Carbon—hydrogen spin—spin coupling constants

An oxetane can trigger profound changes in aqueous solubility, lipophilicity, metabolic stability, and conformational preference when replacing commonly employed functionalities such as gem-dimethyl or carbonyl groups. The magnitude of these changes depends on the structural context. Thus, by substitution of a gem-dimethyl group with an oxetane, aqueous solubility may increase by a factor of 4 to more than 4000 while reducing the rate of metabolic degradation in most cases. The incorporation of an oxetane into an aliphatic chain can cause conformational changes favoring synclinal rather than antiplanar arrangements of the chain. Additionally spirocyclic oxetanes (e.g., 2-oxa-6-aza-spiro[3.3]heptane) bear remarkable analogies to commonly used fragments in drug discovery, such as morpholine, and are even able to supplant the latter in its solubilizing ability. A rich chemistry of oxetan-3-one and derived Michael acceptors provide venues for the preparation of a broad variety of novel oxetanes not previously...

Oxetanes in Drug Discovery: Structural and Synthetic Insights

Twelve 4- and 5-nitroimidazole derivatives, including metronidazole and two of its metabolites, tinidazole, dimetridazole, and nimorazole, were tested for antitrichomonad action on Tritrichomonas foetus (KV(1)) and Trichomonas vaginalis (ATCC 30001) for mutagenicity on a nitroreductase-positive (TA 100) and a nitroreductase-deficient (TA 100-FR(1)) strain of Salmonella typhimurium, as well as for the reducibility of the nitro group by T. foetus homogenates. Compounds with activity <1% of that of metronidazole are regarded as inactive. All antitrichomonad compounds induce mutations and can be reduced. S. typhimurium TA 100 gave mutations under both aerobiosis and anaerobiosis; TA 100-FR(1), however, gave mutations only under anaerobiosis. Certain compounds that are reducible, and the nonreducible derivatives, were inactive. Metronidazole and its inactive 4-nitro analogue were reduced in a four-electron process in ferredoxin- or methyl viologen-mediated reactions with the same velocity. The results underscore the role of the reduction of the nitro group in the antitrichomonad and in the mutagenic activity of nitroimidazoles.

Antitrichomonad Action, Mutagenicity, and Reduction of Metronidazole and Other Nitroimidazoles

Metronidazole was first introduced for the treatment of trichomoniasis. Its therapeutic use has subsequently been expanded to include amoebiasis, giardiasis and, more recently, anaerobic infections. Most of the early pharmacokinetic studies employed nonspecific assays such as microbiological and chemical assays. These assays were not able to differentiate the parent drug from the metabolites or other interfering substances. Pharmacokinetic data obtained through the use of specific Chromatographic techniques provide the basis for this review of recent pharmacokinetic findings concerning metronidazole and other nitroimidazole antibiotics. When given intravenously or orally at usual recommended doses, metronidazole attains concentrations well above the minimum inhibitory concentrations for most susceptible micro-organisms. The drug has an oral bioavailability approaching 100%. Rectal and vaginal administration results in a smaller amount of drug absorption and lower serum concentrations. Metronidazole has limited plasma protein binding but can attain very favourable tissue distribution, including into the central nervous system. The drug is extensively metabolised by the liver to form 2 primary oxidative metabolites: the hydroxy and acetic acid metabolites. The kidney is responsible for the elimination of only a small amount of the parent drug; however, normal excretion of the 2 metabolites is dependent on the integrity of kidney function. The metabolism of metronidazole was found to vary among patient groups. Preterm and term infants have lower total body clearance (CL) and prolonged elimination half-lives. However, children older than 4 years old were observed to have pharmacokinetic parameters similar to those in adults. Reduced CL was also observed in children who are malnourished. Elderly patients have reduced renal excretion of both the parent drug and hydroxy metabolite. Pharmacokinetic parameters in pregnant patients were not significantly different from those in nonpregnant women; however, the drug is distributed into breastmilk and the infant will be exposed to the drug through the nursing mother. Patients undergoing gastrointestinal surgery or having enteric diseases and those who are hospitalised or critically ill also have altered pharmacokinetics. Metabolism of the drug is reduced in patients with liver dysfunction, giving delayed production of metabolites. In contrast, renal failure has little effect on the elimination of the parent drug, but affects the excretion of the metabolites more significantly. Haemodialysis was found to remove a substantial amount of the metronidazole while the effect of peritoneal dialysis was more limited. Energy and protein deficient diets as well as occupational exposure to gasoline did not alter metronidazole pharmacokinetics. However, the effect of alcohol consumption on metronidazole CL requires further study. Drug interactions with warfarin, alcohol, disulfiram, phenytoin, lithium, phenobarbital, phenazone (antipyrine), prednisone, rifampicin, antacids and cholestyramine have been reported. No significant change in pharmacokinetics was observed with concurrent administration of theophylline, alprazolam, lorazepam, diazepam, ciprofloxacin or sulfasalazine. Studies conducted with cimetidine revealed varied findings. Metronidazole is generally well tolerated when administered in dosages of <2g per day. Some adverse reactions, such as gastrointestinal effects, neutropenia, neuropathies and certain central nervous system effects, appear to be related to the dosage and treatment duration. On the basis of the available data on metronidazole pharmacokinetics and microbiology, the traditional dosage recommendation of 500mg every 6h is more than adequate to treat most anaerobic infections. In fact, a regimen of 500mg every 8h can be expected to maintain serum concentrations above the minimum inhibitory concentrations of susceptible anaerobic organisms. Alternatively, once-daily administration has also been suggested. There is also some recent evidence to support a postantibiotic effect of metronidazole on certain anaerobic bacteria. The pharmacokinetics of other nitroimidazole derivatives are similar to those of metronidazole. They all have good oral absorption, and extensive hepatic metabolism and tissue distribution. The elimination half-lives of most of the derivatives are longer than that of metronidazole with the exception of nimorazole. Side effects of the derivatives are generally mild and they are usually well tolerated by patients. One notable exception is misonidazole; its use is often limited by frequent peripheral neuropathy.

Clinical pharmacokinetics of metronidazole and other nitroimidazole anti-infectives.

The mechanism of aerobic oxidation of aromatic and alkyl aromatic compounds using anthracene and xanthene, respectively, as a model compound was investigated using a phosphovanadomolybdate polyoxometalate, H5PV2Mo10O40, as catalyst under mild, liquid-phase conditions. The polyoxometalate is a soluble analogue of insoluble mixed-metal oxides often used for high-temperature gas-phase heterogeneous oxidation which proceed by a Mars−van Krevelen mechanism. The general purpose of the present investigation was to prove that a Mars−van Krevelen mechanism is possible also in liquid-phase, homogeneous oxidation reactions. First, the oxygen transfer from H5PV2Mo10O40 to the hydrocarbons was studied using various techniques to show that commonly observed liquid-phase oxidation mechanisms, autoxidation, and oxidative nucleophilic substitution were not occurring in this case. Techniques used included (a) use of 18O-labeled molecular oxygen, polyoxometalate, and water; (b) carrying out reactions under anaerobic conditi...

Electron and Oxygen Transfer in Polyoxometalate, H5PV2Mo10O40, Catalyzed Oxidation of Aromatic and Alkyl Aromatic Compounds: Evidence for Aerobic Mars−van Krevelen-Type Reactions in the Liquid Homogeneous Phase

1. New halogenated 1,4-naphthoquinones were synthesized and together with other known 1,4-naphthoquinones, were screened for antibacterial activity by a turbidimetric method, and for antifungal activity by the diffusion method on agar plates.

2. The half-wave potentials and the influence on the oxidative phosphorylation of some of these compounds were determined.

3. 2-chloro-3,2′-chloro-ethyl-1,4-naphthoquinone (half-wave potential=-187 mV) was the most active compound, completely inhibiting cell respiration.

4. While the natural active naphthoquinones, vitamin K and ubiquinones, possess, as substituent, the electron repelling methyl group, the microbiologically active 1,4-naphthoquinones are substituted, in the quinone moiety, with electron attracting groups such as OH or Cl.

5. The half-wave potentials can give only an initial indication of the activity of the compounds studied; a good correlation, on the contrary, can be found between the ultraviolet spectra of such compounds and their activity which seems to depend on the ability of active compounds to exist in an extensively conjugated structure and to form hydrogen bonds.

E. Dradi

Papers

Studies on the antibacterial and antifungal properties of 1,4-naphthoquinones.

Studies on antiprotozoans. 3. Isolation, identification and quantitative determination in humans of the metabolites of a new trichomonacidal agent.

Proton and carbon-13 nuclear magnetic resonance spectra of heteroaromatic carbocations. Xanthylium ions

New analgesic-anti-inflammatory drugs. 1-Oxo-2-substituted isoindoline derivatives.

Synthesis and reactions of a new benzoxadiazocine structure