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.     

Ceanothane- and lupane-type triterpenes with antiplasmodial and antimycobacterial activities from Ziziphus cambodiana

One new and eight known ceanothane- and lupane-type triterpenes were isolated from the root bark of Ziziphus cambodiana PIERRE (Rhamnaceae). Based on spectral analyses, the structure of the new compound was elucidated as 3-O-(4-hydroxy-3-methoxybenzoyl)ceanothic acid (3-O-vanillylceanothic acid) (1), while the known compounds were identified as lupeol (2), betulinaldehyde (3), betulinic acid (4), 2-O-E-p-coumaroyl alphitolic acid (5), alphitolic acid (6), zizyberanalic acid (7), zizyberenalic acid (8) and ceanothic acid (9). Compounds 1, 5 and 8 exhibited significant in vitro antiplasmodial activity against the parasite Plasmodium falciparum, with inhibitory concentration (IC50) values of 3.7, 0.9 and 3.0 microg/ml, respectively. Compounds 1 and 3-8 showed antimycobacterial activity against Mycobacterium tuberculosis with respective MIC values of 25, 25, 25, 12.5, 50, 50 and 100 microg/ml.     

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.     

Bioactive constituents of the root bark of Artocarpus rigidus subsp. rigidus

Investigation of the chemical constituents of the root bark of Artocarpus rigidus BLUME subsp. rigidus has led to the isolation of six, structurally diverse phenolic compounds. These included two new compounds with modified skeletons, the flavonoid 7-demethylartonol E (1) and the chromone artorigidusin (2), together with four known phenolic compounds, the xanthone artonol B (3), the flavonoid artonin F (4), the flavonoid cycloartobiloxanthone (5), and the xanthone artoindonesianin C (6). Compounds 1, 4, and 5 exhibited antiplasmodial activity against Plasmodium falciparum. All compounds showed antimycobacterial activity against Mycobacterium tuberculosis, with 4 being the most active compound (MIC 6.25 microg/ml). Compounds 5 and 6 were active against KB cells, whereas 2, 5, and 6 showed varying toxicity to BC cells. Compounds 1-3, 5, and 6 were active in the NCI-H187 cytotoxicity assay, with 3 being the most active compound (IC(50) 1.26 microg/ml).     

Antiparasitic and antimicrobial isoflavanquinones from Abrus schimperi

The EtOH extract of Abrus schimperi (Fabaceae), collected in Kenya, demonstrated significant activity against Leishmania donovani promastigotes with IC50 value of 3.6 microg/mL. Bioassay-guided fractionation of CHCl3 fraction using Centrifugal Preparative TLC afforded two antiparasitic isoflavanquinones, namely amorphaquinone (1) and pendulone (2). They displayed IC50 values of 0.63 microg/mL and 0.43 microg/mL, respectively, against L. donovani promastigotes. Both the compounds were also evaluated against L. donovani axenic amastigotes and amastigotes in THPI macrophage cultures. In addition, compounds 1 and 2 showed antiplasmodial activity against Plasmodium falciparum D6 and W2 strains, while 2 displayed antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus (each IC50 1.44 microg/mL). The 1H and 13C data of 1, not fully assigned previously, were unambiguously assigned using 1D and 2D NMR HMBC and HMQC experiments. In addition, the absolute stereochemistry of the isolated compounds 1 and 2 was revised as C-(3S) based on Circular Dichroism experiments. This appears to be the first report of amorphaquinone (1) and pendulone (2) from the genus Abrus.     

Cholinesterase inhibiting and antiplasmodial steroidal alkaloids from Sarcococca hookeriana

Bioguided phytochemical investigation of Sarcococca hookeriana with respect to the cholinesterase enzyme inhibitory assay yielded two new pregnane-type steriodal alkaloids hookerianamide H (1) and hookerianamide I (2), along with three known alkaloids N(a)-methylepipachysamine D (3), sarcovagine C (4) and dictyophlebine (5). Their structures were determined with the aid of extensive spectroscopic analysis. All compounds showed good inhibitory activities against the enzymes acetylcholinesterase (IC(50) 2.9-34.1 microM) and butyrylcholinesterase (IC(50) 0.3-3.6 microM). These compounds also showed moderate antiplasmodial activity (IC(50) 2.4-10.3 microM) against the Plasmodium falciparum chloroquine resistant W2 strain.     

