RESUMO
Three types of aromatic-polyamine conjugates (6a-6s) were designed, synthesized and evaluated as potential inhibitors for cholinesterases (ChEs). The results showed that anthraquinone-polyamine conjugates (AQPCs) exhibited the most potent acetylcholinesterase (AChE) inhibitory activity with IC50 values from 1.50 to 11.13 µM. Anthracene-polyamine conjugates (APCs) showed a surprising selectivity (from 76- to 3125-fold) and were most potent at inhibiting butyrylcholinesterase (BChE), with IC50 values from 0.016 to 0.657 µM. A Lineweaver-Burk plot and molecular modeling studies indicated that the representative compounds, 6l and 6k, targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of ChEs. Furthermore, APCs did not affect HepG2 cell viability at the concentration of 100 µM. Consequently, these polyamine conjugates could be thoroughly and systematically studied for the treatment of AD.
Assuntos
Acetamidas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Antracenos/farmacologia , Butirilcolinesterase/química , Proliferação de Células/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Poliaminas/farmacologia , Acetamidas/química , Doença de Alzheimer/enzimologia , Peptídeos beta-Amiloides , Antracenos/química , Sítios de Ligação , Domínio Catalítico , Inibidores da Colinesterase/química , Desenho de Fármacos , Células Hep G2 , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Poliaminas/química , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
A series of 4-dimethylamine flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential multi-functional anti-Alzheimer agents. The results showed that most of the synthesized compounds exhibited high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity at the micromolar range (IC50, 1.83-33.20 µM for AChE and 0.82-11.45 µM for BChE). A Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5j with AChE, and molecular modeling study showed that 5j targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, the derivatives showed potent self-induced Aß aggregation inhibitory activity at 20 µM with percentage from 25% to 48%. In addition, some compounds (5j-5q) showed potent oxygen radical absorbance capacity (ORAC) ranging from 1.5- to 2.6-fold of the Trolox value. These compounds should be further investigated as multi-potent agents for the treatment of Alzheimer's disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Dimetilaminas/química , Dimetilaminas/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Dimetilaminas/síntese química , Desenho de Fármacos , Flavonoides/síntese química , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
A novel series of bis-nicotine derivatives (3a-3i) were designed, synthesized and evaluated as bivalent anti-Alzheimer's disease agents. The pharmacological results indicated that compounds 3e-3i inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the micromolar range (IC50, 2.28-117.86 micromol x L(-1) for AChE and 1.67-125 micromol x L(-1) for BChE), which was at the same potency as rivastigmine. A Lineweaver-Burk plot and molecular modeling study showed that these derivatives targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds could significantly inhibit the self-induced Abeta aggregation with inhibition activity (11.85%-62.14%) at the concentration of 20 micromol x L(-1).