The development and evaluation of a microstill with conductance detection for low level ammonia monitoring in chloraminated water.

Monitoring low levels of ammonia in chloraminated water can be challenging but is important for effectively managing potable water disinfection. The lower the concentration of free ammonia that can be determined, the tighter the control at the disinfection point, which supports better maintenance of chloramine residuals in the distribution system. In this study a micro-distillation technique was used to selectively separate ammonia into a boric acid solution allowing determination by conductance (i.e., micro-distillation and conductance measurement instrument - Micro-DCMI). The optimised technique had a linear calibration range of 0.01-60 mg NH3 L-1 with a limit of detection (LOD) of 0.014 mg L-1 and limit of quantification (LOQ) of 0.045 mg L-1. With the optimum operational parameters of 80 °C distillation temperature, 0.3 L min-1 air flow rate, 0.1 mol L-1 boric acid concentration and 8 min pre-concentration time, a sample throughput of 7 samples per hour was achieved. A laboratory comparison between Micro-DCMI and the standard ammonia selective electrode method was conducted on water samples obtained from a chloraminated drinking water distribution system. The results showed that the ratios of the free ammonia values determined by Micro-DCMI and an ammonia selective electrode were between 0.82 and 1.2 for 11 water samples. A custom-built automated analytical system was evaluated at a water treatment plant in Australia and the results compared favourably with the in plant online ammonia ion selective analyser. This study indicated that the Micro-DCMI method was a simple, robust and low cost online monitoring system suitable for determining low concentration ammonia to manage chloramination.

Synthesis of N-alkyl glycine amides as potent inhibitors of leukotriene A4 hydrolase.

The synthesis and biological evaluation of a series of N-alkyl glycine amide analogs as LTA(4)-h inhibitors and the importance of the introduction of a benzoic acid group to the potency and pharmacokinetic parameters of our analogs are described. The lead compound in the series, 4q, has excellent potency and oral bioavailability.

Rapid microstill determination of free and total sulfite in wine with conductimetric detection.

The development and optimization of on-line microdistillation for free and total sulfite (S(IV)) in grape juice and wine is reported. The microstill used both heat and an air stream to separate sulfur dioxide from the wine samples; the distillation product was captured in a peroxide solution, and converted to sulfuric acid, mirroring accepted industry practice. Measured from 1 to 300 mgL(-1) as SO(2) by conductance, sample throughputs of 60 h(-1) for free and 20 h(-1) for total sulfite were achieved. Data for bound S(IV) emphasises the slow kinetics of release reactions in some wines. The microstill method is more efficient for total sulfite than the accepted manual technique. Good correlation was found between the microstill and manual methods under specified control conditions.

The rational design of inhibitors of nitric oxide formation by inducible nitric oxide synthase.

A series of compounds was rationally designed as inhibitors of dimer formation of the inducible isoform of nitric oxide synthase, and subsequent nitric oxide production. The conformation of two fragments obtained from a crystal structure was utilized to design a tether connecting those same two fragments. The resulting compounds were potent dimerization inhibitors that bound to the enzyme in a similar conformation as the fragments.

1-(1,3-Benzodioxol-5-ylmethyl)-3-[4-(1H-imidazol-1-yl)phenoxy]-piperidine analogs as potent and selective inhibitors of nitric oxide formation.

A new series of 1-(1,3-benzodioxol-5-ylmethyl)-3-[4-(1H-Imidazol-1-yl)phenoxy]-piperidine analogs were designed and identified as potent and selective inhibitors of NO formation based both on the crystal structure of a murine iNOS Delta114 monomer domain/ inhibitor complex and inhibition of the NO formation in human A172 cell assays. Compound 12S showed high potency and high iNOS selectivity versus nNOS and eNOS.

Design, synthesis, and activity of 2-imidazol-1-ylpyrimidine derived inducible nitric oxide synthase dimerization inhibitors.

By the screening of a combinatorial library for inhibitors of nitric oxide (NO) formation by the inducible isoform of nitric oxide synthase (iNOS) using a whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were found to inhibit the dimerization of iNOS monomers, thus preventing the formation of the dimeric, active form of the enzyme. Optimization led to the selection of the potent, selective, and orally available iNOS dimerization inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a rat model. Analysis of the crystal structure of the 21b--iNOS monomer complex provided a rationalization for both the SAR and the mechanism by which 21b blocks the formation of the protein--protein interaction present in the dimeric form of iNOS.

Arsenic speciation and toxicity in biological systems.

Although it is now commonly accepted that toxicity and bioavailability varies with As species, extensive research has been carried out on biological and environmental samples to assess toxicity and risk associated with As exposure based on total concentrations that may be in error. The health investigation guideline for the Australian environmental protection measure is 100 mg/kg (As(tot)), which would cause potential risk to human health if all the As present in a sample were bioavailable (ANZECC 1992). Similarly, the MPC for As in food is 1 mg/ kg (fresh weight), but this concentration may include contributions from As(III), AsV, and all organic species. Thus, a food substance, such as seafood, could have a high total concentration exceeding the guidelines, but most of the As would be in forms that are nontoxic to humans; i.e., the bioavailability is low, and the food would therefore be perfectly safe to eat. On the other hand, a food that has high bioavailability of As consequently is more toxic. Overall, it appears that contamination of water by As is probably more harmful to humans than As in food grains or vegetables, because As bioavailability in water is generally higher than its bioavailability in food. Nevertheless, As in food crops could make significant contribution toward total daily intake. Therefore, failure to consider the contribution of As species on their bioavailability could introduce a substantial bias into the estimation of risks associated with exposure as well as evaluation of As toxicity. In conclusion, As must be regarded as an important environmental toxicant because of its acute and chronic toxic properties and extensive presence in the environment. Much remains to be learned about its toxicology and biochemistry for better understanding of this important contaminant.

