Eremane, viscidane and isozizaene diterpenoids from the leaves of Eremophila rigida and their absolute configurations.

Previously undescribed eremane, viscidane, and isozizaene diterpenoids, eremorigidanes A-F, along with six known O-methylated flavonoids and three known triterpenoids were isolated and identified from the leaves of Eremophila rigida Chinnock by combined use of high-resolution PTP1B inhibition profiling, semipreparative- and analytical-scale HPLC separations, HPLC-PDA-HRMS analysis, and NMR spectroscopy. The absolute configuration of the unreported diterpenoids were determined by comparison of their experimental and calculated ECD spectra as well as by biosynthetic arguments. All isolates were evaluated for their PTP1B inhibitory activities, which revealed the flavonoid penduletin (3) to show inhibition with an IC50 value of 18.3 µM, and the triterpenoids 3,4-seco-olean-12-ene-3,28-dioic acid (15), oleanolic acid (16), and 3-oxo-oleanolic acid (17) to show inhibition with IC50 values of 55.7, 9.9, and 6.3 µM, respectively. The preliminary structure-activity relationship (SAR) of isolated flavonoids and triterpenoids is discussed. Plausible biosynthetic steps involved in eremane and isozizaene metabolism are presented and discussed.

Combined Structure- and Ligand-Based Approach for the Identification of Inhibitors of AcrAB-TolC in Escherichia coli.

The inhibition of efflux pumps is a promising approach to combating multidrug-resistant bacteria. We have developed a combined structure- and ligand-based model, using OpenEye software, for the identification of inhibitors of AcrB, the inner membrane protein component of the AcrAB-TolC efflux pump in Escherichia coli. From a database of 1391 FDA-approved drugs, 23 compounds were selected to test for efflux inhibition in E. coli. Seven compounds, including ivacaftor (25), butenafine (19), naftifine (27), pimozide (30), thioridazine (35), trifluoperazine (37), and meloxicam (26), enhanced the activity of at least one antimicrobial substrate and inhibited the efflux pump-mediated removal of the substrate Nile Red from cells. Ivacaftor (25) inhibited efflux dose dependently, had no effect on an E. coli strain with genomic deletion of the gene encoding AcrB, and did not damage the bacterial outer membrane. In the presence of a sub-minimum inhibitory concentration (MIC) of the outer membrane permeabilizer colistin, ivacaftor at 1 µg/mL reduced the MICs of erythromycin and minocycline by 4- to 8-fold. The identification of seven potential AcrB inhibitors shows the merits of a combined structure- and ligand-based approach to virtual screening.

Identification of new PTP1B-inhibiting decipiene diterpenoid esters from Eremophila clarkei by high-resolution PTP1B inhibition profiling, enzyme kinetics analysis, and molecular docking.

In this study, an extract of the leaves of Eremophila clarkei Oldfield & F.Muell. showed protein tyrosine phosphatase 1B (PTP1B) inhibitory activity with an IC50 value of 33.0 µg/mL. The extract was therefore investigated by high-resolution PTP1B inhibition profiling to pinpoint the constituents responsible for the activity. Subsequent isolation and purification using analytical-scale HPLC led to identification of eight previously undescribed decipiene diterpenoids, eremoclarkanes A-H, as well as eremoclarkic acid, a biogenetically related new phenolic acid. In addition, one known decipiene diterpenoid and ten known O-methylated flavonoids were isolated. The structures of the isolated compounds were elucidated by extensive analysis of their HRMS and 1D and 2D NMR spectra. The absolute configuration of decipiene diterpenoids was determined by comparison of experimental and calculated ECD spectra. The flavonoid hispidulin (2b) and the four decipiene diterpenoids 13a, 13b, 13f, and 14b exhibited PTP1B inhibitory activity with IC50 values ranging from 22.8 to 33.6 µM. This is the first report of PTP1B inhibitory activity of decipienes, and enzyme kinetics revealed that 13a and 13b are competitive inhibitors of PTP1B, whereas 13f and 14b displayed mixed-type-mode inhibition of PTP1B. Finally, molecular docking indicated that 13a, 13b, 13f, and 14b showed comparable binding affinity towards the active and/or allosteric site of PTP1B enzyme. Structure-activity relationship (SAR) of the identified O-methylated flavonoids and decipiene diterpenoids towards PTP1B is discussed. Plausible enzymatic and photochemically driven routes for the formation of the decipienes and conversion products thereof are presented and discussed.

