Bioguided chemical study of Boswellia dalzielii Hutch. (Burseraceae) for antibacterial agents and a new glucopyranoxylmethoxybenzyle.

Stem barks of Boswellia dalzielii are used traditionally for the treatment of various bacterial infections. A bioassay guided fractionation of the MeOH-CH2Cl2 (1/1, v/v) stem barks extract led to the isolation of fourteen compounds 1-14, identified based on spectroscopic data. Dalzienoside (1) is reported here for the first time. The broth microdilution method was used to evaluate the antibacterial activity of the crude extract, fractions and compounds against six bacterial strains. The crude extract exhibited moderate antibacterial activity with MIC of 250 µL/ml; two fractions showed significant activities with MICs ranging from 7.8 to 125 µg/ml, while α-boswellic acid (2), ß-boswellic acid (3), acetyl-11-keto-ß-boswellic acid (4) from these fractions exhibited strong activities with MIC value of 3.125 µg/mL against Staphylococcus aureus, Salmonella typhi, Enterobacter cloacae, Streptococcus pneumonia and Pseudomonia aeruginosa. This study gives insight into the antibacterial constituents of the stem bark of B. dalzielii and justifies its use in ethnomedicine.

Screening of the Pan-African natural product library identifies ixoratannin A-2 and boldine as novel HIV-1 inhibitors.

The continued burden of HIV in resource-limited regions such as parts of sub-Saharan Africa, combined with adverse effects and potential risks of resistance to existing antiretroviral therapies, emphasize the need to identify new HIV inhibitors. Here we performed a virtual screen of molecules from the pan-African Natural Product Library, the largest collection of medicinal plant-derived pure compounds on the African continent. We identified eight molecules with structural similarity to reported interactors of Vpu, an HIV-1 accessory protein with reported ion channel activity. Using in vitro HIV-1 replication assays with a CD4+ T cell line and peripheral blood mononuclear cells, we confirmed antiviral activity and minimal cytotoxicity for two compounds, ixoratannin A-2 and boldine. Notably, ixoratannin A-2 retained inhibitory activity against recombinant HIV-1 strains encoding patient-derived mutations that confer resistance to protease, non-nucleoside reverse transcriptase, or integrase inhibitors. Moreover, ixoratannin A-2 was less effective at inhibiting replication of HIV-1 lacking Vpu, supporting this protein as a possible direct or indirect target. In contrast, boldine was less effective against a protease inhibitor-resistant HIV-1 strain. Both ixoratannin A-2 and boldine also inhibited in vitro replication of hepatitis C virus (HCV). However, BIT-225, a previously-reported Vpu inhibitor, demonstrated antiviral activity but also cytotoxicity in HIV-1 and HCV replication assays. Our work identifies pure compounds derived from African plants with potential novel activities against viruses that disproportionately afflict resource-limited regions of the world.

Excelsoside: a new benzylic diglycoside from the leaves of Milicia excelsa.

A new benzylic diglycoside was isolated from the leaves of Milicia excelsa and identified as 3,4-dimethoxybenzyl beta-D-xylopyranosyl (1 --> 2)-beta-D-glucopyranoside (1). It was obtained together with four known secondary metabolites including lupeol acetate (2), ursolic acid (3), triacontyl (E)-ferulate (4), and 2-(3,5-dihydroxyphenyl)benzofuran-5,6-diol (5). Their structures were determined based on their spectroscopic data and by comparison with those reported in the literature.

Elatumic acid: a new ursolic acid congener from Omphalocarpum elatum Miers (Sapotaceae).

A new triterpene diastereomer, 1, of the previously reported 3beta,6beta,19alpha-trihydroxy-urs-12-en-28-oic acid-24-carboxylic acid methyl ester was obtained from the stem bark of Omphalocarpum elatum Miers (Sapotaceae) along with a-amyrin acetate (2), spinasterol (3), spinasterol 3-O-beta-D-glucopyranoside (4), and tormentic acid (5). The structures of the isolates were established on the basis of NMR and mass spectrometric data and by comparison with those previously reported in the literature. Compound 1 showed weak antibacterial activity against E. aerogenes ATCC13048 and EA3, K. pneumoniae ATCC29916, and P aeruginosa; it also displayed moderate cytotoxicity against CCRF-CEM, CEM/ADR5000, and MDA-MB231 cells.

Virtualizing the p-ANAPL library: a step towards drug discovery from African medicinal plants.

