KEAP1-NRF2 protein-protein interaction inhibitors: Design, pharmacological properties and therapeutic potential.

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is considered the master regulator of the phase II antioxidant response. It controls a plethora of cytoprotective genes related to oxidative stress, inflammation, and protein homeostasis, among other processes. Activation of these pathways has been described in numerous pathologies including cancer, cardiovascular, respiratory, renal, digestive, metabolic, autoimmune, and neurodegenerative diseases. Considering the increasing interest of discovering novel NRF2 activators due to its clinical application, initial efforts were devoted to the development of electrophilic drugs able to induce NRF2 nuclear accumulation by targeting its natural repressor protein Kelch-like ECH-associated protein 1 (KEAP1) through covalent modifications on cysteine residues. However, off-target effects of these drugs prompted the development of an innovative strategy, the search of KEAP1-NRF2 protein-protein interaction (PPI) inhibitors. These innovative activators are proposed to target NRF2 in a more selective way, leading to potentially improved drugs with the application for a variety of diseases that are currently under investigation. In this review, we summarize known KEAP1-NRF2 PPI inhibitors to date and the bases of their design highlighting the most important features of their respective interactions. We also discuss the preclinical pharmacological properties described for the most promising compounds.

Synthesis and in vitro study of nitro- and methoxy-2-phenylbenzofurans as human monoamine oxidase inhibitors.

A new series of 2-phenylbenzofuran derivatives were designed and synthesized to determine relevant structural features for the MAO inhibitory activity and selectivity. Methoxy substituents were introduced in the 2-phenyl ring, whereas the benzofuran moiety was not substituted or substituted at the positions 5 or 7 with a nitro group. Substitution patterns on both the phenyl ring and the benzofuran moiety determine the affinity for MAO-A or MAO-B. The 2-(3-methoxyphenyl)-5-nitrobenzofuran 9 was the most potent MAO-B inhibitor (IC50 = 0.024 µM) identified in this series, whereas 7-nitro-2-phenylbenzofuran 7 was the most potent MAO-A inhibitor (IC50 = 0.168 µM), both acting as reversible inhibitors. The number and position of the methoxyl groups on the 2-phenyl ring, have an important influence on the inhibitory activity. Molecular docking studies confirmed the experimental results and highlighted the importance of key residues in enzyme inhibition.

New flavonoid - N,N-dibenzyl(N-methyl)amine hybrids: Multi-target-directed agents for Alzheimer´s disease endowed with neurogenic properties.

The design of multi-target directed ligands (MTDLs) is a valid approach for obtaining effective drugs for complex pathologies. MTDLs that combine neuro-repair properties and block the first steps of neurotoxic cascades could be the so long wanted remedies to treat neurodegenerative diseases (NDs). By linking two privileged scaffolds with well-known activities in ND-targets, the flavonoid and the N,N-dibenzyl(N-methyl)amine (DBMA) fragments, new CNS-permeable flavonoid - DBMA hybrids (1-13) were obtained. They were subjected to biological evaluation in a battery of targets involved in Alzheimer's disease (AD) and other NDs, namely human cholinesterases (hAChE/hBuChE), ß-secretase (hBACE-1), monoamine oxidases (hMAO-A/B), lipoxygenase-5 (hLOX-5) and sigma receptors (σ1R/σ2R). After a funnel-type screening, 6,7-dimethoxychromone - DBMA (6) was highlighted due to its neurogenic properties and an interesting MTD-profile in hAChE, hLOX-5, hBACE-1 and σ1R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6, which could synergistically contribute to neuronal regeneration and block neurodegeneration.

Recent Advances in Neurogenic Small Molecules as Innovative Treatments for Neurodegenerative Diseases.

