RESUMEN
In view of the multifactorial nature of Alzheimer's disease (AD), multitarget small molecules (MTSM) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer's disease therapy. The new MTSM KojoTacrines (KTs) were designed and synthesized by juxtaposition of selected pharmacophoric motifs from kojic acid and tacrine. Among them, 11-amino-2-(hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2',3':5,6] pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as less-hepatotoxic than tacrine, at higher concentration, a moderate, but selective human acetylcholinesterase inhibitor (IC50 = 4.52 ± 0.24 µM), as well as an antioxidant agent (TE = 4.79) showing significant neuroprotection against Aß1-40 at 3 µM and 10 µM concentrations. Consequently, KT2d is a potential new hit-ligand for AD therapy for further biological exploration.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Fármacos Neuroprotectores/farmacología , Tacrina/farmacología , Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Modelos Moleculares , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Relación Estructura-Actividad , Tacrina/síntesis química , Tacrina/químicaRESUMEN
In this study, the enzymatic synthesis of phenylacetoyl glycerol ester was carried out as a response to the increasing consumer demand for natural compounds. 1,3-dihydroxyphenylacetoyl-sn-Glycerol (1,3-di-HPA-Gly), labeled as "natural" compound with interesting biological properties, has been successfully synthesized for the first time in good yield by a direct esterification of glycerol (Gly) with p-hydroxyphenylacetic acid (p-HPA) using immobilized Candida antarctica lipase as a biocatalyst. Spectroscopic analyses of purified esters showed that the glycerol was mono- or di-esterified on the primary hydroxyl group. These compounds were evaluated for their antioxidant activity using two different tests. The glycerol di-esters (1,3-di-HPA-Gly) showed a higher antiradical capacity than that of the butyl hydroxytoluene. Furthermore, compared to the p-HPA, synthesized ester (1,3-di-HPA-Gly) exhibited the most antibacterial effect mainly against Gramâ¯+â¯bacteria. Among synthesized esters the 1,3-di-HPA-Gly was most effective as antioxidant and antibacterial compound. These findings could be the basis for a further exploitation of the new compound, 1,3-di-HPA-Gly, as antioxidant and antibacterial active ingredient in the cosmetic and pharmaceutical fields.
Asunto(s)
Antibacterianos/síntesis química , Antioxidantes/síntesis química , Candida/enzimología , Proteínas Fúngicas/química , Glicerol/síntesis química , Lipasa/química , Antibacterianos/química , Antibacterianos/farmacología , Antioxidantes/química , Cromatografía Líquida de Alta Presión , Enzimas Inmovilizadas/química , Enzimas Inmovilizadas/metabolismo , Proteínas Fúngicas/metabolismo , Glicerol/análogos & derivados , Glicerol/química , Glicerol/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Lipasa/metabolismo , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría de Masas en TándemRESUMEN
We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 µM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Antioxidantes/síntesis química , Antioxidantes/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacología , Humanos , Concentración 50 Inhibidora , Hígado/efectos de los fármacos , Análisis EspectralRESUMEN
AIM: Due to the complex nature of Alzheimer's disease, there is a renewed search for multitarget directed drugs. RESULTS: This paper describes the synthesis and in vitro biological evaluation of six racemic 13-aryl-2,3,4,13-tetrahydro-1H,12H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-triones (1a-6a), and six racemic 15-aryl-8,9,10,11,12,15-hexahydro-14H-benzo[6',7']chromeno[2',3:4,5] pyr-imido [1,2-a]azepine-5,14,16-triones (1b-6b), showing antioxidant and cholinesterase inhibitory capacity. Among these compounds, 13-phenyl-2,3,4,13-tetrahydro-1H,12H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-trione (1a) is a nonhepatotoxic at 300 µmol/l dose concentration, and a selective EeAChE inhibitor showing good antioxidant power. CONCLUSION: A new family of racemic benzochromenopyrimidinetriones has been investigated for their potential use in the treatment of Alzheimer's disease.
Asunto(s)
Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Antioxidantes/farmacología , Inhibidores de la Colinesterasa/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Naftoquinonas/farmacología , Enfermedad de Alzheimer/metabolismo , Antioxidantes/síntesis química , Antioxidantes/química , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Células Hep G2 , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Estructura Molecular , Naftoquinonas/síntesis química , Naftoquinonas/química , Relación Estructura-ActividadRESUMEN
Herein we report an efficient two step synthesis and biological assessment of 12 racemic tetrahydropyranodiquinolin-8-amines derivatives as antioxidant, cholinesterase inhibitors and non-hepatotoxic agents. Based on the results of the primary screening, we identified 7-(3-methoxyphenyl)-9,10,11,12-tetrahydro-7H-pyrano[2,3-b:5,6-h']diquinolin-8-amine (2h) as a particularly interesting non-hepatotoxic compound that shows moderate antioxidant activity (1.83 equiv Trolox in the ORAC assay), a non competitive inhibition of hAChE (IC50 = 0.75 ± 0.01 µM), and brain permeable as determined by the PAMPA-Blood Brain Barrier assay.
Asunto(s)
Aminoquinolinas/farmacología , Antioxidantes/farmacología , Inhibidores de la Colinesterasa/farmacología , Acetilcolinesterasa , Enfermedad de Alzheimer/tratamiento farmacológico , Aminoquinolinas/síntesis química , Antioxidantes/química , Barrera Hematoencefálica/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas , Inhibidores de la Colinesterasa/química , Proteínas Ligadas a GPI/antagonistas & inhibidores , HumanosRESUMEN
Given the complex nature of Alzheimer's disease (AD), compounds that are able to simultaneously address two or more AD-associated targets show greater promise for development into drugs for AD therapy. Herein we report an efficient two-step synthesis and biological evaluation of new racemic benzochromene derivatives as antioxidants, inhibitors of cholinesterase and ß-amyloid (Aß1-42 ) aggregation. Based on the results of the primary screening, we identified 15-(3-methoxyphenyl)-9,11,12,15-tetrahydro-10H,14H-benzo[5,6]chromeno[2,3-d]pyrido[1,2-a]pyrimidin-14-imine (3 e) and 16-(3-methoxyphenyl)-9,10,11,12,13,16-hexahydro-15H-benzo[5',6']chromeno[2',3':4,5]pyrimido[1,2-a]azepin-15-imine (3 f) as new potential multitarget-directed ligands for AD therapy. Further in-depth biological analysis showed that compound 3 f is a good human acetylcholinesterase inhibitor [IC50 =(0.36±0.02)â µm], has strong antioxidant activity (3.61â µmol Trolox equivalents), and moderate Aß1-42 antiaggregating power (40.3 %).