Polypharmacology-Labeled Molecular Networking: An Analytical Technology Workflow for Accelerated Identification of Multiple Bioactive Constituents in Complex Extracts.

Discovery of sustainable and benign-by-design drugs to combat emerging health pandemics calls for new analytical technologies to explore the chemical and pharmacological properties of Nature's unique chemical space. Here, we present a new analytical technology workflow, polypharmacology-labeled molecular networking (PLMN), where merged positive and negative ionization tandem mass spectrometry-based molecular networking is linked with data from polypharmacological high-resolution inhibition profiling for easy and fast identification of individual bioactive constituents in complex extracts. The crude extract of Eremophila rugosa was subjected to PLMN analysis for the identification of antihyperglycemic and antibacterial constituents. Visually easy-interpretable polypharmacology scores and polypharmacology pie charts as well as microfractionation variation scores of each node in the molecular network provided direct information about each constituent's activity in the seven assays included in this proof-of-concept study. A total of 27 new non-canonical nerylneryl diphosphate-derived diterpenoids were identified. Serrulatane ferulate esters were shown to be associated with antihyperglycemic and antibacterial activities, including some showing synergistic activity with oxacillin in clinically relevant (epidemic) methicillin-resistant Staphylococcus aureus strains and some showing saddle-shaped binding to the active site of protein-tyrosine phosphatase 1B. PLMN is scalable in the number and types of assays included and thus holds potential for a paradigm shift toward polypharmacological natural-products-based drug discovery.

Design and synthesis of benzochromene derivatives as AcrB inhibitors for the reversal of bacterial multidrug resistance.

A series of novel benzo[h]chromene compounds were designed, synthesized and evaluated for their biological activity as AcrB inhibitors. The compounds were assessed for their ability to potentiate the effect of antibiotics. Compounds with antibiotic-potentiating effects were then evaluated for inhibition of Nile Red efflux, and for off-target effects including activity on the outer and inner bacterial membranes and toxicity. Six compounds were identified to reduce the MIC values of at least one of the tested antibiotics by at least 4-fold, and further reduced the MICs in the presence of a membrane permeabilizer. The identified compounds were also able to inhibit Nile Red efflux at concentrations between 50 µM and 200 µM. The compounds did not disrupt the bacterial outer membrane nor display toxicity in a nematode model (Caenorhabditis elegans). The 4-methoxyphenoxy)propoxy derivative compound G6 possessed the most potent antibacterial potentiation with erythromycin by 8-fold even without the presence of a membrane permeabilizer. Furthermore, H6, G6, G10 and G11 completely abolished the Nile Red efflux at a concentration of 50 µM. The 3,4-dihydro-2H-benzo[h]chromen-5-yl)(morpholino)methanone core appears to be a promising chemical skeleton to be further studied in the discovery of more putative AcrB inhibitors.

Cinnamaldehyde derivatives act as antimicrobial agents against Acinetobacter baumannii through the inhibition of cell division.