BACKGROUND: Natural products play a key role in drug discovery programs, both serving as drugs and as templates for the synthesis of drugs, even though the quantities and availabilities of samples for screening are often limitted. EXPERIMENTAL APPROACH: A current collection of physical samples of > 500 compound derived from African medicinal plants aimed at screening for drug discovery has been made by donations from several researchers from across the continent to be directly available for drug discovery programs. A virtual library of 3D structures of compounds has been generated and Lipinski's "Rule of Five" has been used to evaluate likely oral availability of the samples. RESULTS: A majority of the compound samples are made of flavonoids and about two thirds (2/3) are compliant to the "Rule of Five". The pharmacological profiles of thirty six (36) selected compounds in the collection have been discussed. CONCLUSIONS AND IMPLICATIONS: The p-ANAPL library is the largest physical collection of natural products derived from African medicinal plants directly available for screening purposes. The virtual library is also available and could be employed in virtual screening campaigns.

Antiproliferative activity of the isofuranonaphthoquinone isolated from Bulbine frutescens against Jurkat T cells.

Cancer is a major public health burden in both developed and developing countries. The quinone moiety has been shown to possess antitumor activity and several cancer drugs in clinical use contain this entity. The effect of isofuranonaphthoquinone isolated from Bulbine frutescens on Jurkat T cells was determined. Cells were exposed to the isofuranonaphthoquinone (IFNQ) at different concentrations. Significant antiproliferative effects were observed which were comparable to that of the anticancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). A combination of IFNQ with BCNU produced synergistic effects which were observed after 72 hrs. It was also observed that combining IFNQ with reduced glutathione abolished the anticancer activity of the compound. It is, therefore, proposed that the isofuranonaphthoquinone may exert part of its effect by producing reactive oxygen species resulting in death of the cells as the effects of this compound were antagonized by reduced glutathione. An investigation on the effects of isofuranonaphthoquinone on glutathione transferase (GST) activity and drug efflux pumps showed that this compound exhibited inhibitory effects on both the GST and the drug efflux pumping activities. Thus, the isofuranonaphthoquinone showed cytotoxicity, works through inhibition of some cellular mechanisms, and could present a potential source of lead compounds for anticancer drug development.

Cytotoxicity of semisynthetic acetal triterpenes from one-pot vicinal diol cleavage following by lactolization: reaction promoted by NaIO4/SiO2 gel in THF.

In situ C-C bond cleavage of vicinal diol following by the lactolisation resulted from separated treatment of Arjunolic acid (1), 24-hydroxytormentic acid (2) and 3-O-ß-D-glucopyranosylsitosterol (3) with sodium periodate and silica gel in dried THF according to the strategic position of hydroxyl functions in the molecule. The reaction led to a lactol pentacyclic triterpenes 1A, 2A and a bicyclotriacetal of ß-sitosterol 3A. These products were further acetylated and the cytotoxicity of all molecules was evaluated against human fibrosarcoma HT1080 cancer cells lines.

A new approach for anthelmintic discovery for humans.

Natural product-based drug discovery has been deemphasized by the pharmaceutical industry. This situation is discordant with the fact that most people in developing countries rely on traditional medicines derived from local biodiversity for healthcare. Despite economic growth in the past 10 years, Africa remains plagued by parasitic infections, out of reach of eradication. Limited regional funding for drug discovery complicates the situation. Novel models are needed to bring sustainability to local drug discovery programs. This Opinion describes an innovative partnership that promotes local leadership to harness a recombinant yeast-based assay to screen for novel anthelmintic candidates in collections of African natural products. Implementation of this strategy in biodiversity-rich but resource-constrained settings can help build sustainable local capacity for drug discovery.

Old plants newly discovered: Cassia sieberiana D.C. and Cassia abbreviata Oliv. Oliv. root extracts inhibit in vitro HIV-1c replication in peripheral blood mononuclear cells (PBMCs) by different modes of action.

ETHNOPHARMACOLOGICAL RELEVANCE: Despite advances in anti-retroviral therapy which has transformed HIV/AIDS from a fatal to a manageable chronic disease, increasing viral drug resistance, side effects and uneven access to anti-retroviral drugs remain considerable therapeutic challenges. Partly as a consequence of these shortcomings and partly based on the fact that HIV/AIDS gives rise to opportunistic infections whose symptoms have been managed in Africa in an HIV/AIDS-independent context by traditional healers for centuries, many HIV/AIDS patients use herbal medicines. The aim of this study was to screen selected medicinal plants from Botswana, used by traditional healers to treat/manage HIV/AIDS, for inhibitory activities on HIV replication. MATERIALS AND METHODS: Based on an ethnomedical survey, ethanolic tannin-containing and tannin-free extracts from 10 medicinal plants were tested for inhibitory properties against a clone of HIV-1c (MJ(4)) measuring cytopathic effect protection and levels of viral p24 antigen in infected PBMCs. RESULTS: Cassia sieberiana D.C., Cassia abbreviata Oliv. Oliv. and Plumbago zeylanica L. extracts showed significant inhibition of HIV-1c (MJ(4)) replication. The inhibitory activity of the Plumbago zeylanica extract could be attributed to its tannin content. Anti-HIV activity of Cassia sieberiana root and bark extracts, and Cassia abbreviata root extracts occurred in a concentration-dependent manner with an effective concentration (EC(50)) of 65.1µg/ml, 85.3µg/ml and 102.8µg/ml, respectively. Experiments to elucidate possible mechanism(s) of action revealed that Cassia sieberiana root and bark extracts blocked HIV replication at its binding- (EC(50)=70.2µg/ml and 90.8µg/ml, respectively) and entry stage (EC(50)=88.9µg/ml and 100.5µg/ml, respectively) while Cassia abbreviata extracts did not. CONCLUSIONS: We report here for the first time a direct inhibitory effect on HIV-1c replication of extracts from two extremely popular medicinal plants, Cassia sieberiana and Cassia abbreviata. Considering the traditional uses of both Cassia species, our findings strongly suggest pilot clinical observational studies involving traditional healers to further evaluate the therapeutic potential of the Cassia extracts.

