Search for dual function inhibitors for Alzheimer's disease: synthesis and biological activity of acetylcholinesterase inhibitors of pyridinium-type and their Abeta fibril formation inhibition capacity.

Alzheimer's disease (AD) represents the most common neurodegenerative disorder, which is expressed through decline of mental function. Current treatment approaches include acetylcholinesterase inhibitors and NMDA-receptor partial antagonists. The most explored recent approaches that are closely related to the pathogenesis of this disease based on formally articulated amyloid hypothesis are: Abeta fibril formation inhibitors, amyloid precursor protein, and secretase inhibitors. [Scarpini, E.; Scheltens, P.; Feldman, H. Lancet Neurol.2003, 2, 539] In view of the development of new AChE inhibitors as drugs capable of reducing the symptoms of AD, the capacity of newly synthesized AChE inhibitors of pyridinium-type to inhibit the AChE was examined and compared to those of other inhibitors of this type presented earlier. [Kapková, P.; Stiefl, N.; Sürig, U.; Engels, B.; Baumann, K.; Holzgrabe, U. Arch. Pharm. Pharm. Med. Chem.2003, 336, 523; Alptüzun, V.; Kapková, P.; Baumann, K.; Erciyas, E.; Holzgrabe, U. J. Pharm. Pharmacol.2003, 55, 1397] Furthermore, the anti-Abeta fibril formation property of AChE inhibitors of pyridinium- and bispyridinium-type was evaluated to expand their activity profile and to reveal potential additive pharmacological effects which may reinforce their therapeutic application besides their capacity of increasing acetylcholine levels. Abeta fibril formation studies were performed by means of thioflavin T fluorescence assay.