Nontypeable Haemophilus influenzae (NTHi), an important human respiratory pathogen, frequently causes biofilm infections. Currently, resistance of bacteria within the biofilm to conventional antimicrobials poses a major obstacle to effective medical treatment on a global scale. Novel agents that are effective against NTHi biofilm are therefore urgently required. In this study, a series of natural and synthetic chalcones with various chemical substituents were evaluated in vitro for their antibiofilm activities against strong biofilm-forming strains of NTHi. Of the test chalcones, 3-hydroxychalcone (chalcone 8) exhibited the most potent inhibitory activity, its mean minimum biofilm inhibitory concentration (MBIC 50 ) being 16 mg/mL (71.35 mM), or approximately sixfold more active than the reference drug, azithromycin (MBIC 50 419.68 mM). The inhibitory activity of chalcone 8, which is a chemically modified chalcone, appeared to be superior to those of the natural chalcones tested. Significantly, chalcone 8 inhibited biofilm formation by all studied NTHi strains, indicating that the antibiofilm activities of this compound occur across multiple strong-biofilm forming NTHi isolates of different clinical origins. According to antimicrobial and growth curve assays, chalcone 8 at concentrations that decreased biofilm formation did not affect growth of NTHi, suggesting the biofilm inhibitory effect of chalcone 8 is non-antimicrobial. In terms of structureactivity relationship, the possible substituent on the chalcone backbone required for antibiofilm activity is discussed. These findings indicate that 3-hydroxychalcone (chalcone 8) has powerful antibiofilm activity and suggest the potential application of chalcone 8 as a new therapeutic agent for control of NTHi biofilm-associated infections.Key words biofilm formation, chalcone, nontypeable Haemophilus influenzae, strong-biofilm producing strain.Nontypeable Haemophilus influenzae is one of the commonest human respiratory pathogens that cause a spectrum of mild (otitis media, sinusitis) to severe (bronchitis, chronic obstructive pulmonary disease, septicemia, meningitis) illnesses. Substantial morbidity, mortality and socioeconomic burden caused by this microorganism are of enormous concern globally (1-3). There is both in vitro and in vivo evidence that NTHi forms biofilm (4, 5). Biofilm infections are notoriously difficult to eradicate because of their resistance to antibiotics and host immune-mediated clearance (6-8). Communal bacteria in a biofilm are upward of 1000-times more resistant to conventional antibiotic treatment than the same organism growing planktonically (9). Usual clinical dosages of antibiotics may therefore fail to adequately clear infections, allowing bacteria to recover, List of Abbreviations: BFI, biofilm forming index; HTM, haemophilus test medium; MBIC, minimum biofilm inhibitory concentration; MIC, minimum inhibitory concentration; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NTHi, nontypeable Haemophilus influenz...
A new ajmaline-type alkaloid, 21-O-methylisoajmaline (1), together with twenty-one known compounds, a mixture of -sitosterol (2) and stigmasterol (3), reserpinine (4), tetrahydroalstonine (5), reserpine (6), venoterpine (7), yohimbine (8), 6'-O-(3,4,5-trimethoxybenzoyl)glomeratose A (9), isoajmaline (10), 3-epi--yohimbine (11), methyl 3,4,5-trimethoxy-trans-cinnamate (12), a mixture of -sitosterol 3-O--D-glucopyranoside (13) and stigmasterol 3-O--Dglucopyranoside (14), rescidine (15), 7-deoxyloganic acid (16), ajmaline (17), suaveoline (18), (+)-tetraphyllicine (19), loganic acid (20), 3-hydroxysarpagine (21), and sarpagine (22), were isolated from the roots of Rauvolfia serpentina. Their structures were elucidated by spectroscopic data analysis and comparison with literature data. Compounds 11, 12 and 15 were for the first time identified from the genus Rauvolfia and 5, 7, 11, 12, 15, 18 and 22 were found from R. serpentina for the first time. Compound 11 showed moderate anticholinesterase activity with IC 50 value of 15.58 M, whereas 6 exhibited strong vasorelaxant activity with the EC 50 value of 0.05 M.
A new ent-abietane lactone, 3-oxojolkinolide A (1), together with 16 known compounds, helioscopinolide E (2), helioscopinolide A (3), 3-methyl-9H-carbazole (4), carbalexin (5), carbalexin B (6), glycaborinine (7), arborinine (8), 1H-indole-3-carbaldehyde (9), glycoamide A (10), glycoamide B (11), 2-(N-methyl-2-phenylacetamido)benzoic acid (12), 2-(methylamine)-methylbenzoate (13), fraxidin (14), scopoletin ( 15), (-)-syringaresinol ( 16) and ferulic acid (17) were isolated from Glycosmis pentaphylla. The structures of these compounds were elucidated using spectroscopic techniques such as NMR and MS. Among them, compounds 1-3, 9 and 12-17 were isolated from the genus Glycosmis for the first time.
α-Glucosyl triazoles have rarely been tested as α-glucosidase inhibitors, partly due to inefficient synthesis of their precursor α-d-glucosylazide (αGA1). Glycosynthase enzymes, made by nucleophile mutations of retaining β-glucosidases, produce αGA1 in chemical rescue experiments. Thermoanaerobacterium xylanolyticus glucosyl hydrolase 116 β-glucosidase (TxGH116) E441G nucleophile mutant catalyzed synthesis of αGA1 from sodium azide and pNP-β-d-glucoside (pNPGlc) or cellobiose in aqueous medium at 45 °C. The pNPGlc and azide reaction product was purified by Sephadex LH-20 column chromatography to yield 280 mg of pure αGA1 (68% yield). αGA1 was successfully conjugated with alkynes attached to different functional groups, including aryl, ether, amine, amide, ester, alcohol, and flavone via copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry reactions. These reactions afforded the 1,4-substituted 1,2,3-triazole-α-d-glucoside derivatives AGT2-14 without protection and deprotection. Several of these glucosyl triazoles exhibited strong inhibition of human lysosomal α-glucosidase, with IC50 values for AGT4 and AGT14 more than 60-fold lower than that of the commercial α-glucosidase inhibitor acarbose.
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