Speciation of arsenic in ground water samples: A comparative study of CE-UV, HG-AAS and LC-ICP-MS.

The performance of capillary electrophoresis-ultraviolet detector (CE-UV), hydride generation-atomic absorption spectrometry (HG-AAS) and liquid chromatography-inductively coupled plasma mass spectrometry (LC-ICP-MS) have been compared for the speciation of arsenic (As) in groundwater samples. Two inorganic As species, arsenite (As(III)), arsenate (As(V)) and one organo species dimethyl arsenic acid (DMA) were mainly considered for this study as these are known to be predominant in water. Under optimal analytical conditions, limits of detection (LD) ranging from 0.10 (As(III), AsT) to 0.19 (DMA) mug/l for HG-AAS, 100 (As(III), DMA) to 500 (As(V)) mug/l for CE-UV and 0.1 (DMA, MMA) to 0.2 (As(III), As(V)) mug/l for LC-ICP-MS, allowed the determination of the above three species present in these samples. Results obtained by all the three methods are well correlated (r(2)=0.996*** for total As) with the precision of <5% R.S.D. except CE-UV. The effect of interfering ions (e.g. Fe(2+), Fe(3+), SO(4)(2-) and Cl(-)) commonly found in ground water on separation and estimation of As species were studied and corrected for. Spike recovery was tested and found to be 80-110% at 0.5mug/l As standard except CE-UV where only 50% of the analyte was recovered. Comparison of these results shows that LC-ICP-MS is the best choice for routine analysis of As species in ground water samples.

Bromide levels in natural waters: its relationship to levels of both chloride and total dissolved solids and the implications for water treatment.

South Australian freshwaters from a wide variety of environments were analysed for bromide and the results correlated with both chloride and total dissolved solids (TDS) concentrations. A linear relationship was obtained which allows chloride data to be successfully used to estimate bromide concentrations. Bromide displayed a slightly better correlation with TDS indicating that an improved estimate of bromide could be made by reference to TDS data which is more easily and commonly obtained, and generally available extensively as historical data. The bromide content in relation to its ratio with both chloride and TDS contents was around seventy percent of the corresponding ratios found in seawater, a finding reported in other published data. The ability to estimate bromide concentrations is a potentially useful tool in the drinking water industry as it enables the assessment of the extent of bromate formation (predicted through the use of mathematical models and other water quality data) which is an important factor when ozonation is being considered as a treatment option, particularly as many water industry regulatory bodies have imposed stringent limits on the levels of acceptable bromate.

Novel 3-oxa lipoxin A4 analogues with enhanced chemical and metabolic stability have anti-inflammatory activity in vivo.

Lipoxin A(4) (LXA(4)) is a structurally and functionally distinct natural product called an eicosanoid, which displays immunomodulatory and anti-inflammatory activity but is rapidly metabolized to inactive catabolites in vivo. A previously described analogue of LXA(4), methyl (5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate (2, ATLa), was shown to have a poor pharmacokinetic profile after both oral and intravenous administration, as well as sensitivity to acid and light. The chemical stability of the corresponding E,E,E-trien-11-yne analogue, 3, was improved over 2 without loss of efficacy in the mouse air pouch model of inflammation. Careful analysis of the plasma samples from the pharmacokinetic assays for both 2 and 3 identified a previously undetected metabolite, which is consistent with metabolism by beta-oxidation. The formation of the oxidative metabolites was eliminated with the corresponding 3-oxatetraene, 4, and the 3-oxatrien-11-yne, 5, analogues of 2. Evaluation of 3-oxa analogues 4 and 5 in calcium ionophore-induced acute skin inflammation model demonstrated similar topical potency and efficacy compared to 2. The 3-oxatrien-11-yne analogue, 5, is equipotent to 2 in an animal model of inflammation but has enhanced metabolic and chemical stability and a greatly improved pharmacokinetic profile.

Structure-activity relationships of substituted benzothiophene-anthranilamide factor Xa inhibitors.

Compound 1 was identified by high throughput screening as a novel, potent, non-amidine factor Xa inhibitor with good selectivity against thrombin and trypsin. A series of modifications of the three aromatic groups of 1 was investigated. Substitution of chlorine or bromine for fluorine on the aniline ring led to the discovery of subnanomolar factor Xa inhibitors. Positions on the anthranilic acid ring that can accommodate further substitution were also identified.

Design, synthesis, and activity of a novel series of factor Xa inhibitors: optimization of arylamidine groups.

A novel series of diaryloxypyridines have been designed as selective nanomolar factor Xa (fXa) inhibitors for use as anticoagulants. In this paper, we describe our efforts to identify an additional interaction and a replacement for the distal amidine group that binds in the S3/S4 pocket of fXa. Introduction of a hydroxyl group para to the proximal amidine group increases the potency vs fXa by 1-2 orders of magnitude, which is the result of a hydrogen bond to Ser195 of the catalytic triad. A methyl imidazoline and a dimethylamide are good alternatives for the second amidine. These substitutions have increased the selectivity vs the related serine proteases trypsin and thrombin. The synthesis, in vitro activity, and hypothetical modes of binding to fXa based on trypsin crystallographic data are outlined.