2026-08-20T06:03:20Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/931002025-09-02T15:07:43Zcom_20.500.14352_14col_20.500.14352_15

00925njm 22002777a 4500 dc Cores Esperón, Ángel author Carmona Zafra, Noelia author Martín Cámara, Olmo author Sánchez Cebrián, Juan Domingo author Duarte, Pablo author Villacampa Sanz, Mercedes author Bermejo Bescos, María De La Paloma author Martín-Aragón Álvarez, Sagrario author León Martínez, Rafael author Menéndez Ramos, José Carlos author 2021 Curcumin shows a broad spectrum of activities of relevance in the treatment of Alzheimer’s disease (AD); however, it is poorly absorbed and is also chemically and metabolically unstable, leading to a very low oral bioavailability. A small library of hybrid compounds designed as curcumin analogues and incorporating the key structural fragment of piperlongumine, a natural neuroinflammation inhibitor, were synthesized by a two-step route that combines a three-component reaction between primary amines, β-ketoesters and α-haloesters and a base-promoted acylation with cinnamoyl chlorides. These compounds were predicted to have good oral absorption and CNS permeation, had good scavenging properties in the in vitro DPPH experiment and in a cellular assay based on the oxidation of dichlorofluorescin to a fluorescent species. The compounds showed low toxicity in two cellular models, were potent inductors of the Nrf2-ARE phase II antioxidant response, inhibited PHF6 peptide aggregation, closely related to Tau protein aggregation and were active against the LPS-induced inflammatory response. They also afforded neuroprotection against an oxidative insult induced by inhibition of the mitochondrial respiratory chain with the rotenone-oligomycin A combination and against Tau hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. This multitarget pharmacological profile is highly promising in the development of treatments for AD and provides a good hit structure for future optimization efforts. Cores Á, Carmona-Zafra N, Martín-Cámara O, Sánchez JD, Duarte P, Villacampa M, Bermejo-Bescós P, Martín-Aragón S, León R, Menéndez JC. Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation. Antioxidants (Basel). 2021 Dec 24;11(1):28. 2076-3921 10.3390/antiox11010028 https://hdl.handle.net/20.500.14352/93100 https://doi.org/10.3390/antiox11010028 https://www.mdpi.com/1420558 Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation