Highly selective inhibition of butyrylcholinesterase by a novel melatonin–tacrine heterodimers

Abstract

Novel inhibitors of cholinesterases, especially butyrylcholinesterase (BuChE), were obtained by coupling melatonin-tacrine heterodimers via the carbamate bond. Compounds 14a-i possessed potent cholinesterase inhibitory activity (with IC50 values as low as 1.18 nM for acetylcholinesterase (AChE) and 0.24 nM for butyrylcholinesterase (BuChE)). These heterodimers exhibit selectivity toward BuChE, being from 4- to 256-fold more active toward BuChE than AChE, but still acting as better AChE inhibitors than tacrine 4.

Benzofuran and Indole: Promising Scaffolds for Drug Development in Alzheimer's Disease

“…Zawadzka et al. report melatonin–tacrine heterodimers (Figure ) as selective inhibitors of BuChE . The heterodimers show 4‐ to 256‐fold higher activity toward BuChE than AChE.…”

Inhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity

“…Carbamate inhibitors bind to the active site of both cholinesterases like organophosphorus inhibitors; however, the covalent bound is not stable and the carbamate moiety is hydrolytically split from the active site after some time [29,53,54]. The mechanism of carbamate binding is sometimes called pseudo-irreversible because of carbamate moiety spontaneous hydrolysis and resurrection of cholinesterase activity.…”

“…(See the next chapter). Tacrine (1,2,3,4-tetrahydroacridin-9-amine) is another synthetic drug which easily crosses the blood brain barrier and is used as a highly effective drug for ameliorating Alzheimer disease manifestation by inhibition AChE and by lower but still effective inhibition of BChE [53,66,67]. It was withdrawn from clinical use because of adverse effects.…”

Donepezil–melatonin hybrids as butyrylcholinesterase inhibitors: Improving binding affinity through varying mode of linking fragments

“…Melatonin‐derived building block 15 was obtained according to a previously developed procedure from N ‐acetylserotonin and 4‐nitrophenyl chloroformate, in the presence of N ‐methylmorpholine . N ‐Benzyl piperidine derivatives 10 and 11 are commercially available.…”

“…The first compounds of this class connect a melatonin‐derived moiety through an amide bond, using the aliphatic tail of the melatonin fragment (Figure a) . Previously, we demonstrated that the modification of the linker to a carbamate bond connected to the aromatic system of the melatonin moiety generates an excellent selectivity toward BChE (Figure b) …”