Acinetobacter baumannii is a pathogen with high intrinsic antimicrobial resistance while multidrug resistant (MDR) and extensively drug resistant (XDR) strains of this pathogen are emerging. Treatment options for infections by these strains are very limited, hence new therapies are urgently needed. The bacterial cell division protein, FtsZ, is a promising drug target for the development of novel antimicrobial agents. We have previously reported limited activity of cinnamaldehyde analogs against Escherichia coli. In this study, we have determined the antimicrobial activity of six cinnamaldehyde analogs for antimicrobial activity against A. baumannii. Microscopic analysis was performed to determine if the compounds inhibit cell division. The on-target effect of the compounds was assessed by analyzing their effect on polymerization and on the GTPase activity of purified FtsZ from A. baumannii. In silico docking was used to assess the binding of cinnamaldehyde analogs. Finally, in vivo and in vitro safety assays were performed. All six compounds displayed antibacterial activity against the critical priority pathogen A. baumannii, with 4-bromophenyl-substituted 4 displaying the most potent antimicrobial activity (MIC 32 µg/mL). Bioactivity was significantly increased in the presence of an efflux pump inhibitor for A. baumannii ATCC 19606 (up to 32-fold) and significantly, for extensively drug resistant UW 5075 (greater than 4-fold), suggesting that efflux contributes to the intrinsic resistance of A. baumannii against these agents. The compounds inhibited cell division in A. baumannii as observed by the elongated phenotype and targeted the FtsZ protein as seen from the inhibition of polymerization and GTPase activity. In silico docking predicted that the compounds bind in the interdomain cleft adjacent to the H7 core helix. Di-chlorinated 6 was devoid of hemolytic activity and cytotoxicity against mammalian cells in vitro, as well as adverse activity in a Caenorhabditis elegans nematode model in vivo. Together, these findings present halogenated analogs 4 and 6 as promising candidates for further development as antimicrobial agents aimed at combating A. baumannii. This is also the first report of FtsZ-targeting compounds with activity against an XDR A. baumannii strain.

Serrulatane diterpenoids with unusual side chain modifications from root bark of Eremophila longifolia.

The plant genus Eremophila is endemic to Australia and widespread in arid regions. Root bark extract of Eremophila longifolia (R.Br.) F.Muell. (Scrophulariaceae) was investigated by LC-PDA-HRMS, and dereplication suggested the presence of a series of diterpenoids. Using a combination of preparative- and analytical-scale HPLC separation as well as extensive 1D and 2D NMR analysis, the structures of 12 hitherto unreported serrulatane diterpenoids, eremolongine A-L, were established. These structures included serrulatanes with unusual side chain modifications to form hitherto unseen skeletons with, e.g., cyclopentane, oxepane, and bicyclic hexahydro-1H-cyclopenta[c]furan moieties. Serrulatane diterpenoids in Eremophila have recently been shown to originate from a common biosynthetic precursor with conserved stereochemical configuration, and this was used for tentative assignment of the relative and absolute configuration of the isolated compounds. Triple high-resolution α-glucosidase/α-amylase/PTP1B inhibition profiling demonstrated that several of the eremolongines had weak inhibitory activity towards targets important for management of type 2 diabetes.

Biodiscoveries within the Australian plant genus Eremophila based on international and interdisciplinary collaboration: results and perspectives on outstanding ethical dilemmas.

In a cross-continental research initiative, including researchers working in Australia and Denmark, and based on joint external funding by a 3-year grant from the Novo Nordisk Foundation, we have used DNA sequencing, extensive chemical profiling and molecular networking analyses across the entire Eremophila genus to provide new knowledge on the presence of natural products and their bioactivities using polypharmocological screens. Sesquiterpenoids, diterpenoids and dimers of branched-chain fatty acids with previously unknown chemical structures were identified. The collection of plant material from the Eremophila genus was carried out according to a 'bioprospecting agreement' with the Government of Western Australia. We recognize that several Eremophila species hold immense cultural significance to Australia's First Peoples. In spite of our best intentions to ensure that new knowledge gained about the genus Eremophila and any potential future benefits are shared in an equitable manner, in accordance with the Nagoya Protocol, we encounter serious dilemmas and potential conflicts in making benefit sharing with Australia's First Peoples a reality.

Bioactivity-guided isolation of compounds from Sophora flavescens with antibacterial activity against Acinetobacter baumannii.

