Despite huge efforts to develop effective disease-modifying drugs for Alzheimer’s disease (AD), the currently available treatments (acetylcholinesterase, AChE, inhibitors and the NMDA receptor antagonist memantine) can provide at best symptomatic relief in earlier stages of disease. The research recently shifted to the more promising Multi-Target-Directed Ligands (MTDLs). Our efforts have long been devoted to discovering dual coumarin-based inhibitors of monoamine oxidase B (MAO B) and AChE, whereas more recently we usefully decorated some other heterocyclic scaffolds to obtain novel MTDL leads for AD.1-3 Herein, the synthesis (Scheme 1) and biological activities toward some AD-related target of 1,2,3,4- tetrahydro-10H-chromeno[3,2-c]pyridine-10-one (THCP) derivatives is reported.As major findings of this study: i) compound 1, bearing benzyl and ethoxy as R1 and R2 groups, respectively, inhibited in vitro human MAO B (IC50 of 0.9 μM) and displayed neuroprotective effects in neuroblastoma SH- SY5Y cell line, significantly recovering cell viability when impaired by Aβ1-42 and pro-oxidation insults; ii) the carbamate derivative 3 proved to be a moderate dual MAO/AChE inhibitor; iii) the chromeno[2,3-d]azocines 4, irrespective of their substituents R2 and R3, lost activity toward the assayed enzymes and pathogenic pathways. Overall, this study highlighted THCP as useful and versatile scaffold for developing new small molecules targeting enzymes and biochemical pathways involved in the pathogenesis of AD.
Identification of chromeno[3,2-c]pyridine as suitable scaffold of novel multitarget-directed ligands for the treatment of Alzheimers disease
Purgatorio, R.
;Catto, M.;Pisani, L.;de Candia, M.;Cellamare, S.;Altomare, C. D.
2019-01-01
Abstract
Despite huge efforts to develop effective disease-modifying drugs for Alzheimer’s disease (AD), the currently available treatments (acetylcholinesterase, AChE, inhibitors and the NMDA receptor antagonist memantine) can provide at best symptomatic relief in earlier stages of disease. The research recently shifted to the more promising Multi-Target-Directed Ligands (MTDLs). Our efforts have long been devoted to discovering dual coumarin-based inhibitors of monoamine oxidase B (MAO B) and AChE, whereas more recently we usefully decorated some other heterocyclic scaffolds to obtain novel MTDL leads for AD.1-3 Herein, the synthesis (Scheme 1) and biological activities toward some AD-related target of 1,2,3,4- tetrahydro-10H-chromeno[3,2-c]pyridine-10-one (THCP) derivatives is reported.As major findings of this study: i) compound 1, bearing benzyl and ethoxy as R1 and R2 groups, respectively, inhibited in vitro human MAO B (IC50 of 0.9 μM) and displayed neuroprotective effects in neuroblastoma SH- SY5Y cell line, significantly recovering cell viability when impaired by Aβ1-42 and pro-oxidation insults; ii) the carbamate derivative 3 proved to be a moderate dual MAO/AChE inhibitor; iii) the chromeno[2,3-d]azocines 4, irrespective of their substituents R2 and R3, lost activity toward the assayed enzymes and pathogenic pathways. Overall, this study highlighted THCP as useful and versatile scaffold for developing new small molecules targeting enzymes and biochemical pathways involved in the pathogenesis of AD.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
