New bicyclic amines: synthesis and SARs of their action against the causative organisms of malaria and sleeping sickness.

Diaryl-substituted bicyclic amines are a scarcely investigated class of compounds. Only few of them are described and their biological activities are reported poorly. During our work in the field of heterocyclic chemistry, we found that 4-dialkylaminobicyclo[2.2.2]octan-2-ones and -ols show antiprotozoal properties against Plasmodium falciparum K(1) and Trypanosoma brucei rhodesiense, the causative organisms of Malaria tropica and of Human African Trypanosomiasis. Therefore, we synthesized over 200 derivatives in order to investigate their antitrypanosomal and antiplasmodial activities as well as their cyctotoxicity using in vitro microplate assays. Even if the target and the mechanism of action of these compounds are still unknown, we can at least provide several structure-activity relationships for this interesting class of compounds. Moreover, we achieved a distinct improvement of their antiplasmodial and antitrypanosomal properties.

Synthesis of new esters and oximes with 4-aminobicyclo[2.2.2]octane structure and evaluation of their antitrypanosomal and antiplasmodial activities.

New 4-amino-6,7-diphenylbicyclo[2.2.2]octane derivatives, esters of bicyclo[2.2.2]octan-2-ols and O-methyl oximes of bicyclo[2.2.2]octan-2-ones were synthesised. Their activities against Trypanosoma brucei rhodesiense (STIB 900) and their activity against the K1 strain of Plasmodium falciparum (resistant to chloroquine and pyrimethamine) were determined by use of microplate assays. The cytotoxicity was assessed using L6 cells. The antiprotozoal activities of the new compounds are compared with those of former prepared derivatives and drugs in use. Structure-activity relationships are discussed.

Measurement of fractional whole-body gluconeogenesis in humans from blood samples using 2H nuclear magnetic resonance spectroscopy.

Several problems limit quantification of gluconeogenesis. We applied in vitro 2H-nuclear magnetic resonance (NMR) spectroscopy to simultaneously measure 2H in all glucose carbons for direct assessment of gluconeogenesis. This method was compared with 2H measurement in carbons 5 and 2 using gas chromatography-mass spectrometry (hexamethylenetetramine [HMT]) and with in vivo 13C magnetic resonance spectroscopy (MRS). After 14 h of fasting, and following 2H2O ingestion, blood was obtained from nine healthy and seven type 2 diabetic subjects. Glucose was purified, acetylated, and analyzed for 2H in carbons 1-6 with 2H-NMR. Using 5:2 ratios, gluconeogenesis increased (P < 0.05) over time and mean gluconeogenesis was lower in control subjects than in type 2 diabetic patients (63 +/- 3 vs. 75 +/- 2%, P < 0.01). 13C-MRS revealed higher hepatic glycogenolysis in control subjects (3.9 +/- 0.4 vs. 2.3 +/- 0.2 micromol.kg(-1).min(-1)) yielding mean contribution of gluconeogenesis of 65 +/- 3 and 77 +/- 2% (P < 0.005). Measurement of gluconeogenesis by 2H-NMR correlated linearly with 13C-MRS (r = 0.758, P = 0.0007) and HMT (r = 0.759, P = 0.0007). In an additional protocol, 2H enrichments demonstrated a fast decline of gluconeogenesis from approximately 100 to approximately 68% (P < 0.02) within 4 h of galactose infusion after 40-44 h of fasting. Thus, in vitro 2H-NMR offers an alternative approach to determine fractional gluconeogenesis in good agreement with standard methods and allows monitoring of rapid metabolic alterations.

On the degradability of tetrachloroethene in biologically treated wastes.

Investigation on the degradability of tetrachloroethene was performed using fresh and mechanically-biologically pretreated household waste. The corresponding metabolites were determined and the experimental conditions were characterized by the concentrations of methane, organic acids, sulfate and nitrate as well as by pH and redox potential. Furthermore, sorption studies on the substances in different wastes were carried out. With pretreated waste the degradation efficiency was much higher than with fresh waste. On the other hand, the fresh waste showed higher sorption capacity for the chlorinated compounds.