The central nervous system of adult mammals has long been considered as a complex static structure unable to undergo any regenerative process to refurbish its dead nodes. This dogma was challenged by Altman in the 1960s and neuron self-renewal has been demonstrated ever since in many species, including humans. Aging, neurodegenerative, and some mental diseases are associated with an exponential decrease in brain neurogenesis. Therefore, the controlled pharmacological stimulation of the endogenous neural stem cells (NSCs) niches might counteract the neuronal loss in Alzheimer's disease (AD) and other pathologies, opening an exciting new therapeutic avenue. In the last years, druggable molecular targets and signalling pathways involved in neurogenic processes have been identified, and as a consequence, different drug types have been developed and tested in neuronal plasticity. This review focuses on recent advances in neurogenic agents acting at serotonin and/or melatonin systems, Wnt/ß-catenin pathway, sigma receptors, nicotinamide phosphoribosyltransferase (NAMPT) and nuclear erythroid 2-related factor (Nrf2).

Potent and selective MAO-B inhibitory activity: amino- versus nitro-3-arylcoumarin derivatives.

In this study we synthesized and evaluated a new series of amino and nitro 3-arylcoumarins as hMAO-A and hMAO-B inhibitors. Compounds 2, 3, 5 and 6 presented a better activity and selectivity profile against the hMAO-B isoform (IC50 values between 2 and 6nM) than selegiline. In general, the amino derivatives (4-6) proved to be more selective against MAO-B than the nitro derivatives (1-3). Additionally, a theoretical study of some physicochemical properties, PAMPA and reversibility assays for the most potent derivative, and molecular docking simulations were carried out to further explain the pharmacological results, and to identify the hypothetical binding mode for the compounds inside the hMAO-B.

Discovery of a potent melatonin-based inhibitor of quinone reductase-2 with neuroprotective and neurogenic properties.

5-Methoxy-3-(5-methoxyindolin-2-yl)-1H-indole (3), whose structure was unambiguously elucidated by X-ray analysis, was identified as a multi-target compound with potential application in neurodegenerative diseases. It is a low nanomolar inhibitor of QR2 (IC50 = 7.7 nM), with greater potency than melatonin and comparable efficacy to the most potent QR2 inhibitors described to date. Molecular docking studies revealed the potential binding mode of 3 to QR2, which explains its superior potency compared to melatonin. Furthermore, compound 3 inhibits hMAO-A, hMAO-B and hLOX-5 in the low micromolar range and is an excellent ROS scavenger. In phenotypic assays, compound 3 showed neuroprotective activity in a cellular model of oxidative stress damage, it was non-toxic, and was able to activate neurogenesis from neural stem-cell niches of adult mice. These excellent biological properties, together with its both good in silico and in vitro drug-like profile, highlight compound 3 as a promising drug candidate for neurodegenerative diseases.

8-Amide and 8-carbamate substitution patterns as modulators of 7-hydroxy-4-methylcoumarin's antidepressant profile: Synthesis, biological evaluation and docking studies.

Psychiatric and neurological disorders affect millions of people worldwide. Currently available treatments may help to improve symptoms, but they cannot cure the diseases. Therefore, there is an urgent need for potent and safe therapeutic solutions. 8-Amide and 8-carbamatecoumarins were synthetized and evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. Comparison between both scaffolds has been established, and we hypothesized that the introduction of different substituents can modulate hMAO activity and selectivity. N-(7-Hydroxy-4-methylcoumarin-8-yl)-4-methylbenzamide (9) and ethyl N-(7-hydroxy-4-methylcoumarin-8-yl)carbamate (20) proved to be the most active and selective hMAO-A inhibitors (IC50 = 15.0 nM and IC50 = 22.0 nM, respectively), being compound 9 an irreversible hMAO-A inhibitor twenty-four times more active in vitro than moclobemide, a drug used in the treatment of depression and anxiety. Based on PAMPA assay results, both compounds proved to be good candidates to cross the blood-brain barrier. In addition, these compounds showed non-significant cytotoxicity on neuronal viability assays. Also, the best compound proved to have a t1/2 of 6.84 min, an intrinsic clearance of 195.63 µL min-1 mg-1 protein, and to be chemically stable at pH 3.0, 7.4 and 10.0. Docking studies were performed to better understand the binding affinities and selectivity profiles for both hMAO isoforms. Finally, theoretical drug-like properties calculations corroborate the potential of both scaffolds on the search for new therapeutic solutions for psychiatric disorders as depression.

