Poly(malic acid) Nanoconjugates of Pyrazinoic Acid for Lung Delivery in the Treatment of Tuberculosis.

Tuberculosis (TB) remains a major global infection, and TB treatments could be improved by site-specific targeting with delivery systems that allow tissue and cell uptake. To increase the drug concentration at the target sites following lung delivery, polymeric nanoconjugates based on biodegradable poly(malic acid) were designed. Pyrazinoic acid (POA), the active moiety of pyrazinamide─a first-line antituberculosis drug─was covalently bound to poly(malic acid) using a hydrophobic linker at mole ratios of 25%, 50%, and 75%. Three linkers, hexanediol, octanediol, and decanediol, were considered. Independently of the linker or ratio, all the conjugates were able to self-assemble, forming nanoconjugates (NCs) in water with 130-190 nm in diameter. Pyrazinoic acid could be released in a controlled manner without any burst release effect. Its kinetics can be adjusted by modifying the grafting ratio and linker length. No cytotoxicity was observed on RAW 264.7 macrophages up to ∼14 µg/mL of POA. In addition, the nanoconjugates were efficiently taken up by these cells over 5 h. Thanks to their high loading capacity and modulable release profiles, these nanoconjugates hold great promise for more effective treatment of tuberculosis.

Unraveling C-Selective Ring-Opening of Phosphiranes with Carboxylic Acids and Other Nucleophiles: A Mechanistically-Driven Approach.

Phosphiranes are weak Lewis bases reacting with only a limited number of electrophiles to produce the corresponding phosphiranium ions. These salts are recognized for their propensity to undergo reactions with oxygen pronucleophiles at the phosphorus site, leading to the formation of phosphine oxide adducts. Building on a thorough mechanistic understanding, we have developed an unprecedented approach that enables the selective reaction of carboxylic acids, and other nucleophiles, at the carbon site of phosphiranes. This method involves the photochemical generation of highly reactive carbenes, which react with 1-mesitylphosphirane to yield ylides. The latter undergoes a stepwise reaction with carboxylic acids, resulting in the production of the desired phosphines. In addition to DFT calculations, we have successfully isolated and fully characterized the key intermediates involved in the reaction.

Transition Metal-Free Regioselective Phosphonation of Pyridines: Scope and Mechanism.

Regioselective phosphonation of pyridines is an interesting transformation in synthesis and medicinal chemistry. We report herein a metal-free approach enabling access to various 4-phosphonated pyridines. The method consists of simply activating the pyridine ring with a Lewis acid (BF3·OEt2) to facilitate the nucleophilic addition of a phosphine oxide anion. The formed sigma complex is subsequently oxidized with an organic oxidant (chloranil) to yield the desired adducts in good to excellent yields. We furthermore showed that access to C2-phosphoinated pyridines can be achieved in certain cases with strong Lewis basic phosphorus nucleophiles or with strong Lewis acidic pyridines. Both experimental and computational mechanistic investigations were undertaken and allowed us to understand the factors controlling the reactivity and selectivity of this reaction.

Chemical Composition and Biological Activities of Essential Oils of Four Asarum Species Growing in Vietnam.

The essential oils (EOs) of the aerial parts of four Asarum species (A. geophilum, A. yentunensis, A. splendens and A. cordifolium) were isolated by steam distillation and analyzed by the GC/MS method. The A. cordifolium EO contains 33 constituents with the main component being elemicine (77.20%). The A. geophilum EO was contains 49 constituents with the main components being determined as 9-epi-(E)-caryophyllene (18.43%), eudesm-7(11)-en-4-ol (13.41%), ß-caryophyllene (8.05%) and phytol (7.23%). The A. yentunensis EO contains 26 constituents with the main components being safrole (64.74%) and sesquicineole (15.34%). The EO of A. splendens contains 41 constituents with the main components being 9-epi-(E)-caryophyllene (15.76%), eudesm-7(11)-en-4-ol (14.21%), ß-caryophyllene (9.52%) and trans-bicyclogermacrene (7.50%). For antimicrobial activity, the A. yentunensis EO exhibited the highest inhibition activity against Staphylococcus aureus and the A. cordifolium EO against Bacillus subtillis (MIC values of 100 µg/mL). For antioxidant activity, the A. geophilum EO showed the highest potential with an SC (%) value of 63.34 ± 1.0%, corresponding to an SC50 value of 28.57 µg/mL. For anti-inflammatory activity, the A. splendens EO exhibited the highest potential with an IC50 value of 21.68 µg/mL, corresponding to an inhibition rate of NO production of 69.58 ± 1.3% and the percentage of cell life was 81.85 ± 0.9%.

Facile iodine-promoted synthesis of bis(1-imidazo[1,5-a]pyridyl)arylmethanes and exploration of applications.

A practical strategy for the iodine-promoted synthesis of bis(1-imidazo[1,5-a]pyridyl)arylmethane and its derivatives has been developed. These compounds exhibit high cytotoxicity toward various cancer cell lines and moreover they are promising ligands for the Cu-catalysed synthesis of quinolines.

Regulation of NF-κB- and STAT1-mediated plasmacytoid dendritic cell functions by A20.

