RESUMEN
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.
Asunto(s)
Acetamidas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Antracenos/farmacología , Butirilcolinesterasa/química , Proliferación Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Poliaminas/farmacología , Acetamidas/química , Enfermedad de Alzheimer/enzimología , Péptidos beta-Amiloides , Antracenos/química , Sitios de Unión , Dominio Catalítico , Inhibidores de la Colinesterasa/química , Diseño de Fármacos , Células Hep G2 , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Poliaminas/química , Conformación Proteica , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Dimetilaminas/química , Dimetilaminas/farmacología , Flavonoides/química , Flavonoides/farmacología , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Butirilcolinesterasa/química , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Dimetilaminas/síntesis química , Diseño de Fármacos , Flavonoides/síntesis química , Humanos , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
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).
Asunto(s)
Acetilcolinesterasa/metabolismo , Péptidos beta-Amiloides , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Nicotina/análogos & derivados , Nicotina/síntesis química , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Sitios de Unión , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Nicotina/química , Nicotina/farmacologíaRESUMEN
A series of tacrine-methoxybenzene hybrids (5a-5i) were designed, synthesized and evaluated as inhibitors of cholinesterases (ChEs). All the compounds had better ChEs inhibitory activities than tacrine with IC50 values at the nanomolar range. Compound 5h exhibited the strongest inhibition on acetylcholinesterase (AChE) with an IC50 value of 6.74 nmol x L(-1) and compound 5f showed the most potent inhibition on butyrylcholinesterase with IC50 value of 3.83 nmol x L(-1). Kinetic and molecular modeling studies showed that these hybrids targeted both the catalytic active site and the peripheral anionic site of AChE.