Phosphodiesterase I-inhibiting Diels-Alder adducts from the leaves of Morus mesozygia.

A new 2-arylbenzofuran derivative, (+)-dimethylsmoracin O (1), and three new Diels-Alder type adducts, mesozygins A­C (2­4), in addition to eight known compounds, artonin I (5), chalcomaracin (6), norartocarpetin (7), moracin L (8), mulberrofuran F (9), moracin M (10), moracin C (11), and morachalcone A (12),were isolated from the leaves of Morus mesozygia Stapf. Structures were elucidated by spectroscopic data analyses. Compounds 2-7 displayed a potent phosphodiesterase I inhibitory activity.

Antimicrobial activities of the methanol extract and compounds from Artocarpus communis (Moraceae).

BACKGROUND: Artocarpus communis is used traditionally in Cameroon to treat several ailments, including infectious and associated diseases. This work was therefore designed to investigate the antimicrobial activities of the methanol extract (ACB) and compounds isolated from the bark of this plant, namely peruvianursenyl acetate C (1), α-amyrenol or viminalol (2), artonin E (4) and 2-[(3,5-dihydroxy)-(Z)-4-(3-methylbut-1-enyl)phenyl]benzofuran-6-ol (5). METHODS: The liquid microdilution assay was used in the determination of the minimal inhibitory concentration (MIC) and the minimal microbicidal concentration (MMC), against seven bacterial and one fungal species. RESULTS: The MIC results indicated that ACB as well as compounds 4 and 5 were able to prevent the growth of all tested microbial species. All other compounds showed selective activities. The lowest MIC value of 64 µg/ml for the crude extract was recorded on Staphylococcus aureus ATCC 25922 and Escherichia coli ATCC 8739. The corresponding value of 32 µg/ml was recorded with compounds 4 and 5 on Pseudomonas aeruginosa PA01 and compound 5 on E. coli ATCC 8739, their inhibition effect on P. aeruginosa PA01 being more than that of chloramphenicol used as reference antibiotic. CONCLUSION: The overall results of this study provided supportive data for the use of A. communis as well as some of its constituents for the treatment of infections associated with the studied microorganisms.

Hepatoprotective and antioxidant arylbenzofurans and flavonoids from the twigs of Morus mesozygia.

The chemical investigation of the twigs of Morus mesozygia resulted in the isolation of three new prenylated 2-arylbenzofurans, named moracin KM, LM, and SC (1-3), nine known 2-arylbenzofurans (4-12), and two known flavonoids (13-14). The structures of the new compounds were established as [2'',3'':6,7]-(6-(S)-hydroxymethyl-6-methylpyrano)-2-(3,5-dihydroxyphenyl)benzofuran-5-ol (1), [2'',3'':6,7]-(4,7-dihydro-6-methyloxepine)-2-(3-hydroxy-5-methoxyphenyl)benzofuran-5-ol (2), and [2'',3'':6,7]-(6,6-dimethylpyrano)-2-(3,5-dihydroxyphenyl)benzofuran (3). One of the new compounds, moracin LM (2), displayed modest antioxidant activity, whereas known compounds 4, 13, and 14 showed significant hepatoprotective and antioxidant activities.

The evaluation of novel natural products as inhibitors of human glutathione transferase P1-1.