Dendritic cells (DCs) are professional antigen presenting cells involved in the induction of T cell-mediated adaptive immunity. Plasmacytoid DCs (pDCs) originate from lymphoid precursors and produce type I interferons (IFNs) in response to pathogens. A20 is considered as a negative regulator of toll-like receptor (TLR) signaling pathways, in which Toxoplasma gondii- derived profilin (TgPRF) is a TLR11/12 ligand recognised by DCs to stimulate their maturation/activation. Little is known about contributions of A20 to changes in biological properties of pDCs. The present study, therefore, explored whether pDC functions are influenced by A20. To this end, bone marrow cells were isolated and cultured with Flt3L to attain CD8DCs, CD11bDCs and pDCs and followed by challenge with TgPRP in the presence or absence of A20 siRNA. Expression of maturation markers were analysed by flow cytometry, and secretion of inflammatory cytokines by ELISA, cell migration by a transwell migration assay and expression of signalling molecules by western blotting. As a result, treatment with A20 siRNA enhanced activations of IκB-α and STAT-1, leading to increases in expressions of maturation markers and cytokine productions as well as migration of TgPRP-treated pDCs, while mature CD11bDCs produced at higher levels of TNF-α and IL-6 only. In addition, functions of CD8DCs remained unaltered following A20 silencing. The effects of A20 on pDC maturation and activation were completely abolished by IKK inhibitor and partially blunted by fludarabine. In conclusion, the inhibitory effects of A20 on pDC functions are expected to affect the immune response in T. gondii infection.

The epidemiology and aetiology of diarrhoeal disease in infancy in southern Vietnam: a birth cohort study.

OBJECTIVES: Previous studies indicate a high burden of diarrhoeal disease in Vietnamese children, however longitudinal community-based data on burden and aetiology are limited. The findings from a large, prospective cohort study of diarrhoeal disease in infants in southern Vietnam are presented herein. METHODS: Infants were enrolled at birth in urban Ho Chi Minh City and a semi-rural district in southern Vietnam, and followed for 12 months (n=6706). Diarrhoeal illness episodes were identified through clinic-based passive surveillance, hospital admissions, and self-reports. RESULTS: The minimum incidence of diarrhoeal illness in the first year of life was 271/1000 infant-years of observation for the whole cohort. Rotavirus was the most commonly detected pathogen (50% of positive samples), followed by norovirus (24%), Campylobacter (20%), Salmonella (18%), and Shigella (16%). Repeat infections were identified in 9% of infants infected with rotavirus, norovirus, Shigella, or Campylobacter, and 13% of those with Salmonella infections. CONCLUSIONS: The minimum incidence of diarrhoeal disease in infants in both urban and semi-rural settings in southern Vietnam was quantified prospectively. A large proportion of laboratory-diagnosed disease was caused by rotavirus and norovirus. These data highlight the unmet need for a rotavirus vaccine in Vietnam and provide evidence of the previously unrecognized burden of norovirus in infants.

Chemical components from the leaves of Ardisia insularis and their cytotoxic activity.

One new oleanane triterpene glycoside, ardinsuloside (1), and twelve known compounds, demethoxybergenin (2), norbergenin (3), bergenin (4), 4-O-galloylbergenin (5), quercitrin (6), myricitrin (7), myricetin 3-O-(3''-O-galloyl)-α-L-rhamnopyranoside (8), desmanthine-2 (9), epicatechin 3-O-galloyl ester (10), 3'-methoxyepicatechin 3-O-galloyl ester (11), gallic acid (12), and methyl galloate (13) were isolated from the leaves of Ardisia insularis. Their structures were established on the basis of spectral and chemical evidence, which were in agreement with those reported in literature. The cytotoxic activities of these compounds were evaluated on three cancer cell lines namely A-549 (human lung cancer), HT-29 (Human colon adenocarcinoma), and OVCAR (human ovarian carcinoma). The results revealed that compound 1 inhibited A-549, HT-29, and OVCAR cell lines with IC50 values of 8.5 ± 1.2, 16.4 ± 3.1, and 13.6 ± 2.4 µM, respectively. The remaining compound showed weak cytotoxic activity. This result indicated that compound 1 could be useful in the treatment of cancer disease.

Chemical components of Ardisia splendens leaves and their activity against coxsackie A16 viruses.

Using a combination of chromatographic methods, one new flavonol glycoside, myricetin 3,7-di-O-alpha-L-rhamnopyranoside (1), and nine known compounds myricitrin (2), quercetin 3,7-di-O-alpha-L-rhamnopyranoside (3), quercitrin (4), desmanthin-l (5), myricetin 3-O-(3"-O-galloyl)-alpha-L-rhamnopyranoside (6), (+)-catechin (7), benzyl O-1-D-glucopyranoside (8), 2-phenylethyl O-beta-D-glucopyranoside (9), and corilagin (10) were isolated from the leaves of Ardisia splendens Pit. Based on an in vitro test against Coxsackie viruses A16 by SRB assay, only compounds 2, 5, and 10 exhibited activity against Coxsackie viruses A16 with IC50 values of 40.1, 32.2, and 30.5 microM, respectively. This result suggested that compounds 2, 5, and 10 might be potential agents for treating hand, foot and mouth diseases.

Identification of Anopheles minimus complex and related species in Vietnam.

Anopheles minimus A and C and several closely related species of mosquitoes have been identified in Vietnam, where some have been implicated in malaria transmission. Morphological variation within and between Anopheles minimus A and C makes identification using alpha taxonomy difficult and several molecular techniques have been developed to separate them. However the difficulties of applying these techniques and the benefits of morphological identification in the field have seen morphological characteristics, such as the humeral pale spot on the costa, being used to separate these two species. In this study, the morphological and molecular examinations of 2,206 specimens collected in Vietnam indicate that pale scaling on the proboscis reliably separates An. aconitus from An. minimus s.l., but hind tarsal banding cannot separate An. jeyporiensis from An. minimus s.l., and the presence or absence of the humeral pale spot is not a reliable characteristic for differentiating An. minimus A from C due to variation of this characteristic in An. minimus C.