The preparation, in vitro screening and molecular docking of symmetrical bisquaternary cholinesterase inhibitors containing a but-(2E)-en-1,4-diyl connecting linkage

Abstract

Carbamate inhibitors (e.g. pyridostigmine bromide) are used as a pre-treatment for the prevention of organophosphorus poisoning. They work by blocking the native function of acetylcholinesterases (AChE) and thus protect AChE against irreversible inhibition by organophosphorus compounds. However, carbamate inhibitors are known for their many undesirable side effects related to the carbamylation of AChE. In this paper, we describe 17 novel bisquaternary compounds and have analysed their effect on AChE inhibition. The newly prepared compounds were evaluated in vitro using both human erythrocyte AChE and human plasmatic butyrylcholinesterase. Their inhibitory ability was expressed as the half maximal inhibitory concentration (IC₅₀) and then compared to the standard carbamate drugs and two AChE reactivators. One of these novel compounds showed promising AChE inhibition in vitro (nM range) and was better than the currently used standards. Additionally, a kinetic assay confirmed the non-competitive inhibition of hAChE by this novel compound. Consequently, the docking results confirmed the apparent π-π or π-cationic interactions with the key amino acid residues of hAChE and the binding of the chosen compound at the enzyme catalytic site.

Bis-isoquinolinium and bis-pyridinium acetylcholinesterase inhibitors: in vitro screening of probes for novel selective insecticides

“…All these structures have been recently reported as potential candidates for the treatment for AD or myasthenia gravis. [20][21][22] The rst group consisted of symmetrical bis-pyridinium compounds (see Fig. 1), which was selected based on the linker length and its previously reported inhibition effect.…”

“…Our aim was to screen selected recently reported AChE inhibitors from our in-house library [20][21][22] and nd out if any of them provided selectivity to insect AChE. These selective inhibitors could be used as new structure leads for further research.…”

Synthesis, cholinesterase inhibition and molecular modelling studies of coumarin linked thiourea derivatives

“…Hence subsequently, development of ChEIs plays an important role in determining the cholinergic transmission disorders mechanism [12,13]. ChEIs can also be used for the treatment of glaucoma, myasthenia gravis and in case of phosphate compounds poisoning as they act as competitors for cholinesterase sites in case of poisoning [14]. Since last few years, the discovery of several anti-AChE factors like tacrine, donepezil, rivastigmine and galantamine has been observed [15][16][17][18][19].…”

Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisonings

“… 11 – 14 The latter compounds were derived from 4-( tert -butyl)pyridinium or 4-positioned pyridinium analogs bridged also by varying linkage ( Figure 3 ). 15 , 16 …”

“…The IC 50 data were compared to pattern bisquaternary molecules with similar mechanism of action (ambenonium dichloride, BW284c51 or SAD-128). 15 , 16 The selected promising compounds from all prepared series are presented in Figure 5 and Table 1 .…”