Bioactivity-guided fraction of an extract of Sophora flavescens to identify antibacterial compounds against Acinetobacter baumannii, led to the isolation of two new compounds, (2″R)-5-methoxy-7-hydroxy-8-lavandulylchromone (13) and (2S,ßS)-(-)-sophobiflavonoid CE (19), and 18 known flavonoids, (6aR,11aR)-(-)-maackiain (1), (2S)-(-)-8-prenylnaringenin (2), (2S)-(-)-exiguaflavanone K (3), (2S)-(-)-sophoraflavanone G (4), (2S)-(-)-leachianone A (5), (2S)-(-)-kushenol E (6), (2S)-(-)-leachianone G (7), (±)-kushenol F (8), (2S)-(-)-kurarinone (9), (2S)-(-)-kurarinol (10), (2 R,3R)- (+)-3,7,4'-trihydroxy-5-methoxy-8-prenylflavanone (11), (2S)-(-)-isoxanthohumol (12), (2S)-(-)-2'-methoxykurarinone (14), (2 R,3R)-(+)-kushenol I (15), calycosin (16), kuraridin (17), (2S)-(-)-kushenol A (18), and trifolirhizin (20). Their structures were elucidated based on NMR, MS, and CD spectroscopic analysis. Among them, 1, 2, 5, and 15 exerted modest antibacterial activity against A. baumannii, with MIC95 of 128-256 µg/mL for 2 and 256-512 µg/mL for 1, 5 and 15.

Genotoxicity of advanced glycation end products in vitro is influenced by their preparation temperature, purification and cell exposure time.

Advanced glycation end products (AGEs) are formed via non-enzymatic reactions between amino groups of proteins and the carbonyl groups of reducing sugars. Previous studies have shown that highly glycated albumin prepared using a glucose-bovine serum albumin (Glu-BSA) model system incubated at 60°C for 6 weeks induces genotoxicity in WIL2-NS cells at 9 days of exposure measured by the cytokinesis-block micronucleus cytome (CBMNcyt) assay. However, this AGE model system is not physiologically relevant as normal body temperature is 37°C and the degree of glycation may exceed the extent of albumin modification in vivo. We hypothesised that the incubation temperature and purification method used in these studies may cause changes to the chemical profile of the glycated albumin and may influence the extent of genotoxicity observed at 3, 6 and 9 days of exposure. We prepared AGEs generated using Glu-BSA model systems incubated at 60°C or 37°C purified using trichloroacetic acid (TCA) precipitation or ultrafiltration (UF) and compared their chemical profile (glycation, oxidation, and aggregation) and genotoxicity in WIL2-NS cells using the CBMNcyt assay after 3, 6 and 9 days of exposure. The number of micronuclei (MNi) was significantly higher for cells treated with Glu-BSA incubated at 60°C and purified via TCA (12 ± 1 MNi/1000 binucleated cells) compared to Glu-BSA incubated at 37°C and purified using UF (6 ± 1 MNi/1000 binucleated cells) after 9 days (P < 0.0001). The increase in genotoxicity observed could be explained by a higher level of protein glycation, oxidation, and aggregation of the Glu-BSA model system incubated at 60°C relative to 37°C. This study highlighted that the incubation temperature, purification method and cell exposure time are important variables to consider when generating AGEs in vitro and will enable future studies to better reflect in vivo situations of albumin glycation.

Reversal of ABCG2/BCRP-Mediated Multidrug Resistance by 5,3',5'-Trihydroxy-3,6,7,4'-Tetramethoxyflavone Isolated from the Australian Desert Plant Eremophila galeata Chinnock.

