Fenton's oxidation: a tool for the investigation of potential drug metabolites.

Within the scope of searching for new lead structures in the field of anti-infectives, we ascertained Fenton's reagent to be an easy-to-handle and non-expensive tool for screening the metabolic profile of new bioactive compounds. The underlying chemistry of the Fenton's one-electron oxidation is comparable to that of cytochrome P450, which is the main metabolism enzyme. To study the metabolic screening capability, we subjected different antibiotics and the antiplasmodial naphthylisoquinoline alkaloid dioncophylline A to Fenton's reagent and examined the obtained compound libraries by liquid chromatography/tandem mass spectrometry (LC-MS/MS). For ciprofloxacin and linezolid about half of literature-known metabolites were identified as products of Fenton's oxidation. For dioncophylline A six new possible metabolites were discovered.

Targeting acetylcholinesterase to treat neurodegeneration.

Neurodegenerative disorders, such as Alzheimer's disease, are often characterised by the degeneration of the cholinergic system. Thus, the aim of many treatment regimens is to support this system either by means of muscarinic agonists or by inhibitors of acetylcholinesterase (AChE), the latter being able to increase the concentration of acetylcholine. However, both pharmacological groups of drugs can only help in the beginning of the progressive disease. The finding that the occupation of the peripheral anionic site of AChE is able to stop the formation of the amyloid plaque led to the development of bivalent ligands that occupy both the active and the peripheral site. This dual action might be more beneficial for treatment of Alzheimer s disease than simple inhibition of the acetylcholine hydrolysis. Thus, the new bivalent ligands are the focus of this review.

Random chemistry as a new tool for the generation of small-compound libraries.

Advances in modern medicinal chemistry have enabled scientists to engineer new pathways aiming at the generation of novel chemical entities. Random chemistry, the serendipitous synthesis of small-compound libraries by gamma-irradiation of a highly active lead compound or pharmacophoric fragments of active compounds, represents a complementary methodology, which provides both, compounds with resembling molecular structure and rearranged structures not previously known. Since the libraries are likely to be derived from radical chemistry, Fenton's reagent was applied to a methanol/water solution of tacrine to mimic the irradiation. Indeed, the experiment resulted in a similar product spectrum as found for tacrine in water and methanol solutions after (60)Co irradiation. However, the application of Fenton's reagent is limited due to its poor solubility in organic solvents. Since the drugs we are aiming for should exhibit high water solubility, this limitation can be regarded as an advantage at the same time. Further extension of the random chemistry approach led to the successful irradiation of non-active but drugable single fragments and combinations of fragments, i.e. the irradiation of tetrahydroisoquinoline and benzylamine, both being fragments of naphthylisoquinolines with antiplasmodial activity. The obtained isoquinoline derivatives were found to exhibit anti-infective activities and thus are promising new lead structures.