Effects of a tacrine-8-hydroxyquinoline hybrid (IQM-622) on Aß accumulation and cell death: involvement in hippocampal neuronal loss in Alzheimer's disease.

Several studies have implicated the enzyme acetylcholinesterase (AChE) as well as several biometals in the pathogenesis of Alzheimer's disease (AD). A multifunctional molecule, the hybrid tacrine-8-hydroxyquinoline (named IQM-622), displays cholinergic, antioxidant, copper-complexing and neuroprotective properties. Using in vitro and in vivo models, we investigated the modulating effects of IQM-622 on amyloid ß-protein (Aß)-induced pathology as well as on chemically induced neurodegeneration by domoic acid. In the first experimental model, we observed a significant decrease in brain Aß deposits in IQM-622-treated APP/Ps1 mice for four weeks. Moreover, IQM-622 promoted the degradation of intracellular Aß in astrocytes, and protected against Aß toxicity in cultured astrocytes and neurons. These findings suggest that the neuroprotective effect of IQM-622 is not only related to AChE inhibition, but also involves other mechanisms, including the modulation of Aß-degradation pathways in AD brain. In this study we also compare the neuronal loss in CA1 hippocampal field of AD patients and of mice treated with domoic acid, giving similar patterns. Thus, we used a second experimental model by killing hippocampal neurons by domoic acid damage, in which IQM-622 increased survival in the CA1 and dentate gyrus regions of the hippocampus. Our observations suggest that administration of IQM-622 may have significant beneficial effects in neurodegenerative diseases, including AD, which course with acute or progressive neuronal death.

An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter ß-TrCP delivers anti-inflammatory responses in mouse liver.

It is widely accepted that activating the transcription factor NRF2 will blast the physiological anti-inflammatory mechanisms, which will help combat pathologic inflammation. Much effort is being put in inhibiting the main NRF2 repressor, KEAP1, with either electrophilic small molecules or disrupters of the KEAP1/NRF2 interaction. However, targeting ß-TrCP, the non-canonical repressor of NRF2, has not been considered yet. After in silico screening of ∼1 million compounds, we now describe a novel small molecule, PHAR, that selectively inhibits the interaction between ß-TrCP and the phosphodegron in transcription factor NRF2. PHAR upregulates NRF2-target genes such as Hmox1, Nqo1, Gclc, Gclm and Aox1, in a KEAP1-independent, but ß-TrCP dependent manner, breaks the ß-TrCP/NRF2 interaction in the cell nucleus, and inhibits the ß-TrCP-mediated in vitro ubiquitination of NRF2. PHAR attenuates hydrogen peroxide induced oxidative stress and, in lipopolysaccharide-treated macrophages, it downregulates the expression of inflammatory genes Il1b, Il6, Cox2, Nos2. In mice, PHAR selectively targets the liver and greatly attenuates LPS-induced liver inflammation as indicated by a reduction in the gene expression of the inflammatory cytokines Il1b, TNf, and Il6, and in F4/80-stained liver resident macrophages. Thus, PHAR offers a still unexplored alternative to current NRF2 activators by acting as a ß-TrCP/NRF2 interaction inhibitor that may have a therapeutic value against undesirable inflammation.

Antinociceptive and modulatory effect of pathoplastic changes in spinal glia of a TLR4/CD14 blocking molecule in two models of pain in rat.

The role of spinal glia in the development and maintenance of chronic pain has become over the last years a subject of increasing interest. In this regard, toll-like receptor 4 (TLR4) signaling has been proposed as a major trigger mechanism. Hence, in this study we explored the implications of TLR4 inhibition in the periphery and primarily in the CNS, focusing on the impact this inhibition renders in pain development and glia activation in the dorsal horn in two models of pain. Making use of a synthetic cluster of differentiation 14 (CD14)/TLR4 antagonist, the effect of TLR4 blockade on tactile allodynia and heat hyperalgesia was evaluated in osteoarthritic and postoperative rat models. An in vitro parallel artificial membrane permeation assay was performed to determine the proneness of the drug to permeate the blood-brain barrier prior to systemic and central administration. Findings suggest a dominant role of peripheral TLR4 in the model of incisional pain, whilst both peripheral and central TLR4 seem to be responsible for osteoarthritic pain. That is, central and peripheral TLR4 may be differently involved in the etiopathology of diverse types of pain what potentially seems a promising approach in the management of pain.