Multidrug resistance (MDR) is a major challenge in cancer treatment, and the breast cancer resistance protein (BCRP) is an important target in the search for new MDR-reversing drugs. With the aim of discovering new potential BCRP inhibitors, the crude extract of leaves of Eremophila galeata, a plant endemic to Australia, was investigated for inhibitory activity of parental (HT29par) as well as BCRP-overexpressing HT29 colon cancer cells resistant to the chemotherapeutic SN-38 (i.e., HT29SN38 cells). This identified a fraction, eluted with 40% acetonitrile on a solid-phase extraction column, which showed weak growth-inhibitory activity on HT29SN38 cells when administered alone, but exhibited concentration-dependent growth inhibition when administered in combination with SN-38. The major constituent in this fraction was isolated and found to be 5,3',5'-trihydroxy-3,6,7,4'-tetramethoxyflavone (2), which at a concentration of 25 µg/mL potentiated the growth-inhibitory activity of SN-38 to a degree comparable to that of the known BCRP inhibitor Ko143 at 1 µM. A dye accumulation experiment suggested that 2 inhibits BCRP, and docking studies showed that 2 binds to the same BCRP site as SN-38. These results indicate that 2 acts synergistically with SN-38, with 2 being a BCRP efflux pump inhibitor while SN-38 inhibits topoisomerase-1.

Navigating through chemical space and evolutionary time across the Australian continent in plant genus Eremophila.

Eremophila is the largest genus in the plant tribe Myoporeae (Scrophulariaceae) and exhibits incredible morphological diversity across the Australian continent. The Australian Aboriginal Peoples recognize many Eremophila species as important sources of traditional medicine, the most frequently used plant parts being the leaves. Recent phylogenetic studies have revealed complex evolutionary relationships between Eremophila and related genera in the tribe. Unique and structurally diverse metabolites, particularly diterpenoids, are also a feature of plants in this group. To assess the full dimension of the chemical space of the tribe Myoporeae, we investigated the metabolite diversity in a chemo-evolutionary framework applying a combination of molecular phylogenetic and state-of-the-art computational metabolomics tools to build a dataset involving leaf samples from a total of 291 specimens of Eremophila and allied genera. The chemo-evolutionary relationships are expounded into a systematic context by integration of information about leaf morphology (resin and hairiness), environmental factors (pollination and geographical distribution), and medicinal properties (traditional medicinal uses and antibacterial studies), augmenting our understanding of complex interactions in biological systems.

Antimicrobial Action and Reversal of Resistance in MRSA by Difluorobenzamide Derivatives Targeted at FtsZ.

The bacterial cell division protein, FtsZ, has been identified as a target for antimicrobial development. Derivatives of 3-methoxybenzamide have shown promising activities as FtsZ inhibitors in Gram-positive bacteria. We sought to characterise the activity of five difluorobenzamide derivatives with non-heterocyclic substituents attached through the 3-oxygen. These compounds exhibited antimicrobial activity against methicillin resistant Staphylococcus aureus (MRSA), with an isopentyloxy-substituted compound showing modest activity against vancomycin resistant Enterococcus faecium (VRE). The compounds were able to reverse resistance to oxacillin in highly resistant clinical MRSA strains at concentrations far below their MICs. Three of the compounds inhibited an Escherichia coli strain lacking the AcrAB components of a drug efflux pump, which suggests the lack of Gram-negative activity can partly be attributed to efflux. The compounds inhibited cell division by targeting S. aureus FtsZ, producing a dose-dependent increase in GTPase rate which increased the rate of FtsZ polymerization and stabilized the FtsZ polymers. These compounds did not affect the polymerization of mammalian tubulin and did not display haemolytic activity or cytotoxicity. These derivatives are therefore promising compounds for further development as antimicrobial agents or as resistance breakers to re-sensitive MRSA to beta-lactam antibiotics.

Design and synthesis of novel 4-substituted quinazoline-2-carboxamide derivatives targeting AcrB to reverse the bacterial multidrug resistance.

Novel 4-substituted quinazoline-2-carboxamide derivatives targeting AcrB were designed, synthesized and evaluated for their biological activity as AcrB inhibitors. In particular, the ability of the compounds to potentiate the activity of antibiotics, to inhibit Nile Red efflux and to target AcrB was investigated. In this study, 19 compounds were identified to reduce the MIC values of at least one tested antibacterial by 2- to 16-fold at a lower concentration. Identified modulating compounds also possessed considerable inhibition on Nile red efflux at concentrations as low as 50 µM and did not display off-target effects on the outer membrane. Among the above compounds with characteristics of ideal AcrB inhibitors, the most outstanding ones are A15 and B5-B7. In particular, A15 and B7 exhibited not only the most prominent performance in the synergistic effect, but also completely abolished Nile Red efflux at concentrations of 50 and 100 µM, respectively. In docking simulations, A15 was observed to have the most favorable docking score and was predicted to bind in the hydrophobic trap as has been noted with other inhibitors such as MBX2319. It is worth noting that the 4-morpholinoquinazoline-2-carboxamide core appears to be a promising chemical skeleton to be further optimized for the discovery of more potent AcrB inhibitors.

