New Synthetic Thrombin Inhibitors: Molecular Design and Experimental Verification

BACKGROUND: The development of new anticoagulants is an important goal for the improvement of thromboses treatments. OBJECTIVES: The design, synthesis and experimental testing of new safe and effective small molecule direct thrombin inhibitors for intravenous administration. METHODS: Computer-aided molecular design of new thrombin inhibitors was performed using our original docking program SOL, which is based on the genetic algorithm of global energy minimization in the framework of a Merck Molecular Force Field. This program takes into account the effects of solvent. The designed molecules with the best scoring functions (calculated binding energies) were synthesized and their thrombin inhibitory activity evaluated experimentally in vitro using a chromogenic substrate in a buffer system and using a thrombin generation test in isolated plasma and in vivo using the newly developed model of hemodilution-induced hypercoagulation in rats. The acute toxicities of the most promising new thrombin inhibitors were evaluated in mice, and their stabilities in aqueous solutions were measured. RESULTS: New compounds that are both effective direct thrombin inhibitors (the best K(I) was <1 nM) and strong anticoagulants in plasma (an IC(50) in the thrombin generation assay of approximately 100 nM) were discovered. These compounds contain one of the following new residues as the basic fragment: isothiuronium, 4-aminopyridinium, or 2-aminothiazolinium. LD(50) values for the best new inhibitors ranged from 166.7 to >1111.1 mg/kg. A plasma-substituting solution supplemented with one of the new inhibitors prevented hypercoagulation in the rat model of hemodilution-induced hypercoagulation. Activities of the best new inhibitors in physiological saline (1 µM solutions) were stable after sterilization by autoclaving, and the inhibitors remained stable at long-term storage over more than 1.5 years at room temperature and at 4°C. CONCLUSIONS: The high efficacy, stability and low acute toxicity reveal that the inhibitors that were developed may be promising for potential medical applications

Gas-phase oxidation of alcohols with O2 and N2O catalyzed by Au/TiO2: A comparative study

Gas-phase oxidation of alcohols (EtOH, PrOH, i-PrOH, BuOH) to their carbonyl derivatives was used as test reaction to elucidate the mechanism of a low-temperature catalytic activity of Au/TiO2. The reactions were carried out in the presence of molecular oxygen, nitrous oxide as well as in the absence of the gas-phase oxidants. The relative contribution of oxidative and non-oxidative dehydrogenation pathways was thus estimated. The presence of oxygen in the feed brought about to a double peak profile of catalytic activity as a function of temperature for all the alcohols. The low-temperature peak fells on 120–130 °C. In contrast, the use of N2O as an oxidant gave rise to usual profile of catalytic activity, which is similar to that of anaerobic dehydrogenation of alcohols. The results obtained allowed to suggest the mechanism of the alcohols oxidation. The low temperature peak is probably related to participation of active oxygen species, generated from O2 on the catalyst surface. Oxidation with N2O is interpreted by preliminary dehydrogenation of alcohols to corresponding carbonyl derivatives followed by H2 oxidation

Gas-phase oxidation of alcohols with dioxygen over Au/TiO2 catalyst: The role of reactive oxygen species

The activity of the (3% Au)/TiO2 catalyst with an average gold particle size of 3.6 ± 1.0 nm in the gas-phase oxidation of lower aliphatic alcohols (ethanol, propanol, isopropanol, and butanol) into the corresponding carbonyl compounds (acetaldehyde, propanal, acetone, and butanal) has been studied. A two-peak profile of the activity of the catalyst as a function of temperature has been observed in all of the reactions. The first peak falls within the temperature range from 120 to 130°C, while the complete conversion of the alcohols is achieved at 200–300°C. It is hypothesized that the low-temperature activity is due to the generation of a thermally unstable reactive oxygen species on the catalyst surface

Gas-phase oxidation of alcohols with O2 and N2O catalyzed by Au/TiO2: A comparative study

Gas-phase oxidation of alcohols (EtOH, PrOH, i-PrOH, BuOH) to their carbonyl derivatives was used as test reaction to elucidate the mechanism of a low-temperature catalytic activity of Au/TiO2. The reactions were carried out in the presence of molecular oxygen, nitrous oxide as well as in the absence of the gas-phase oxidants. The relative contribution of oxidative and non-oxidative dehydrogenation pathways was thus estimated. The presence of oxygen in the feed brought about to a double peak profile of catalytic activity as a function of temperature for all the alcohols. The low-temperature peak fells on 120–130 °C. In contrast, the use of N2O as an oxidant gave rise to usual profile of catalytic activity, which is similar to that of anaerobic dehydrogenation of alcohols. The results obtained allowed to suggest the mechanism of the alcohols oxidation. The low temperature peak is probably related to participation of active oxygen species, generated from O2 on the catalyst surface. Oxidation with N2O is interpreted by preliminary dehydrogenation of alcohols to corresponding carbonyl derivatives followed by H2 oxidation

Gas-phase oxidation of alcohols with dioxygen over Au/TiO2 catalyst: The role of reactive oxygen species

The activity of the (3% Au)/TiO2 catalyst with an average gold particle size of 3.6 ± 1.0 nm in the gas-phase oxidation of lower aliphatic alcohols (ethanol, propanol, isopropanol, and butanol) into the corresponding carbonyl compounds (acetaldehyde, propanal, acetone, and butanal) has been studied. A two-peak profile of the activity of the catalyst as a function of temperature has been observed in all of the reactions. The first peak falls within the temperature range from 120 to 130°C, while the complete conversion of the alcohols is achieved at 200–300°C. It is hypothesized that the low-temperature activity is due to the generation of a thermally unstable reactive oxygen species on the catalyst surface