Investigations of 3-Hydroxy Chromone Derivatives as Multipotent Therapeutics for the Treatment of Alzheimer’s Disease: <i>In Silico</i> and <i>In Vitro</i> Interventions and Fluorescence Studies

Chromone-based small organic molecules are designed and synthesized as putative multipotent ligands to intervene in several interlinked pathological pathways of Alzheimer's disease. The synthesized compounds were evaluated as acetylcholinesterase, monoamine oxidase, and amyloid β aggregation inhibitors using biochemical assays. Most of the compounds were found to inhibit the enzymes in a lower micromolar concentration range. In the series, two compounds, <i>i.e</i>., <b>NSS-16</b> and <b>NSS-18</b>, displayed a balanced activity profile with the IC₅₀ values of 1.77 and 1.53 μM against AChE and 2.06 and 1.51 μM against MAO-B. <b>NSS-16</b> and <b>NSS-18</b> showed moderate inhibitory activity against the self-induced Aβ aggregation with inhibition percentages of 17.8 and 24.0%, respectively. These compounds also showed potent antioxidant activity and formed metal chelates. In addition, the compounds were tested against SH-SY5Y neuronal cells and found to be neuroprotective and noncytotoxic. Moreover, the compounds inhibited reactive oxygen species (ROS) production up to 70% and exhibited a mixed type of inhibition in enzyme kinetic studies of AChE. These chromone derivatives showed a strong fluorescence intensity with a quantum yield of 30-50% and can be utilized in various biological studies including <i>in vitro</i> and <i>in vivo</i> assessments. Computational studies showed that the lead compounds fit well in the active cavity of enzymes and displayed thermodynamic stability for a time interval of 100 ns. Thus, these compounds displayed a multipotent activity profile and have the potential to be developed as potential therapeutics for AD.