Antioxidant and Antiglycation Activities of Syzygium paniculatum Gaertn and Inhibition of Digestive Enzymes Relevant to Type 2 Diabetes Mellitus.

Advanced glycation end-products (AGEs) may be a contributing factor in the development of diabetes-specific vascular pathologies that affect the retina, glomerulus and peripheral nerves. In this study, Australian native food plant species Syzygium paniculatum was investigated for activities relevant to Type 2 diabetes mellitus including inhibition of α-amylase, α-glucosidase and protein glycation. A methanolic extract of the leaves showed the strongest α-amylase inhibition (IC50 = 14.29 ± 0.82 µg/mL, p < 0.05) when compared with other extracts. For inhibition of α-glucosidase, the strongest inhibition was shown for the water, methanolic and acetone extracts of leaves with IC50 values ranging from 4.73 ± 0.96 to 7.26 ± 0.92 µg/mL. In the BSA-glucose model, fruit and leaf extracts inhibited formation of protein-bound fluorescent AGEs with IC50 values ranging between 11.82 ± 0.71 and 96.80 ± 13.41 µg/mL. Pearson's correlation analysis showed that the AGE inhibition significantly correlated with DPPH (rp = -0.8964, p < 0.05) and ABTS (rp = -0.8326, p < 0.05). α-amylase inhibitory activities strongly correlated with DPPH (rp = -0.8964, p < 0.001). α-glucosidase inhibition strongly correlated with TPC (rp = -0.9243, p < 0.05), FRAP (rp = -0.9502, p < 0.01), DPPH (rp = -0.9317, p < 0.01) and ABTS (rp = -0.9486, p < 0.01). This study provides a strong rationale for further investigation aimed at isolating and identifying the active compounds responsible for the observed effects on targets relevant to diabetes.

Can a digital slide scanner and viewing technique assist the visual scoring for the cytokinesis-block micronucleus cytome assay?

The cytokinesis-block micronucleus cytome (CBMNcyt) assay is a comprehensive method to measure DNA damage, cytostasis and cytotoxicity caused by nutritional, radiation and chemical factors. A slide imaging technique has been identified as a new method to assist with the visual scoring of cells for the CBMNcyt assay. A NanoZoomer S60 Digital Pathology slide scanner was used to view WIL2-NS cells treated with hydrogen peroxide (H2O2) and measure CBMNcyt assay biomarkers using a high-definition desktop computer screen. The H2O2-treated WIL2-NS cells were also scored visually using a standard light microscope, and the two visual scoring methods were compared. Good agreement was found between the scoring methods for all DNA damage indices (micronuclei, nucleoplasmic bridges and nuclear buds) and nuclear division index with correlation R values ranging from 0.438 to 0.789, P < 0.05. Apoptotic and necrotic cell frequency was lower for the NanoZoomer scoring method, but necrotic frequency correlated well with the direct visual microscope method (R = 0.703, P < 0.0001). Considerable advantages of the NanoZoomer scoring method compared to direct visual microscopy includes reduced scoring time, improved ergonomics and a reduction in scorer fatigue. This study indicates that a digital slide scanning and viewing technique may assist with visual scoring for the CBMNcyt assay and provides similar results to conventional direct visual scoring.

PTP1B-Inhibiting Branched-Chain Fatty Acid Dimers from Eremophila oppositifolia subsp. angustifolia Identified by High-Resolution PTP1B Inhibition Profiling and HPLC-PDA-HRMS-SPE-NMR Analysis.

