RESUMO
With the purpose of expanding the structural variety of chemical compounds available as pharmacological tools for the treatment of Alzheimer's disease, we synthesized and evaluated a novel series of indole-benzoxazinones (Family I) and benzoxazine-arylpiperazine derivatives (Family II) for potential human acetylcholinesterase (hAChE) inhibitory properties. The most active compounds 7a and 7d demonstrated effective inhibitory profiles with Ki values of 20.3 ± 0.9 µM and 20.2 ± 0.9 µM, respectively. Kinetic inhibition assays showed non-competitive inhibition of AChE by the tested compounds. According to our docking studies, the most active compounds from both series (Families I and II) showed a binding mode similar to donepezil and interact with the same residues.
Assuntos
Acetilcolinesterase/efeitos dos fármacos , Benzoxazinas/farmacologia , Inibidores da Colinesterase/farmacologia , Piperazinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Benzoxazinas/síntese química , Benzoxazinas/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Donepezila , Desenho de Fármacos , Humanos , Indanos/farmacologia , Simulação de Acoplamento Molecular , Piperazinas/síntese química , Piperazinas/química , Piperidinas/farmacologia , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
A series of functionalized indolylalkylarenes 3-16(a and b) were synthesized and their affinities for the serotonin transporter were investigated in vitro. Compounds 3-12(a and b) were obtained by nucleophilic substitution of 3-(1H-indol-3-yl)propyl-4-methylbenzenesulfonates 2(a and b) with a series of azaheterocycles. Compounds 14-16(a and b) were prepared in a two-step sequence by reaction of 3-(1H-indol-3-yl)-2-methylpropanal with substituted 1,2-phenylenediamines. Compounds 3b, 4b, and 5b showed good binding affinities (K(i) = 33.0, 48.0, and 17 nM, respectively). The other synthesized compounds showed moderate or no affinity in the binding studies.