticed in the human neuroblastoma cell line (SHSY5Y). In silico study suggested the compounds preferred the peripheral anionic site (PAS) to the catalytic anionic site (CAS), which was different from AChE inhibitors (tacrine and galanthamine). We had proposed the molecular design guided for quinoxaline derivatives targeting the PAS site. Therefore, the quinoxaline derivatives could offer the lead for the newly developed candidate as potential acetylcholinesterase inhibitors.     

Chemical and bioactivity evaluation of the bark of Neonauclea purpurea

Bioassay-guided fractionation of the MeOH extract from the stem bark of Neonauclea purpurea used in traditional medicine, resulted in the isolation of 2 indole alkaloids, cadambine (1) and alpha-dihydrocadambine (2), as well as a quinolic compound, 2,6-dimethoxy-1,4-benzoquinone (3). Antimalarial activity evaluation showed that compounds 2 and 3 exhibited mild in vitro antimalarial activity against Plasmodium falciparum, the chloroquine-resistant strain K1 with IC50 values of 6.6 and 11.3 microM, respectively. Compounds 1 and 2 showed no cytotoxicity to monkey (Vero) cells, but compound 3 showed weak cytotoxicity with an IC50 value of 1.19 microM.     

Novel glycoconjugates of diospyrin, a quinonoid plant product: synthesis and evaluation of cytotoxicity against human malignant melanoma (A375) and laryngeal carcinoma (Hep2)

Glycoside derivatives of diospyrin (1) were synthesized for the first time, and the cytotoxicity of the novel compounds vis-à-vis their precursors were evaluated against two human cancer cell lines, viz. malignant melanoma (A375) and laryngeal carcinoma (Hep2). The IC(50) values were in the low micromolar range for all the compounds tested, and A375 cells showed comparatively greater sensitivity than Hep2. Most of the compounds exhibited enhanced activity as compared to the plant-derived quinonoid precursor of the series (1), while the aminophenyl mannosyl (6) was found to be the most effective derivative. In A375 cells, 6 (IC(50) = 0.02 microM) showed the maximum increase in cytotoxicity (approximately 35-fold) over that of 1 (IC(50) = 0.82 microM). Again, when the glycosides were evaluated at a given concentration (0.1 microM) for their relative capacity to generate ROS from A375 cells, the compound 6 could produce the highest amount of ROS. Incidentally, this derivative also showed a comparatively lower toxicity (IC(50) approximately 41 microM) when tested against normal human peripheral blood mononuclear cells, indicating a fair prospect of its development as a novel chemotherapeutic agent for the treatment of malignant melanoma.     

Antioxidant and antimutagenic polyisoprenylated benzophenones and xanthones from Rheedia acuminata

Dichloromethane extract of the stem bark of Rheedia acuminata yielded three benzophenones with antioxidant activity, the new one named acuminophenone A (1), guttiferone K (2) and isoxanthochymol (3), along with the known xanthones formoxanthone C (4) and macluraxanthone (5). The structures were established through interpretation of their spectroscopic data, the stereochemistry of compounds (1) and (2) were resolved by experimental and computational experiments and their antioxidant activities were measured using the DPPH, ABTS and TEAC assays. The antioxidant results showed that metabolites 1, 4 and 5 had a better antioxidant activity than the reference compound quercetin. In addition, we evaluate the mutagenicity and antimutagenicity of the CH2Cl2 extract as well as of the free radical scavenger compounds 1, 4 and 5 by the AMES Salmonella/microsomal test. No mutagenicity was found in the CH2Cl2 extract using Salmonella typhimurium strains TA98, TA100, TA102, TA1537 and TA1538, with or without S9 metabolic activation. The pure compounds neither showed mutagenicity in TA 102 strain and the most important result was the strong reduction of mutagenic effect induced by hydrogen peroxide in S. typhimurium TA102, with or without S9, showed by the compounds 1 (more than 93%) and 4 (more than 88%) at 0.02 microg/plate.     

Anti-plasmodial and cholinesterase inhibiting activities of some constituents of Psorospermum glaberrimum

Glaberianthrone (1), a new bianthrone was isolated from the hexane extract of the stem bark of Psorospermum glaberrimum together with thirteen known compounds: 3-geranyloxyemodin anthrone (2), friedelan-3-one (3), 3-prenyloxyemodin anthrone (4), 3-geranyloxyemodin (5), 3-prenyloxyemodin (6), friedelan-3-ol (7), acetylvismione D (8), betulinic acid (9), 2-geranylemodin (10), bianthrone A2b (11), bianthrone 1a (12), emodin (13) and 2-prenylemodin (14). The structures of the isolated compounds were established by means of spectroscopic methods. The extracts and the isolated compounds were tested in vitro for their anti-plasmodial activity against Plasmodium falciparum (chloroquine resistant strain W2) and for their acetyl- and butyrylcholinesterase inhibitory properties. The n-hexane extract showed good anti-plasmodial activity against P. falciparum W2 strain, with IC(50) of 0.87 microg/ml. It also exhibited 65.5% and 98.2% of acetyl- and butyrylcholinesterase inhibition at 0.2 mg/ml, respectively. Compounds 2 and 8 showed the best potencies against P. falciparum W2 strain with IC(50) of 1.68 microM and 0.12 microM, (0.66 microg/ml and 0.054 microg/ml) respectively. All tested compounds showed good butyrylcholinesterase inhibition activities with compound 12 displaying the best potency (IC(50) 9.25+/-0.25 microM). All the tested compounds showed weak inhibitory activity against acetylcholinesterase.     

Potent inhibitory effects of N-aryl S-alkylthiocarbamate derivatives on the dopa oxidase activity of mushroom tyrosinase

This study reports the potent inhibitory effect of N-aryl S-alkylthiocarbamate derivatives on mushroom tyrosinase (MT) activity. N-Aryl S-alkylthiocarbamate derivatives were found to exhibit a potent inhibitory effect on the dopa (3,4-dihydroxyphenylalanine) oxidase activity of mushroom tyrosinase. Most of the N-aryl S-alkylthiocarbamate derivatives (compounds from A to J) exhibited higher inhibitory effects than kojic acid (IC50=318 microM), a well known tyrosinase inhibitor. Tyrosinase was the most inhibited by S-phenetyl N-phenylthiocarbamate (compound E, IC50=7.25 microM), and this inhibition was 44 times stronger than that of kojic acid. Compound E exhibited 95.0% of inhibition at 100 microM. A kinetic study of MT inhibition by compound E using the Lineweaver-Burk plots analysis was performed. And the kinetics profiles observed suggest that compound E competitively inhibits MT.     

Isolation and cholinesterase activity of Amaryllidaceae alkaloids from Nerine bowdenii

Amaryllidaceae species are known as ornamental plants. Some contain galanthamine, an acetylcholinesterase inhibitor. The chemical composition of the alkaloid extract of bulbs of Nerine bowdenii Watson has been analyzed by means of GC/MS. Twenty-two compounds were detected and nineteen of them identified, one of which was belladine. The alkaloid extract showed promising cholinesterase inhibitory activities against human blood acetylcholinesterase (HuAChE; IC50 = 87.9 +/- 3.5 microg/mL) and human plasma butyrylcholinesterase (HuBuChE; IC50 = 14.8 +/- 1.1 microg/mL). Belladine inhibited HuAChE and HuBuChE in a dose-dependent manner with IC50 values of 781 +/- 12.5 microM and 284.8 +/-4.2 microM, respectively.     

Xanthine oxidase inhibitors from the heartwood of Vietnamese Caesalpinia sappan

From the MeOH extract of Vietnamese Caesalpinia sappan, a novel biogenetically exclusive benzindenopyran, with a new carbon framework, neoprotosappanin (1), and a new compound, protosappanin A dimethyl acetal (3), were isolated together with protosappanin E-2 (2), neosappanone A (4), and 13 previously reported phenolic compounds (5-17). Their structures were elucidated on the basis of spectroscopic data. Compounds 1-4, 7, 13, and 15-17 showed significant xanthine oxidase inhibitory activity in a concentration-dependent manner, and sappanchalcone (17) showed the most potent activity with an IC50 value of 3.9 microM, comparable to that of positive control allopurinol (IC50, 2.5 microM). The kinetic study of these inhibitors indicated that they are competitive inhibitors, the same as allopurinol, except for 1 and 16 which are noncompetitive inhibitors.     

Chemical composition, antimicrobial, antiradical and anticholinesterase activity of the essential oil of Pulicaria stephanocarpa from Soqotra

The chemical composition of the hydrodistilled leaf essential oil from Pulicaria stephanocarpa Balf. Fil was determined by GC-MS analysis, and its antimicrobial, antioxidant and anticholinesterase (AChE) activities were evaluated. Eighty-three compounds were identified representing 97.2% of the total oil. (E)-Caryophyllene 13.4%, (E)-nerolidol 8.5%, caryophyllene oxide 8.5%, alpha-cadinol 8.2% spathulenol 6.8% and tau-cadinol 4.7%, were the main components. Antimicrobial activity of the oil, evaluated using the disc diffusion and broth dilution methods, demonstrated the highest susceptibility on Gram-positive bacteria and Candida albicans. The free radical scavenging ability of the oil was assessed by the DPPH assay to show antiradical activity with IC50 of 330 microg/mL. Moreover, the oil revealed an AChE inhibitory activity of 47% at a concentration of 200 microg/mL using Ellman's method.     

Sesquiterpenoids and flavonoids from the aerial parts of Tithonia diversifolia and their cytotoxic activity

Cytotoxicity-guided fractionation of the 80% EtOH extract of Tithonia diversifolia has resulted in the isolation of twelve sesquiterpenoids (1-12), including three new ones (4, 10, 12), and three known flavonoids (13-15). The structures of the new compounds were determined by analysis of their spectroscopic data. The isolated compounds showed cytotoxic activity against HL-60 leukemia cells with IC(50) values ranging from 0.13 to 13.0 microM, when etoposide used as a positive control gave an IC(50) value of 0.43 microM. The cancer growth inhibitory property of 9, the main cytotoxic compound in T. diversifolia, was examined using a disease-oriented panel composed of 39 human cancer cell lines in the Japanese Foundation for Cancer Research.     

Tyrosinase inhibitors from Rhododendron collettianum and their structure-activity relationship (SAR) studies

A new coumarinolignoid 8'-epi-cleomiscosin A (1) together with the new glycoside 8-O-beta-D-glucopyranosyl-6-hydroxy-2-methyl-4H-1-benzopyrane-4-one (2) have been isolated from the aerial parts of Rhododendron collettianum and their structures determined on the basis of spectroscopic evidences. Tyrosinase inhibition study of these compounds and their structure-activity relationship (SAR) were also investigated. The compounds exhibited potent to mild inhibition activity against the enzyme. Especially, the compound 1 showed strong inhibition (IC50=1.33 microM) against the enzyme tyrosinase, as compared to the standard tyrosinase inhibitors kojic acid (IC50=16.67 microM) and L-mimosine (IC50=3.68 microM), indicating its potential used for the treatment of hyperpigmentation associated with the high production of melanocytes.