Molecular design of O-phosphorylated oximes—Selective inhibitors of butyrylcholinesterase

Abstract

Anticholinesterase compounds, including organophosphorus inhibitors (OPIs), are used to treat glaucoma, schistosomiasis, Alzheimer’s disease, myasthenia gravis, and other diseases. These compounds arealso widely used in agriculture as insecticides and inindustry [1]. The varied use of such compounds isbased on their common mechanism of action, which isassociated with the inhibition of acetylcholinesterase(AChE, EC 3.1.1.7), the biological role of which is thehydrolysis of the key neurotransmitter acetylcholine.In the treatment of Alzheimer’s disease (AD) underconditions of deficiency of central acetylcholine andreduced cholinergic transmission, the inhibition ofAChE in the brain provides cognition enhancement,which, however, may be accompanied by manifestations of acute toxicity and other side effects associatedwith inhibition of peripheral AChE [2].Many OPIs interact in the body with otheresterases. These interactions may lead to differentpharmacological and toxicological effects. For example, the neuropathy target esterase (NTE, EC 3.1.1.5),which normally catalyzes deacylation of phosphatidylcholine of cell membranes [3], is an “antitarget”responsible for the development of organophosphateinduced delayed neurotoxicity (OPIDN). This phenomenon is due to the fact that its inhibition and subsequent rapid “aging” initiates distal degeneration ofsensory and motor axons in the peripheral nervous system and/or spinal cord, causing paralysis [1]. This disease is characterized by a latent period of up to severalweeks; specific drugs for its treatment are still notknown. Thus, the possibility of initiation of delayedneurotoxicity is an important risk factor in industrialand medical applications of OPIs.Other serine esterases, such as butyrylcholinesterase (BChE, EC 3.1.1.8) and carboxylesterase (CaE,EC 3.1.1.1), function as stoichiometric scavengers,providing protection against the toxic effect of anticholinesterase agents [4]. BChE and CaE of bloodplasma and liver are also in volved in the metabolism ofmany drugs containing ester groups, significantlyaffecting their pharmacokinetics.Recent studies have shown that BChE is alsoinvolved in cholinergic transmission and is able tocompensate for some functions of AChE, optimizingthe cholinergic neurotransmission by hydrolysis ofacetylcholine under conditions when AChE is, forsome reason, unable to perform this function(for example, in severe forms of AD, when the activityof AChE is significantly reduced). It was found thatselective inhibitors of BChE increase the level of acetylcholine in the brain and provide cognition enhancement in rodents, having no side effects of classicalinhibitors of AChE. In this regard, the development ofselective inhibitors of BChE is a new strategy toimprove the quality of life of patients with AD, especially in severe cases, when the activity of AChE in thebrain is depleted along with a decrease in the level ofacetylcholine, whereas the activity of BChE isincreased [2].Within the considered scheme of interaction withthe four serine esterases, the esterase profile of aninhibitor can be described by four activity values(the inhibitory activity with respect to AChE