Ten new branched-chain fatty acid (BCFA) dimers with a substituted cyclohexene structure, five new monomers, and two known monomers, (2E,4Z,6E)-5-(acetoxymethyl)tetradeca-2,4,6-trienoic acid and its 5-hydroxymethyl analogue, were identified in the leaf extract of Eremophila oppositifolia subsp. angustifolia using a combination of HPLC-PDA-HRMS-SPE-NMR analysis and semipreparative-scale HPLC. The dimers could be classified as three types of Diels-Alder reaction products formed between monomers at two different sites of unsaturation of the dienophile. Two of the monomers represent potential biosynthetic intermediates of branched-chain fatty acids. Several compounds were found by high-resolution bioactivity profiling to inhibit PTP1B and were purified subsequently by semipreparative-scale HPLC. The dimers were generally more potent than the monomers with IC50 values ranging from 2 to 66 µM, compared to 38-484 µM for the monomers. The ten fatty acid dimers represent both a novel class of compounds and a novel class of PTP1B inhibitors.

Antibacterial Performance of Terpenoids from the Australian Plant Eremophila lucida.

Plants in the Australian genus Eremophila (Scrophulariaceae) have attracted considerable recent attention for their antimicrobial compounds, which possess a wide range of chemical structures. As they are typically associated with the oily-waxy resin layer covering leaves and green branchlets, and Eremophila lucida is prominent among the species containing a pronounced sticky resin layer, this species was considered of interest for assessing its antibacterial constituents. The n-hexane fraction of the crude acetone extract of the leaves exhibited antibacterial activity against Staphylococcus aureus. Isolation led to the known compounds cembratriene, (3Z, 7E, 11Z)-15-hydroxycembra-3,7,11-trien-19-oic acid (1), the sesquiterpenoid, farnesal (2) and the viscidane diterpenoid, 5α-hydroxyviscida-3,14-dien-20-oic acid (3). The purified compounds were tested for antibacterial activity with 2 and 3 showing moderate antibacterial activity against Gram-positive bacteria.

Advances in the Use of Anti-inflammatory Agents to Manage Chemotherapy-induced Oral and Gastrointestinal Mucositis.

Mucositis is a side effect associated with the use of chemotherapy, and has a significant impact on the quality of life. Mucositis, by definition, refers to the inflammation of the mucosa and occurs throughout the alimentary tract from the mouth to anus. Nuclear Factor kappa B (NFκB) encompasses a family of transcription factors, which upregulate pro-inflammatory cytokines. These are recognized as key targets in developing therapeutic interventions for chemotherapy-induced mucositis, and cyclooxygenase (COX)-2 inhibition may also be beneficial in reducing the severity and duration. This review focuses on the pathobiology of chemotherapy-induced oral and gastrointestinal mucositis and recent research examining the role of agents with anti-inflammatory activity in treatment and prevention of the condition. We consider agents in clinical use as well as some others under current investigation including plant-derived and other natural medicines.

Novel 5-methyl-2-phenylphenanthridium derivatives as FtsZ-targeting antibacterial agents from structural simplification of natural product sanguinarine.

A novel series of 5-methyl-2-phenylphenanthridium derivatives were displayed outstanding activity against a panel of antibiotic-sensitive and -resistant bacteria strains compared with their precursor sanguinarine, ciprofloxacin and oxacillin sodium. Compounds 7 l, 7m and 7n were found to display the most effective activity against five sensitive strains (0.06-2 µg/mL) and three resistant strains (0.25-4 µg/mL). The kinetic profiles indicated that compound 7l possessed the strongest bactericidal effect on S. aureus ATCC25923, with the MBC value of 16 µg/mL. The cell morphology and the FtsZ polymerization assays indicated that these compounds inhibited the bacterial proliferation by interfering the function of bacterial FtsZ. The SARs showed that all the 4-methyl-substituted 5-methyl-2-phenylphenanthridium subseries could be further investigated as the FtsZ-targeting antibacterial agents.