Design and development of new modulators of acetylcholinesterase potentially used in therapy of neurodegenerative disorders and as antidotes in case of poisoning by organophosphorus inhibitors

Acetylcholinesterase (AChE, E.C. 3.1.1.7) is an enzyme that catalyzes the breakdown of acetylcholine (ACh) into choline and acetate. AChE is mainly found at neuromuscular junctions and/or cholinergic synapses in the central nervous system (CNS). Nowadays, a huge number of therapeutic/toxic substances are well-known to block the activity of AChE causing thus ACh accumulation in the synaptic cleft. In pharmacology, AChE inhibitors are mainly used as drugs against Alzheimer's disease (AD). Unfortunately, due to the complexity of the pathophysiology of AD, the pharmacological modulation of a single target - AChE – seems to be insufficient for achieving the desired therapeutic effect. Organophosphorus inhibitors (OP) of AChE represent a group of toxic compounds affecting the activity of AChE in a harmful way. This type of inhibitor is widely used as a pesticide or as a nerve agent (e.g., sarin, soman, tabun). The standard countermeasures against OP poisoning involve inhibition of muscarinic receptors, GABA-ergic potentiation, and administration of an AChE reactivator (oxime). The use of the latter is, however, limited by the (un)versatility of reactivators to different types of OPs and by their low penetration into the brain. This second constraint is a major drawback of the currently used oximes since OPs indeed affect mainly the functioning of the CNS. The aim of the current project is to prepare new centrally active AChE modulators which could find their use in anti-Alzheimer´s disease therapy or as antidotes against nerve agents. The process of designing new compounds will primarily focus on the properties not sufficiently possessed by currently available modulators, i.e., blood-brain barrier penetration in the case of AChE reactivators and/or the multifactorial nature of new anti-Alzheimer´s drugs. The newly designed and synthesized compounds will be subsequently validated by biological screening for their potential within the above-mentioned indications.