Resveratrol-Based MTDLs to Stimulate Defensive and Regenerative Pathways and Block Early Events in Neurodegenerative Cascades.

By replacing a phenolic ring of (E)-resveratrol with an 1,3,4-oxadiazol-2(3H)-one heterocycle, new resveratrol-based multitarget-directed ligands (MTDLs) were obtained. They were evaluated in several assays related to oxidative stress and inflammation (monoamine oxidases, nuclear erythroid 2-related factor, quinone reductase-2, and oxygen radical trapping) and then in experiments of increasing complexity (neurogenic properties and neuroprotection vs okadaic acid). 5-[(E)-2-(4-Methoxyphenyl)ethenyl]-3-(prop-2-yn-1-yl)-1,3,4-oxadiazol-2(3H)-one (4e) showed a well-balanced MTDL profile: cellular activation of the NRF2-ARE pathway (CD = 9.83 µM), selective inhibition of both hMAO-B and QR2 (IC50s = 8.05 and 0.57 µM), and the best ability to promote hippocampal neurogenesis. It showed a good drug-like profile (positive in vitro central nervous system permeability, good physiological solubility, no glutathione conjugation, and lack of PAINS or Lipinski alerts) and exerted neuroprotective and antioxidant actions in both acute and chronic Alzheimer models using hippocampal tissues. Thus, 4e is an interesting MTDL that could stimulate defensive and regenerative pathways and block early events in neurodegenerative cascades.

Synthesis, In Vitro Profiling, and In Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors.

The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field.

From the Design to the In Vivo Evaluation of Benzohomoadamantane-Derived Soluble Epoxide Hydrolase Inhibitors for the Treatment of Acute Pancreatitis.

The pharmacological inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Numerous potent sEH inhibitors (sEHIs) present adamantyl or phenyl moieties, such as the clinical candidates AR9281 or EC5026. Herein, in a new series of sEHIs, these hydrophobic moieties have been merged in a benzohomoadamantane scaffold. Most of the new sEHIs have excellent inhibitory activities against sEH. Molecular dynamics simulations suggested that the addition of an aromatic ring into the adamantane scaffold produced conformational rearrangements in the enzyme to stabilize the aromatic ring of the benzohomoadamantane core. A screening cascade permitted us to select a candidate for an in vivo efficacy study in a murine model of cerulein-induced acute pancreatitis. The administration of 22 improved the health status of the animals and reduced pancreatic damage, demonstrating that the benzohomoadamantane unit is a promising scaffold for the design of novel sEHIs.

Optical control of muscular nicotinic channels with azocuroniums, photoswitchable azobenzenes bearing two N-methyl-N-carbocyclic quaternary ammonium groups.

By linking two N-methyl-N-carbocyclic quaternary ammonium groups to an azobenzene scaffold in meta- or para-positions we generated a series of photoswitchable neuromuscular ligands for which we coined the term "azocuroniums". These compounds switched between the (E)- and (Z)-isomers by light irradiation at 400-450 nm and 335-340 nm, respectively. Meta-azocuroniums were potent nicotinic ligands with a clear selectivity for the muscular nAChRs compared to neuronal α7 and α4ß2 subtypes, showed good solubility in physiologic media, negligible cell toxicity, and would not reach the CNS. Electrophysiological studies in muscle-type nAChRs expressed in Xenopus laevis oocytes showed that (E)-isomers were more potent than (Z)-forms. All meta-azocuroniums were neuromuscular blockers, with the exception of the pyrrolidine derivative that was an agonist. These new meta-azocuroniums, which can be modulated ad libitum by light, could be employed as photoswitchable muscle relaxants with fewer side effects for surgical interventions and as tools to better understand the pharmacology of muscle-type nAChRs.

Identification of tetracyclic lactams as NMDA receptor antagonists with potential application in neurological disorders.

