NRF2 acts by controlling gene expression, being the master regulator of the Phase II antioxidant response, and also being key to the control of neuroinflammation. NRF2 activity is regulated at several levels, including protein degradation by the proteasome, transcription, and post-transcription. The purpose of this review is to offer a concise and critical overview of the main mechanisms of NRF2 regulation and their actual or potential use as targets for the treatment of neurodegenerative diseases.

The formation of neurofibrillary tangles (NFTs), oxidative stress and neuroinflammation have emerged as key targets for the treatment of Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder. These pathological hallmarks are closely related to the over-activity of the enzyme GSK3β and the downregulation of the defense pathway Nrf2-EpRE observed in AD patients. Herein, we report the synthesis and pharmacological evaluation of a new family of multitarget 2,4-dihydropyrano[2,3-c]pyrazoles as dual GSK3β inhibitors and Nrf2 inducers. These compounds are able to inhibit GSK3β and induce the Nrf2 phase II antioxidant and anti-inflammatory pathway at micromolar concentrations, showing interesting structure-activity relationships. The association of both activities has resulted in a remarkable anti-inflammatory ability with an interesting neuroprotective profile on in vitro models of neuronal death induced by oxidative stress and energy depletion and AD. Furthermore, none of the compounds exhibited in vitro neurotoxicity or hepatotoxicity and hence they had improved safety profiles compared to the known electrophilic Nrf2 inducers. In conclusion, the combination of both activities in this family of multitarget compounds confers them a notable interest for the development of lead compounds for the treatment of AD.

Synthesis. -New 2-pyrrolin-5-ones (IV) are prepared by Hantzsch-type microwave-assisted, solvent-free sequential three-component reaction of primary amines, -carbonyl compounds, and -bromoester and utilized e.g. as synthetic building blocks in a target-oriented project for the synthesis of compound (VI) that is postulated as a candidate for HIV increase inhibition on the basis of computational studies. -(CORES, A.; ESTEVEZ, V.; VILLACAMPA, M.; MENENDEZ*, J. C.; RSC Adv. 6 (2016) 45, 39433-39443,

Two multitarget hybrids, derived from an aza-analogue of CGP37157, a mitochondrial Na + /Ca 2+ exchanger antagonist, and lipoic acid were designed in order to combine in a single molecule the antioxidant and Nrf2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The hybrid derivatives showed Nrf2 induction and radical scavenging properties, leading to a good neuroprotective profile against oxidative stress, together with an interesting antineuroinflammatory activity.The results obtained show differences in activity depending on the configuration of the chiral center of LA. K E Y W O R D Santi-inflammatory activity, neuroprotection, Nrf2 induction, radical scavenging

Oxidative stress is crucial to the outbreak and advancement of neurodegenerative diseases and is a common factor to many of them. We describe the synthesis of a library of derivatives of the 4-arylmethylen-2-pyrrolin-5-one framework by sequential application of a three-component reaction of primary amines, β-dicarbonyl compounds, and α-haloketones and a Knoevenagel condensation. These compounds can be viewed as cyclic amides of caffeic and ferulic acids, and are also structurally related to the bisavenanthramide family of natural antioxidants. Most members of the library showed low cytotoxicity and good activity as inductors of Nrf2, a transcription factor that acts as the master regulator of the antioxidant response associated with activation of the antioxidant response element (ARE). Nrf2-dependent protein expression was also proved by the significant increase in the levels of the HMOX1 and NQO1 proteins. Some compounds exerted neuroprotective properties in oxidative stress situations, such as rotenone/oligomycin-induced toxicity, and also against protein hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. Compound 3i, which can be considered a good candidate for further hit-to-lead development against neurodegenerative diseases due to its well-balanced multitarget profile, was further characterized by proving its ability to reduce phosphorylated Tau levels.