Cytotoxic compounds from the leaves of Gaillardia aristata Pursh. growing in Egypt

Ten compounds, neopulchellin (1), 6α- hydroxyneopulchellin (2), β-sitosterol-3-O-β-D-glucoside (3), apigenin (4), quercitin (5), eupafolin (6), kaempferol-3-methoxy-7-O-α-L-rhamnoside (7), apigenin-7-O-β-D-glucopyranoside (8), α-amyrin (9) and β-sitosterol (10), were isolated from the leaves of Gaillardia aristata by applying bioassay guided fractionation. The cytotoxicity was traced against two human cancer cell lines (breast (MCF7) and colon (HCT116)). The highest cytotoxicity was revealed by compounds 1 and 2 (isolated from chloroform extract); with IC(50) values of 0.43, 0.32?μg?mL(-1) against MCF7 and 0.46, 0.34?μg?mL(-1) against HCT116, respectively. Compounds 9 and 10 (isolated from the n-hexane extract) exhibited lower IC(50) values of 3.05, 2.35?μg?mL(-1) against MCF7 and 3.05, 2.35?μg?mL(-1) against HCT116, respectively, while compounds 4-7 obtained from the ethyl acetate extract revealed the lowest cytotoxicity. Identification of the aforementioned compounds was carried out on the basis of their physico-chemical properties and spectral analysis (UV, EI/MS, 1D and 2D).     

Identification of a new naphthalene and its derivatives from the bulb of eleutherine americana with inhibitory activity on lipopolysaccharide-induced nitric oxide production

A new naphthoquinone, (-)-3-[2-(acetyloxy)propyl]-2-hydroxy-8-methoxy-1,4-naphthoquinone (1) was isolated from the bulb of Eleutherine americana MERR. et HEYNE (Iridaceae) together with two known compounds, eleutherinol (6) and 1,5-dihydroxy-3-methylanthraquinone (7) which were found in this species for the first time. The other known compounds, (-)-isoeleutherin (2), (+)-eleutherin (3), (-)-hongconin (4), and (+)-dihydroeleutherinol (5) which were reported previously from this species, were also isolated in the present study. Compounds 2-6 exhibited potent inhibitory activity on nitric oxide production in RAW 264.7 lipopolysaccharide-activated mouse macrophage cells with IC(50) values of 7.7, 11.4, 19.8, 21.7, and 34.4 microM, respectively, whereas the other two compounds, 1 and 7, were inactive. The structure of compound 1 was elucidated by spectroscopic data analysis including 1D and 2D NMR experiments.     

The microbial hydroxylation of levonorgestrel

The microbial transformation of levonorgestrel (1) by Cunningham elegans resulted in the formation of five hydroxylated metabolites, 13-ethyl-10beta, 17beta-dihydroxy-18,19-dinor-17alpha-pregn-4-en-20-yn-3-one(2), 13-ethyl-6beta,17beta-dihydroxy-18,19-dinor-17alpha-pregn-4-en-20-yn-3-one (3) 13-ethyl 6beta, 10beta, 17beta-trihydroxy-18,19-dinor-17alpha-pregn-4-en-20-yn-3-one (4) 13-ethyl-15alpha-17beta-dihydroxy-18,19-dinor-17alpha-pregn-4-en-20-yn-3-one (5) and 13-ethyl-11alpha, 17beta-dihydroxy-18,19-dinor-17alpha-pregn-4en-20-yn-3-one. The fermentation of one with Rhizopus stolonifer, Fusarium lini and Curvularia lunata afforded compound 2 as a major metabolise. These metabolites were structurally characterized on the basis of spectroScopic techniques. Metabolite 6 was identified as a new compound. Compounds 2 2 ad 5 displayed inhibitory activity against the acetylcholinesterase ( AChE, EC. 3.1.1.7) with IC50 values of 79.2 and 24.5 microM, respectively. The metabolites 2 and 5 also showed inhibitory activity against the butyryLcholinesterase ( BChE, E.C 3.1.1.8) with IC50 values ranging between 9.4 and 309.8 microM.     

