Alzheimer's disease is a chronic progressive neurodegenerative brain disorder. The etiology of this disease is not entirely understood, although it is known that accumulation of amyloid β peptide, protein tau and oxidative stress in the brain cause neuronal death and synaptic loss. This neurodegeneration is most severe in the cholinergic neurotransmitter system and results in a decrease in the levels of the neurotransmitter acetylcholine, which in turn produces memory deficits, characteristic for patients with Alzheimer's disease. Currently, there are no means to cure or prevent Alzheimer's disease, and only four drugs are available to patients for alleviating its symptoms. Cholinesterases acetylcholinesterase and butyrycholinesterase terminate cholinergic neurotransmission in the brain by catalyzing the hydrolysis of acetylcholine. In the healthy brain, acetylcholinesterase accounts for 80% and butyrycholinesterase accounts for 20% of the cholinesterase enzymatic activity. As the disease progresses, enzymatic activity of acetylcholinesterase is reduced, while that of butyrycholinesterase increases. Three out of the four approved drugs for alleviating symptoms of patients with AD are cholinesterase inhibitors: the selective acetycholinesterase inhibitors donepezil and galantamine, and the pseudo-irreversible acetylcholinesterase and butyrycholinesterase inhibitor rivastigmine. These drugs have numerous limitations due to inhibition of acetycholinesterase (adverse side effects due to acetylcholinesterase inhibition in the peripheral nervous system, limited dosing and limited clinical efficacy in advanced stages of the disease) which can be overcome by selectively inhibiting butyrylcholinesterase. We have designed, synthesized and evaluated a comprehensive series of new selective reversible butyrycholinesterase inhibitors: sulfonamide and N-propargypiperidine derivatives of hit compound 1 (IC50 = 21.3 nM) and determined their structure–activity relationships. For preparing key intermediates in the synthesis of designed compounds, we developed a general and simple synthetic procedure. Sulfonamide derivative 2 (IC50 = 4.9 nM) is promising candidate for further preclinical development. This compound is noncytotoxic and protects neuronal cells from toxic amyloid β peptide species. Its inhibits butyrycholinesterase in rat brain slices and partitions into the brains of rats after intraperitoneal injection. Compound 2 and improves memory, cognitive functions, and learning abilities of mice in a disease model of the cholinergic hypofunction in Alzheimer's disease. In the brains of patients with Alzheimer's disease the enzymatic activity of monoamine oxidase B is increased and products formed in the reaction catalyzed by this enzyme contribute to the neurodegeneration. We developed three N-propargypiperidines derivatives of hit compound 1 that inhibit both butyrycholinesterase and monoamine oxidase B. N-propargylpiperidine 6 also has neuroprotective activity and therefore represents a lead compound for design of multitarget-directed ligands against Alzheimer’s disease. In this thesis, we describe the use of structural modifications of hit compound 1 to obtain (i) a promising candidate for further preclinical development, (ii) four crystal structures of complexes of butyrycholinesterase with its inhibitors, (iii) orthogonally protected intermediates for synthesis of new cholinesterase inhibitors, and (iv) lead compounds for design of new multitarget-directed ligands.
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