NEW HYBRID COUMARIN–SUBSTITUTED ALICYCLIC AMINES AS POTENTIAL MULTITARGET DIRECT LIGANDS FOR THE TREATMENT OF ALZHEIMER'S DISEASE

In order to achieve disease-modifying therapies for the treatment of Alzheimer's disease (AD), the well-known multitarget directed ligands (MTDL) approach was adopted to ensure synergistic action on multiple drug targets by a single molecule. For this purpose, we designed and synthesized twenty new hybrids consisting of the coumarin nucleus and substituted alicyclic amines (donezepil-like piperazino and piperidino derivatives), linked by an alkyl chain of variable length in position 4- and 7- of the coumarin. The coumarin nucleus has various biological activities (antioxidant, ChEs and MAO-B inhibitor) useful in neuroprotection [1]. In addition, the basic fragment ensures affinity for ChEs and, if an aromatic ring (phenyl or benzyl) is present, anti-aggregating activity on β-amyloid could be found [2]. All compounds have been tested for their antioxidant activity trough the colorimetric DPPH assay. The inhibition of human acetylcholinesterase (hAChE) and equine serum butyrylcholinesterase (esBChE) was determined through the Ellman assay at the concentration of 10 μM and the IC50 was then determined for the most active compounds. All tested compounds show a weak antioxidant activity, mainly due to the coumarin system but lower than that of the starting compounds due to functionalization of the hydroxyl group. Compounds with n = 4 have a higher antioxidant activity than compounds with n = 3. The enzyme inhibition results show, however, that all compounds are able to inhibit at least one of the two enzymes. The best IC50 of the tested compounds are strongly encouraging with values between 0.31±0.06 and 6.05±0.59 μM for hAChE and between 2.08±0.38 and 19.6±2.0 μM on esBChE. In conclusion, a moderate selectivity for AChE is observed and the 7-substitution provides better inhibitory activity. The benzyl on piperazine leads to greater inhibition, while the length of the alkyl linker decreases the activity on AChE whereas it appears to increase it on BChE. These positive outcomes justify further studies on the inhibitory capacity of β-amyloid aggregation and MAO-B. References 1) Pisani, L.; Catto, M.; Muncipinto, G.; Nicolotti, O.; Carrieri, A.; Rullo, M.; Stefanachi, A.; Leonetti, F.; Altomare, C. A Twenty-Year Journey Exploring Coumarin-Based Derivatives as Bioactive Molecules. Front. Chem. 2022, 10, 1002547. https://doi.org/10.3389/fchem.2022.1002547. 2) Tasso, B.; Catto, M.; Nicolotti, O.; Novelli, F.; Tonelli, M.; Giangreco, I.; Pisani, L.; Sparatore, A.; Boido, V.; Carotti, A.; Sparatore, F. Quinolizidinyl Derivatives of Bi- and Tricyclic Systems as Potent Inhibitors of Acetyl- and Butyrylcholinesterase with Potential in Alzheimer's Disease. Eur. J. Med. Chem. 2011, 46 (6), 2170–2184. https://doi.org/10.1016/j.ejmech.2011.02.071.