Evaluation of the histamine H₃ receptor antagonists from LINS01 series as cholinesterases inhibitors: Enzymatic and modeling studies

Abstract

Histamine is involved in several central nervous system processes including cognition. In the last years, H 3 receptor (H 3 R) antagonists have been widely explored for their potential on dementias and other cognitive dysfunctions, and the cooperative role between histamine and acetylcholine neurotransmissions on cognitive processes is widely known in literature. This motivated us to assess the potential of 1-[(2,3-dihydrobenzofuran-1-yl)methyl]piperazines (LINS01 compounds) as inhibitors of cholinesterases, and thus this work presents the inhibitory effect of such compounds against acetyl (AChE) and butyrylcholinesterase. A set of 16 selected compounds were evaluated, being compounds 2d and 2e the most potent inhibitors of both cholinesterases (IC 50 13.2-33.9 μM) by competitive mechanism, as indicated by the kinetic assays. Molecular docking simulations suggested that the allylpiperazine and dihydrobenzofuran motifs present in these compounds are important to perform πinteractions with key tryptophan residues from the enzymes, increasing their affinity for both H 3 R and cholinesterases. Metric analysis support that compound 2d (LINS01022) should be highlighted due to its balanced lipophilicity (ClogP 2.35) and efficiency (LE 0.32) as AChE inhibitor. The results add important information to future design of dual H 3 R-cholinesterases ligands.

Berberine derivatives as inhibitors of acetylcholinesterase: A systematic review

“…The current treatment option for AD is limited to AChEIs: donepezil (1), rivastigmine (2), galantamine (3), and tacrine (4, withdrawn from the market due to hepatotoxic effect), NMDA receptor antagonist: memantine (5) and recently approved Aβ modulator aducanumab (Figure 3; Marucci et al, 2021; Zhou & Huang, 2022b). Although ChEIs do not reduce the progression of the disease, they have been proven to improve the learning and memory function and are the main drugs in the management of AD (Lopes et al, 2022; Umar et al, 2022; Vogel & Schwabe, 2016). Therefore, developing novel multifunctional ChEIs is a hot topic of interest for most of the researchers across the globe (Zhou & Huang, 2021).…”