New cinnamic - N-benzylpiperidine and cinnamic - N,N-dibenzyl(N-methyl)amine hybrids as Alzheimer-directed multitarget drugs with antioxidant, cholinergic, neuroprotective and neurogenic properties.
Here we describe new families of multi-target directed ligands obtained by linking antioxidant cinnamic-related structures with N-benzylpiperidine (NBP) or N,N-dibenzyl(N-methyl)amine (DBMA) fragments. Resulting hybrids, in addition to their antioxidant and neuroprotective properties against mitochondrial oxidative stress, are active at relevant molecular targets in Alzheimer's disease, such as cholinesterases (hAChE and hBuChE) and monoamine oxidases (hMAO-A and hMAO-B). Hybrids derived from umbellic - NBP (8), caffeic - NBP (9), and ferulic - DBMA (12) displayed balanced biological profiles, with IC50s in the low-micromolar and submicromolar range for hChEs and hMAOs, and an antioxidant potency comparable to vitamin E. Moreover, the caffeic - NBP hybrid 9 is able to improve the differentiation of adult SGZ-derived neural stem cells into a neuronal phenotype in vitro.
Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/Juan de la Cierva 3, 28006, Madrid, Spain.
Martín
M
Estrada
Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/Juan de la Cierva 3, 28006, Madrid, Spain.
Clara
C
Herrera-Arozamena
Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/Juan de la Cierva 3, 28006, Madrid, Spain.
Concepción
C
Pérez
Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidad de Santiago de Compostela, 15782, Santiago de Compostela, Spain.
Dolores
D
Viña
Departamento de Toxicología y Farmacología, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040, Madrid, Spain.
Alejandro
A
Romero
Instituto de Investigaciones Biomédicas "Alberto Sols", (IIB-CSIC), C/Arturo Duperier 4, 28029, Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), C/Valderrebollo 5, 28031, Madrid, Spain.
José A
JA
Morales-García
Instituto de Investigaciones Biomédicas "Alberto Sols", (IIB-CSIC), C/Arturo Duperier 4, 28029, Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), C/Valderrebollo 5, 28031, Madrid, Spain.
Ana
A
Pérez-Castillo
Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/Juan de la Cierva 3, 28006, Madrid, Spain. Electronic address: isabelrguez@iqm.csic.es.
María Isabel
MI
Rodríguez-Franco
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000588:Amines / Q000737:chemistry*; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002802:Cholinesterases / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D008995:Monoamine Oxidase / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
D000588:Amines; D000975:Antioxidants; D018696:Neuroprotective Agents; D010880:Piperidines; C071293:1-benzylpiperidine; D008995:Monoamine Oxidase; D002802:Cholinesterases
Antioxidants; Cinnamic-based hybrids; Human cholinesterases; Human monoamine oxidases; Neurogenic agents; Neuroprotectants