Alzheimer's disease (AD), discovered in 1907, is a chronic progressive neurodegenerative disease that represents 60 – 80 % of all forms of dementia. Most commonly affected are the elderly. It affects 10 % of people after 70 years of age and the percentage increases with age. AD is a complicated disease, which is characterized by many different factors. One of the main factors is the deficiency in levels of neurotransmitter acetylcholine, located in the neurons. In the central nervous system there are two cholinesterases, which are responsible for the decomposition of acetylcholine – acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Although AChE accounts for the majority of decomposed acetylcholine, in AD the significance of BChE rises. With the progression of the disease, the BChE is accountable for bigger and bigger share of decomposed acetylcholine in neurons. Among other important factors are oxidative stress and metal ions. They are responsible for the production of reactive oxygen and nitrogen species, which strongly contributes to the damages in the neurons and to the neurodegeneration. AD is a multifactorial disease, which is almost impossible to successfully treat with only one approach. For successful treatment it is necessary to tackle the disease with a number of different approaches – both pharmacological and nonpharmacological.
The subject of this master thesis is the synthesis and biochemical evaluation of a number of different multifunctional compounds for the treatment of Alzheimer's disease. On the basis of recently discovered inhibitor of BChE, we optimized the structure by variating the substituents on position of piperidin ring.
Compounds 45, 49, 34b and 42 inhibit BChE in the nanomolar range with IC50 value lower than the hit compound (IC50 = 80,0 nM). The most promising inhibitor is compound 45 with IC50 value of 5,58 nM. All synthesized compounds selectively inhibit BChE. Compounds 45 and 44 also showed antioxidant activity, which was evaluated by the DPPH assay. From the results gathered with ThT test we can conclude, that these compounds do not inhibit the aggregation of Aβ1–42. Nonetheless, compound 45 represents a good basis for further development and design of multifunctional compounds for the treatment of Alzheimer’s disease.