RESUMO
In our quest to find new inhibitors able to inhibit acetylcholinesterase (AChE) and, at the same time, to protect neurons from beta amyloid toxicity, i.e., inhibitors interacting with the catalytic anionic subsite as well as with the peripherical anionic site of AChE, a virtual screening of the Centre d'Etudes et de Recherche sur le Medicament de Normandie (CERMN) chemical library was carried out. Two complementary approaches were applied, i.e., a ligand- and a structure-based screening. Each screening led to the selection of different compounds, but only two were present in both screening results. In vitro tests on AChE showed that one of those compounds presented a very good inhibition activity, of the same order as Donepezil. This result shows the real complementary of both methods for the discovery of new ligands.
Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Sequência de Aminoácidos , Animais , Electrophorus/metabolismo , Humanos , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Alinhamento de Sequência , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Torpedo/metabolismoRESUMO
Pharmacomodulations of previously reported thiaindanones related to donepezil were achieved with the aim to enhance their AChE inhibitory activity. Condensation of the cyclopentane carbonyl group into hydrazone or cyanolefine derivatives, as well as its hydrogenation and the subsequent substitution of the resulting hydroxyl group led to new 2-(4-benzylpiperazin-1-yl)-N-(1,3-dibromo-6-hydroxy-5,6-dihydro-4H-cyclopenta[c]thien-4-yl) acetamides. The in vitro evaluation of this new series, according to the method of Ellman, shows however that it conserved only partially the biological activity. The best compound remains the alcohol 11 (IC(50) = 0.40 microM, against 0.02 microM for donepezil).
Assuntos
Inibidores da Colinesterase/síntese química , Indanos/síntese química , Indanos/farmacologia , Acetamidas/síntese química , Acetamidas/farmacologia , Inibidores da Colinesterase/farmacologia , Donepezila , Humanos , Concentração Inibidora 50 , Piperidinas , Relação Estrutura-AtividadeRESUMO
Sixty-four new indanones and thiaindanones related to donepezil were synthesized and evaluated in vitro as potential AChE inhibitors. Among them, 11 derivatives were found to inhibit the enzyme in the submicromolar range; the best compound revealed its inhibitory activity with an IC50 in the same range (0.06 microM) than the reference compound, donepezil (IC50=0.02 microM).