<i>In Silico</i> and <i>In Vitro</i> Evaluation of Quinoline Derivatives as Potential Inhibitors of AChE, BACE1, and GSK3β for Neurodegenerative Diseases Treatment

Neurodegenerative diseases are characterized by the structural and functional loss of neurons, which impacts populations worldwide. Enzymes such as acetylcholinesterase (AChE), beta-site APP cleaving enzyme-1 (BACE1), and glycogen synthase kinase 3-beta (GSK3β) are implicated in their progression. Therefore, developing compounds that inhibit these enzymes is relevant for treating these conditions. This study investigated the potential of quinoline analogs as multitarget enzyme inhibitors through in silico and in vitro assays. In silico analyses highlighted one of the derivatives as the most potent inhibitor for all proteins. In vitro assays confirmed that the quinoline derivatives modulated the activity of the three targets. The best derivative in silico also exhibited significant AChE inhibition of 94.6 %. For GSK3β and BACE1, four derivatives, with quinoline linked to the sulfonamide nitrogen, showed inhibition values above 40 %. Two of them demonstrated no cytotoxicity for human glioblastoma cell proliferation, and the most potent was noncytotoxic at 7.8 and 3.9 μg mL^-1. In murine fibroblasts, the most potent derivative showed no cytotoxicity, unlike its effect on glioblastoma cells. Similarly, other derivatives were noncytotoxic at concentrations less than 62.5 μg mL^-1. These findings highlight one of the derivatives as promising multitarget enzyme inhibitors for the treatment of neurodegenerative diseases.