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DESIGN AND IN SILICO EVALUATION OF NOVEL TACRINE-FERULIC ACID DERIVATIVES

IULIAN CĂLUIAN 1, ANDREEA-TEODORA IACOB 1*, MARIA APOTROSOAEI 1, ALEXANDRU SAVA 2, LENUȚA PROFIRE 1

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The present study conducted an in silico screening of novel aryl-heterocyclic compounds with potential therapeutic applications for Alzheimer’s disease (AD). The affinity and selectivity of the designed molecules towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two key enzymes involved in AD, were evaluated using AutoDock 4.2.6. Pharmacokinetic and toxicological profiles were predicted through ADMET (absorption, distribution, metabolisation, excretion and toxicity) analysis using pkCSM, SwissADME and toxCSM tools. Additionally, oral bioavailability was assessed according to Lipinski’s rule of five. The compounds demonstrated higher binding affinity for the active sites of AChE and BChE, as indicated by lower binding energy values compared to the reference cholinesterase inhibitors (donepezil and rivastigmine). Pharmacokinetic evaluation indicated excellent intestinal absorption but low-to-moderate permeability across the blood-brain barrier (BBB). Notably, the introduction of a chlorine atom at position 7 of the tetrahydroacridine ring markedly reduced the risks of hepatotoxicity and mutagenicity, while concomitantly increasing the risk of cardiotoxicity. The in silico results indicate that the studied compounds are promising AD candidates, though further experimental, toxicological and BBB-permeability studies are required to confirm their therapeutic potential.