N-Methyl-d-aspartate receptors (NMDARs) are crucial for the normal function of the central nervous system (CNS), and fundamental in memory and learning-related processes. The overactivation of these receptors is associated with numerous neurodegenerative and psychiatric disorders. Therefore, NMDAR is considered a relevant therapeutic target for many CNS disorders. Herein, we report the synthesis and pharmacological evaluation of a new scaffold with antagonistic activity for NMDAR. Specifically, a chemical library of eighteen 1-aminoindan-2-ol tetracyclic lactams was synthesized and screened as NMDAR antagonists. The compounds were obtained by chiral pool synthesis using enantiomerically pure 1-aminoindan-2-ols as chiral inductors, and their stereochemistry was proven by X-ray crystallographic analysis of two target compounds. Most compounds reveal NMDAR antagonism, and eleven compounds display IC50 values in a Ca2+ entry-sensitive fluo-4 assay in the same order of magnitude of memantine, a clinically approved NMDAR antagonist. Docking studies suggest that the novel compounds can act as NMDAR channel blockers since there is a compatible conformation with MK-801 co-crystallized with NMDAR channel. In addition, we show that the tetracyclic 1-aminoindan-2-ol derivatives are brain permeable and non-toxic, and we identify promising hits for further optimization as modulators of the NMDAR function.

Tuning melatonin receptor subtype selectivity in oxadiazolone-based analogues: Discovery of QR2 ligands and NRF2 activators with neurogenic properties.

New multi-target indole and naphthalene derivatives containing the oxadiazolone scaffold as a bioisostere of the melatonin acetamido group have been developed. The novel compounds were characterized at melatonin receptors MT1R and MT2R, quinone reductase 2 (QR2), lipoxygenase-5 (LOX-5), and monoamine oxidases (MAO-A and MAO-B), and also as radical scavengers. We found that selectivity within the oxadiazolone series can be modulated by modifying the side chain functionality and co-planarity with the indole or naphthalene ring. In phenotypic assays, several oxadiazolone-based derivatives induced signalling mediated by the transcription factor NRF2 and promoted the maturation of neural stem-cells into a neuronal phenotype. Activation of NRF2 could be due to the binding of indole derivatives to KEAP1, as deduced from surface plasmon resonance (SPR) experiments. Molecular modelling studies using the crystal structures of QR2 and the KEAP1 Kelch-domain, as well as the recently described X-ray free-electron laser (XFEL) structures of chimeric MT1R and MT2R, provided a rationale for the experimental data and afforded valuable insights for future drug design endeavours.

2-Oxaadamant-1-yl Ureas as Soluble Epoxide Hydrolase Inhibitors: In Vivo Evaluation in a Murine Model of Acute Pancreatitis.

In vivo pharmacological inhibition of soluble epoxide hydrolase (sEH) reduces inflammatory diseases, including acute pancreatitis (AP). Adamantyl ureas are very potent sEH inhibitors, but the lipophilicity and metabolism of the adamantane group compromise their overall usefulness. Herein, we report that the replacement of a methylene unit of the adamantane group by an oxygen atom increases the solubility, permeability, and stability of three series of urea-based sEH inhibitors. Most of these oxa-analogues are nanomolar inhibitors of both the human and murine sEH. Molecular dynamics simulations rationalize the molecular basis for their activity and suggest that the presence of the oxygen atom on the adamantane scaffold results in active site rearrangements to establish a weak hydrogen bond. The 2-oxaadamantane 22, which has a good solubility, microsomal stability, and selectivity for sEH, was selected for further in vitro and in vivo studies in models of cerulein-induced AP. Both in prophylactic and treatment studies, 22 diminished the overexpression of inflammatory and endoplasmic reticulum stress markers induced by cerulein and reduced the pancreatic damage.

The Melatonin Analog IQM316 May Induce Adult Hippocampal Neurogenesis and Preserve Recognition Memories in Mice.