Glutathione transferase P1-1 is over expressed in some cancer cells and contributes to detoxification of anticancer drugs, leading to drug-resistant tumors. The inhibition of human recombinant GSTP1-1 by natural plant products was investigated using 10 compounds isolated from plants indigenous to Southern and Central Africa. Monochlorobimane and 1-chloro-2,4-dinitrobenzene were used to determine GST activity. Each test compound was screened at 33 and 100 µM. Isofuranonapthoquinone (1) (from Bulbine frutescens) showed 68% inhibition at 33 µM, and sesquiterpene lactone (2) (from Dicoma anomala) showed 75% inhibition at 33 µM. The IC(50) value of 1 was 6.8 µM. The mode of inhibition was mixed, partial (G site) and noncompetitive (H site) with K(i) values of 8.8 and 0.21 µM, respectively. Sesquiterpene 2 did not inhibit the CDNB reaction. Therefore, isofuranonapthoquinone 1 needs further investigations in vivo because of its potent inhibition of GSTP1-1 in vitro.

Terpenoids from Turraeanthus species.

Chemical investigation of the root bark of Turraeanthus mannii and the stem of T. longipes resulted in the isolation of two new diterpenes, 13-methyl-labda-8(17)-en-15-oic acid (1) and 13-(hydroxymethyl)-14-hydroxy-ent-labda-8(17)-en-15-oic acid (2), along with two known diterpenes, 19-hydroxy-ent-labda-8(17),13-dien-15,16-olide (3) and 19-acetoxy-ent-labda-8(17),13-dien-15,16-olide (4), and the phytosterol, stigmasterol. The structure elucidation of the new compounds has been achieved using spectroscopic techniques.

Duboscic acid: a potent α-glucosidase inhibitor with an unprecedented triterpenoidal carbon skeleton from Duboscia macrocarpa.

Duboscic acid (1), a triterpenoid with a unique carbon backbone, was isolated from Duboscia macrocarpa Bocq. It is the first member of a new class of triterpenoids, for which the name "dubosane" is proposed. Duboscic acid has a potent α-glucosidase inhibition, and its structure was unambiguously deduced by a single-crystal X-ray diffraction study.

Doubly linked, A-type proanthocyanidin trimer and other constituents of Ixora coccinea leaves and their antioxidant and antibacterial properties.

Phytochemical investigation of the ethyl acetate fraction of the methanol extract of the leaves of Ixora coccinea led to the isolation and identification of an A-type trimeric proanthocyanidin epicatechin-(2ß→O→7, 4ß→8)-epicatechin-(5→O→2ß, 6→4ß)-epicatechin named ixoratannin A-2 along with seven known compounds, epicatechin, procyanidin A2, cinnamtannin B-1, and four flavon-3-ol rhamnosides viz: kaempferol-7-O-α-L-rhamnnoside, kaempferol-3-O-α-L-rhamnoside, quercetin-3-O-α-L-rhamnopyranoside, and kaempferol-3,7-O-α-L-dirhamnoside. The structures were elucidated by the application of IR, UV, MS, 1D-, and 2D-NMR spectroscopic analyses and by comparison with literature data. Antioxidant evaluation of isolated compounds revealed that ixoratannin A-2 and cinnamtannin B-1 were the most active compounds in DPPH, inhibition of lipid peroxidation and nitric oxide radical scavenging assays. Antibacterial activities were assessed by means of agar-diffusion assays using Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Bacillus subtilis. All tested compounds inhibited the growth of B. subtilis, while only epicatechin and quercetin-3-O-α-L-rhamnopyranoside inhibited the growth of E. coli.

A new bianthracene C-arabinopyranoside from Senna septemtrionalis.

Chrysophanol, physcion, emodin, floribundone-1, 5,7'-physcion-fallacinol, and the novel 5,7'-physcion-physcion-10'-C-alpha-arabinopyranoside were isolated from the stem bark of Senna septemtrionalis. The structures of these secondary metabolites were determined on the basis of spectroscopic analysis, especially from NMR spectra in conjunction with COSY, HMQC, HMBC and TOCSY.

Glutathione transferase from Plasmodium falciparum--interaction with malagashanine and selected plant natural products.

A glutathione transferase (PfGST) isolated from Plasmodium falciparum has been associated with chloroquine resistance. A range of natural products including malagashanine (MG) were screened for inhibition of PfGST by a GST assay with 1-chloro-2,4-dinitrobenzene as a substrate. Only the sesquiterpene (JBC 42C), the bicoumarin (Tral-1), ellagic acid and curcumin, were shown to be potent inhibitors of PfGST with IC(50) values of 8.5, 12, 50 and 69 µM, respectively. Kinetic studies were performed on PfGST using ellagic acid as an inhibitor. Uncompetitive and mixed types of inhibition were obtained for glutathione (GSH) and 1-chloro-2, 4-dinitrobenzene (CDNB). The K(i) for GSH and CDNB were -0.015 µM and 0.011 µM, respectively. Malagashanine (100 µM) only reduced the activity of PfGST to 80% but showed a time-dependent inactivation of PfGST with a t(1/2) of 34 minutes compared to >120 minutes in the absence of MG or in the presence of 5 mM GSH. This work facilitates the understanding of the interaction of PfGST with some plant derived compounds.