Anti-plasmodial activity of some constituents of the root bark of Harungana madagascariensis LAM. (Hypericaceae)

Bazouanthrone (1), a new anthrone derivative, has been isolated from the root bark of Harungana madagascariensis, together with known compounds, feruginin A (2), harunganin (3), harunganol A (4), harunganol B (5), friedelan-3-one (6) and betulinic acid (7). The structure of the compound (1) was assigned as 3,5,8,9-tetrahydroxy-2,4,4-tri-(3,3-dimethylallyl)-6-methyl-1-(4H)-anthracenone, by means of spectroscopic analysis. The anti-plasmodial activity of the isolated compounds was evaluated in culture against W2 strain of Plasmodium falciparum. All the compounds were found to be active against the Plasmodium parasites with bazouanthrone (1) showing particular potency (IC50=1.80 microM).     

Endodesmiadiol, a friedelane triterpenoid, and other antiplasmodial compounds from Endodesmia calophylloides

From the ethyl acetate extract of the stem bark of Endodesmia calophylloides (Guttiferae), a novel friedelane triterpenoid named endodesmiadiol (1), as well as the known compounds friedelin (2), canophyllol (3), canophyllal (4), cerin (5), morelloflavone (6), volkensiflavone (7), 8-deoxygartanin (8), 3 beta-acetoxyoleanolic acid (9) and 1,8-dihydroxy-3-isoprenyloxy-6-methylxanthone (10) have been isolated. The structures of these compounds were established by spectroscopic analysis, and the relative configuration of endodesmiadiol (1) was confirmed by X-ray diffraction. The antiplasmodial activity of the isolated compounds was evaluated against the W2 strain of Plasmodium falciparum which is resistant to chloroquine and other antimalarial drugs. All the compounds were found to be active with IC50 values ranging from 7.2 to 23.6 microM. The IC50 of endodesmiadiol was found to be 11.8 microM.     

Synthesis and antiplasmodial activity of 3-furyl and 3-thienylquinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives

The aim of this study was to identify new compounds active against Plasmodium falciparum based on our previous research carried out on 3-phenyl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives. Twelve compounds were synthesized and evaluated for antimalarial activity. Eight of them showed an IC(50) less than 1 microM against the 3D7 strain. Derivative 1 demonstrated high potency (IC(50)= 0.63 microM) and good selectivity (SI=10.35), thereby becoming a new lead-compound.     

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.     

Renin inhibitors. II. Synthesis and structure-activity relationships of N-terminus modified inhibitors containing a homostatine analogue.

The synthesis and structure-activity relationships of N-terminus modified renin inhibitors containing the homostatin analogue, (2RS,4S,5S)-5-amino-2-ethyl-4-hydroxy-7-methyloctanoic acid, are described. The compounds having a 3-alkyl (or aryl)sulfonylpropionyl residue at the N-terminus are found to be potent inhibitors which contain two amino acids. (2RS,4S,5S)-N-Isobutyl-5-[N-[(2S)-3-ethylsulfonyl-2-(1- naphthylmethyl)propionyl]-L-norleucyl]-amino-2-ethyl-4-hydroxy-7- methyloctanamide (20) has an IC50 of 0.5 nM against human plasma renin and the oral bioavailability of 20 is 0.73% in rats. Interaction between renin and the N-terminus of 1 and 20 is discussed in molecular modeling studies.     

Leishmanicidal and cholinesterase inhibiting activities of phenolic compounds from Allanblackia monticola and Symphonia globulifera

