4-(ALKYL)AMINOMETHYL-SUBSTITUTED COUMARINS AS POTENT AND SELECTIVE ACHE AND MAO-B DUAL INHIBITORS WITH A THERAPEUTIC POTENTIAL IN NEURODEGENERATIVE DISORDERS

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