ADAMANTANE AMINE DERIVATIVES AS MULTITARGET COMPOUNDS FOR ALZHEIMER'S DISEASE: IN SILICO, IN VITRO, AND IN VIVO STUDIES

Adamantoid amino compounds were investigated for their effects on two primary targets in Alzheimer’s disease, acetylcholinesterase (AChE) and NMDA receptor. The compounds were synthesized in two steps: the hydroxyl group of adamantane-1-methanol was substituted with iodine, followed by replacement with an amine. Compounds were tested as acetylcholinesterase inhibitors (iAChE - Ellman test) and antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH). Toxicity was evaluated employing the Artemia salina and Allium cepa assays. Cytotoxicity was determined in glial cells (U87) and mouse fibroblasts (L929) by the MTT test. Compounds exhibited high AChE inhibition capacity (78-97%) and low antioxidant activity (less than 35%). The samples had different cytotoxic performances. Compounds 1, 2, 3, and 5, which had a terminal NH2 group, were more cytotoxic than the samples with this group replaced, reinforcing its importance for biological activity. This pattern was also observed in the iAChE test and confirmed by molecular docking studies. Compound 3 was the most promising, exhibiting higher enzyme inhibition (iAChE, 97%) and no toxic effects in the Artemia salina assay. The C elegans trial confirmed the ability of compound 3 to act on different therapeutic targets, modulating the cholinergic and glutamatergic activity in the pharyngeal beat test and locomotor parameters of the nematode.