Neurogenesis in the adult hippocampus is a unique process in neurobiology that requires functional integration of newly generated neurons, which may disrupt existing hippocampal network connections and consequently loss of established memories. As neurodegenerative diseases characterized by abnormal neurogenesis and memory dysfunctions are increasing, the identification of new anti-aging drugs is required. In adult mice, we found that melatonin, a well-established neurogenic hormone, and the melatonin analog 2-(2-(5-methoxy-1 H-indol-3-yl)ethyl)-5-methyl-1,3,4-oxadiazole (IQM316) were able to induce hippocampal neurogenesis, measured by neuronal nuclei (NeuN) and 5-bromo-2'-deoxyuridine (BrdU) labeling. More importantly, only IQM316 administration was able to induce hippocampal neurogenesis while preserving previously acquired memories, assessed with object recognition tests. In vitro studies with embryonic neural stem cells replicated the finding that both melatonin and IQM316 induce direct differentiation of neural precursors without altering their proliferative activity. Furthermore, IQM316 induces differentiation through a mechanism that is not dependent of melatonergic receptors (MTRs), since the MTR antagonist luzindole could not block the IQM316-induced effects. We also found that IQM316 and melatonin modulate mitochondrial DNA copy number and oxidative phosphorylation proteins, while maintaining mitochondrial function as measured by respiratory assays and enzymatic activity. These results uncover a novel pharmacological agent that may be capable of inducing adult hippocampal neurogenesis at a healthy and sustainable rate that preserves recognition memories.

Multi-target-directed ligands for Alzheimer's disease: Discovery of chromone-based monoamine oxidase/cholinesterase inhibitors.

There has been a substantial research effort to design multi-target ligands for the treatment of Alzheimer's disease (AD), an approach that is moved by the knowledge that AD is a complex and multifactorial disease affecting many linked to pathological pathways. Accordingly, we have devoted efforts to develop multi-target ligands based on the chromone scaffold. As a result, a small library of chromone derivatives was synthesized and screened towards human cholinesterases and monoamine oxidases. Compounds 2-(dimethylamino)ethyl (E)-3-(4-oxo-2-(p-methylphenlcarbamoyl)-4H-chromen-6-yl)acrylate (9a) and 2-(dimethylamino)ethyl (E)-3-(4-oxo-3-(phenylcarbamoyl)-4H-chromen-6-yl)acrylate (23a) were identified as the most promising multi-target inhibitors of the series. Compound 9a acted as a potent, selective and bifunctional AChEI (IC50 = 0.21 µM, Ki = 0.19 µM) and displayed dual hMAO inhibitory activity (hMAO-A IC50 = 0.94 µM, Ki = 0.057 µM and hMAO-B IC50 = 3.81 µM, Ki = 0.48 µM). Compound 23a acted as a selective IMAO-B (IC50 = 0.63 µM, Ki = 0.34 µM) while still displaying hChE inhibitory and bifunctional activity in the low micromolar range. Overall, these two compounds stand out as reversible multi-target inhibitors with favourable permeability, toxicological and drug-like profiles, thus being valid candidates for subsequent optimization and pre-clinical studies.

Neurogenic and neuroprotective donepezil-flavonoid hybrids with sigma-1 affinity and inhibition of key enzymes in Alzheimer's disease.

In this work we describe neurogenic and neuroprotective donepezil-flavonoid hybrids (DFHs), exhibiting nanomolar affinities for the sigma-1 receptor (σ1R) and inhibition of key enzymes in Alzheimer's disease (AD), such as acetylcholinesterase (AChE), 5-lipoxygenase (5-LOX), and monoamine oxidases (MAOs). In general, new compounds scavenge free radical species, are predicted to be brain-permeable, and protect neuronal cells against mitochondrial oxidative stress. N-(2-(1-Benzylpiperidin-4-yl)ethyl)-6,7-dimethoxy-4-oxo-4H-chromene-2-carboxamide (18) is highlighted due to its interesting biological profile in σ1R, AChE, 5-LOX, MAO-A and MAO-B. In phenotypic assays, it protects a neuronal cell line against mitochondrial oxidative stress and promotes maturation of neural stem cells into a neuronal phenotype, which could contribute to the reparation of neuronal tissues. Molecular modelling studies of 18 in AChE, 5-LOX and σ1R revealed the main interactions with these proteins, which will be further exploited in the optimization of new, more efficient DFHs.