The failure of the ongoing therapeutic protocols to treat neurodegenerative diseases (NDs), has been linked to the multifactorial nature of NDs connoted by a complex network of, often unrelated, cellular events. Although the etiopahtogenesis of many NDs is still obscure, growing evidence suggested that mitochondrial dysfunction, metal dyshomeostasis, oxidative stress, protein misfolding and dysregulated signaling pathways play a pivotal role in ND. The lack of disease-modifying therapies in NDs claimed for a new medicinal chemistry approach rooted on the rational design of molecular entities able to modulate multiple and aberrant biochemical mechanisms. Among the altered biochemical mechanisms, a key role of two enzymes (AChE and MAO) in the onset and progression of neural disorders has been supported by several experimental proofs. AChE is responsible for the catalytic degradation of acetylcholine and MAO is involved in the catabolism of several endogenous and exogenous amines including many neurotransmitters. The possibility of blocking simultaneously the activity of these two enzymes might restore a proper balance of neurotransmitter levels and, in addition, exert an additional beneficial effect by MAO inhibition that reduces the production of hydrogen peroxide thus avoiding the formation of reactive oxygen species.(1) Among naturally occurring heterocycles, coumarins have been largely explored as MAO inhibitors.(2) and reported also as dual binding sites AChE inhibitors.(3) As a further extension of previous investigations,(4) herein we report the design of coumarin-based dual inhibitors of AChE and MAO-B that bear small/medium sized amino groups at position 4 and a proper substituent at position 7. This design was grounded on previous 3D-QSAR studies that indicated positions 4 and 7 as preferred spatial regions, to assure a strong and selective binding at MAO-B. Moreover, structural modifications at position 4 aimed at an adequate modulation of the pharmacokinetic molecular properties, in particular, brain targeting and lipophilic balance for an in vivo activity at the CNS. The careful exploration of position 4 with basic, linear, unhindered, hydrogen bonding donor amino groups afforded promising dual inhibitors with IC50s in the low nanomolar range for MAO-B and low micromolar range for AChE.

Acetylcholinesterase (AChE) inhibitors still comprise the majority of the marketed drugs for Alzheimer's disease (AD). The structural arrangement of the enzyme, which features a narrow gorge that separates the catalytic and peripheral anionic subsites (CAS and PAS, respectively), inspired the development of bivalent ligands that are able to bind and block the catalytic activity of the CAS as well as the role of the PAS in beta amyloid (Aβ) fibrillogenesis. With the aim of discovering novel AChE dual binders with improved drug-likeness, homo- and heterodimers containing 2H-chromen-2-one building blocks were developed. By exploring diverse linkages of neutral and protonatable amino moieties through aliphatic spacers of different length, a nanomolar bivalent AChE inhibitor was identified (3-[2-(4-[(dimethylamino)methyl]-2-oxo-2H-chromen-7-yloxy)ethoxy]-6,7-dimethoxy-2H-chromen-2-one (6 d), IC50 =59 nm) from originally weakly active fragments. To assess the potential against AD, the disease-related biological properties of 6 d were investigated. It performed mixed-type AChE enzyme kinetics (inhibition constant Ki =68 nm) and inhibited Aβ self-aggregation. Moreover, it displayed an outstanding ability to protect SH-SY5Y cells from Aβ1-42 damage.

The enantiomer separation of a number of racemic 7-[(1-alkylpiperidin-3-yl)methoxy]coumarin derivatives, some of which show outstanding in vitro multitarget neuroprotective activities, was successfully achieved on a polysaccharide-based chiral stationary phase, bearing amylose tris(3,5-dimethylphenylcarbamate) as chiral selector, in normal polar mode (methanol and acetonitrile as the mobile phases). The majority of the screened selectands, especially those bearing 1-(3-X-benzyl)piperidin-3-yl moieties, showed baseline enantiomer separations, and compound 8 (X = NO2) was the best resolved (α = 2.01; RS = 4.27). Linear free-energy relationships, usefully complemented by molecular docking calculations, proved the key role in enantioselective retention of aromatic interactions between π-donor moieties in the chiral selector and π-acceptor moieties in selectand, strengthened by hydrogen bond interaction between a hydrogen bond donor in the chiral selector and the hydrogen bond acceptor group(s) in the selectand. Statistically reliable equations highlighted the importance of the substituent's size and substitution pattern (meta better than para) to affect the enantiorecognition of the title compounds. The chromatographic data support the scalability of the optimized experimental conditions for preparative purposes. This article is protected by copyright. All rights reserved.

The socioeconomic burden of multi-factorial pathologies, such as neurodegenerative diseases (NDs), is enormous worldwide. Unfortunately, no proven disease-modifying therapy is available yet and in most cases (e.g., Alzheimer's and Parkinson's disease) the approved drugs exert only palliative and symptomatic effects. Nowadays, an emerging strategy for the discovery of disease-modifying drugs is based on the multi-target directed ligand (MTDL) design, an innovative shift from the traditional approach one-drug-one-target to the more ambitious one-drug-more-targets goal. Herein, we review the discovery strategy, the mechanism of action and the biopharmacological evaluation of multipotent ligands exhibiting monoamine oxidase (MAO) inhibition as the core activity with a potential for the treatment of NDs. In particular, MAO inhibitors exhibiting additional acetylcholinesterase (AChE) or nitric oxide synthase (NOS) inhibition, or ion chelation/antioxidant-radical scavenging/anti-inflammatory/A2A receptor antagonist/APP processing modulating activities have been thoroughly examined.

The present invention relates to the use of compounds having a galloyl benzamide structure in the treatment and/or prevention of medical conditions mediated through c-Jun N-terminal kinases (JNKs) and to pharmaceutical compositions comprising said compounds.