In a preliminary antiprotozoal screening of several Clusiaceae species, the methanolic extracts of Allanblackia monticola and Symphonia globulifera showed high in vitro leishmanicidal activity. Further bioguided phytochemical investigation led to the isolation of four benzophenones: guttiferone A (1), garcinol (2), cambogin (3) and guttiferone F (4), along with three xanthones: allanxanthone A (5), xanthone V1 (6) and globulixanthone C (7) as active constituents. Compounds 1 and 6 were isolated from S. globulifera leaves, while compounds 2-5 were obtained from A. monticola fruits. Guttiferone A (1) and F (4) showed particulary strong leishmanicidal activity in vitro, with IC50 values (0.2 microM and 0.16 microM, respectively) comparable to that of the reference compound, miltefosine (0.46 microM). Although the leishmanicidal activity is promising, the cytotoxicity profile of these compounds prevent at this state further in vivo biological evaluation. In addition, all the isolated compounds were tested in vitro for their anticholinesterase properties. The four benzophenones showed potent anticholinesterase properties towards acetylcholinesterase (AChE) and butylcholinesterase (AChE). For AChE, the IC50 value (0.66 microM) of garcinol (2) was almost equal to that of the reference compound galanthamine (0.50 microM). Furthermore, guttiferone A (1) and guttiferone F (4) (IC50 = 2.77 and 3.50 microM, respectively) were more active than galanthamine (IC50 = 8.5) against BChE.     

Anthraquinones with antiplasmodial activity from the roots of Rennellia elliptica Korth. (Rubiaceae)

Dichloromethane root extract of Rennellia elliptica Korth. showed strong inhibition of Plasmodium falciparum growth in vitro with an IC?? value of 4.04 μg/mL. A phytochemical study of the dichloromethane root extract has led to the isolation and characterization of a new anthraquinone, 1,2-dimethoxy-6-methyl-9,10-anthraquinone (1), and ten known anthraquinones: 1-hydroxy-2-methoxy-6-methyl-9,10-anthraquinone (2), nordamnacanthal (3), 2-formyl-3-hydroxy-9,10-anthraquinone (4), damnacanthal (5), lucidin-ω-methyl ether (6), 3-hydroxy-2-methyl-9,10-anthraquinone (7), rubiadin (8), 3-hydroxy-2-methoxy-6-methyl-9,10-anthraquinone (9), rubiadin-1-methyl ether (10) and 3-hydroxy-2-hydroxymethyl-9,10-anthraquinone (11). Structural elucidation of all compounds was accomplished by modern spectroscopic methods, notably 1D and 2D NMR, IR, UV and HREIMS. The new anthraquinone 1, 2-formyl-3-hydroxy-9,10-anthraquinone (4) and 3-hydroxy-2-methyl-9,10-anthraquinone (7) possess strong antiplasmodial activity, with IC?? values of 1.10, 0.63 and 0.34 μM, respectively.     

A new fatty ester and a new triterpene from Skimmia laureola

Aerial parts of Skimmia laureola yielded a new fatty ester, (+)-skimmilaureol (1), and a new triterpene 16-29-dihydroxy, 20-ene cyclolaudenol (2). Five known compounds, namely, O-methyl-cyclolaudenol (3), (R)-7-methoxy-6-(3'-hydroxy-2'R-methoxy-3'-methyl butyl)coumarin (4), (+)-(S)-psi-ribalinine (5), (R)-(+)-ribalinine (6) and methyl isoplatydesmine (7), previously isolated from this plant were subjected to enzymatic bioassays for the first time. Compounds 3 and 4 were found to be prolyl endopeptidase inhibitors with IC(50) 8.21 +/- 0.407 and 39.63 +/- 1.502 microM, respectively, while compounds 5-7 were found to be acetyl-cholinesterase and butyryl-cholinesterase inhibitors with IC(50) 62.46 +/- 1.58, 153.31 +/- 1.9, 74.5 +/- 1.05 and 150.04 +/- 0.45, 12.99 +/- 0.31, 78.3 +/- 1.86 microM, respectively.     

Three new lignans, longipedunins A-C, from Kadsura longipedunculata and their inhibitory activity against HIV-1 protease

Three new lignans, longipedunins A (1), B (2) and C (3), together with three known compounds, benzoyl-binankadsurin A (4), acetyl-binankadsurin A (5) and schisanlactone A (6), were isolated from Kadsura longipedunculata. Their structures and stereochemistry were determined by spectral and single-crystal X-ray analyses. Compounds 1 and 6 showed appreciable inhibitory activity against HIV-1 protease with IC50 values of 50 and 20 microM, respectively.