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.

Matrix metalloproteinases (MMP) are well-known biological targets implicated in tumour progression, homeostatic regulation, innate immunity, impaired delivery of pro-apoptotic ligands, and the release and cleavage of cell-surface receptors. Hence, the development of potent and selective inhibitors targeting these enzymes continues to be eagerly sought. In this paper, a number of alloxan-based compounds, initially conceived to bias other therapeutically relevant enzymes, were rationally modified and successfully repurposed to inhibit MMP-2 (also named gelatinase A) in the nanomolar range. Importantly, the alloxan core makes its debut as zinc binding group since it ensures a stable tetrahedral coordination of the catalytic zinc ion in concert with the three histidines of the HExxHxxGxxH metzincin signature motif, further stabilized by a hydrogen bond with the glutamate residue belonging to the same motif. The molecular decoration of the alloxan core with a biphenyl privileged structure allowed to sample the deep S1′ specificity pocket of MMP-2 and to relate the high affinity towards this enzyme with the chance of forming a hydrogen bond network with the backbone of Leu116 and Asn147 and the side chains of Tyr144, Thr145 and Arg149 at the bottom of the pocket. The effect of even slight structural changes in determining the interaction at the S1′ subsite of MMP-2 as well as the nature and strength of the binding is elucidated via molecular dynamics simulations and free energy calculations. Among the herein presented compounds, the highest affinity (pIC50 = 7.06) is found for BAM, a compound exhibiting also selectivity (>20) towards MMP-2, as compared to MMP-9, the other member of the gelatinases.

The multifactorial nature of chemotherapy failure in controlling cancer is often associated with the occurrence of multidrug resistance (MDR), a phenomenon likely related to the increased expression of members of the ATP binding cassette (ABC) transporter superfamily. In this respect, the most extensively characterized MDR transporters include ABCB1 (also known as MDR1 or P-glycoprotein) and ABCC1 (also known as MRP1) whose inhibition remains a priority to circumvent drug resistance. Herein, we report how the simple galloyl benzamide scaffold can be easily and properly decorated for the preparation of either MRP1 or P-gp selective inhibitors. In particular, some gallamides and pyrogallol-1-monomethyl ethers congeners showed remarkable affinity and selectivity toward MRP1 (e.g. 15g: IC50 = 9.50 μM, > 100 μM). On the other hand, trimethyl ether galloyl anilides, with few exceptions, exhibited moderate to very high and selective P-gp inhibition (e.g., 11g: IC50 = 0.2 μM, > 100μM).

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.