Evaluation of the histamine H-3 receptor antagonists from LINS01 series as cholinesterases inhibitors: Enzymatic and modeling studies

Autor(es)

Lopes, Flavia B. ; Aranha, Cecilia M. S. Q. ; Correa, Michelle F. ; Fernandes, Gustavo A. B. ; Okamoto, Debora N. ; Simoes, Leonardo P. M. ; Junior, Nailton M. N. ; Fernandes, Joao Paulo S.

• Tipo de documento: Artigo Científico
• Fonte: CHEMICAL BIOLOGY & DRUG DESIGN; v. 100, n. 5, p. 8-pg., 2022-09-08.

Resumo

Histamine is involved in several central nervous system processes including cognition. In the last years, H-3 receptor (H3R) 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 (IC50 13.2-33.9 mu M) 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 pi-interactions with key tryptophan residues from the enzymes, increasing their affinity for both H3R 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 H3R-cholinesterases ligands. (AU)

• Processo FAPESP: 21/03387-0 - Potenciais agentes multialvo para o tratamento de neurodegenerações: inibidores duais H3R/AChE com propriedades quelantes associadas
• Beneficiário: Flávia Barrio Lopes
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 19/24028-8 - Aril-alquilamido-piperazinas substituídas como ligantes multialvo: síntese e avaliação da atividade em alvos relevantes para o tratamento de desordens do SNC
• Beneficiário: João Paulo dos Santos Fernandes
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/23139-2 - Síntese e avaliação biológica de compostos da série LINS01 como agentes pró-cognitivos: uma abordagem multialvo
• Beneficiário: Michelle Fidelis Corrêa
• Modalidade de apoio: Bolsas no Brasil - Doutorado