Exploitation of the multitarget role of new ferulic and gallic acid derivatives in oxidative stress-related Alzheimer's disease therapies: design, synthesis and bioevaluation

Monoamine oxidases (MAOs) inhibitors could decrease Reactive Oxygen Species (ROS) generation, enhance mono-aminergic neural transmission, and have major therapeutic benefits for the treatment of Alzheimer's disease (AD). Following the conjunction of ferulic acid (FA)/gallic acid (GA) with sulfonamide, alanine and 2-aminobenzothiazole, we planned to assess the radical scavenging and antioxidant properties of synthesized analogs by using 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and ferric ion reducing antioxidant power (FRAP) assays. GA analog 28 was identified as the most potent antioxidant compound with IC₅₀ values of 1.77 μM and 2.06 μM in DPPH and ABTS assays respectively. In the in vitro Enzyme inhibition assays, synthesized derivative 23 emerged as a potent multitarget inhibitor of hMAO-B, eeAChE. COX-2 and 5-LOX with IC₅₀ values of 0.037 μM, 0.071 μM, 14.3 μM and 0.59 μM, respectively. Moreover, selected compounds 23, 25, 26 and 28 displayed good to moderate inhibition of self-mediated amyloid β_1-42 peptide aggregation. More importantly, compounds 23, 25, 28 and 29 showed no neurotoxicity on SH-SY5Y cells and also showed excellent neuroprotective effects against H₂O₂-induced SH-SY5Y cells. In the in vivo experiment, antioxidant Enzymes superoxide dismutase (SOD), catalase and Glutathione Peroxidase (GSH-Px) were studied in the brain of male BALB/c mice at the dose of 5 mg kg^-1. All the tested compounds, except 29, have shown good to in vivo antioxidant potential. Docking studies on 3D crystallographic structures of AChE and MAO-B showed significant interactions with catalytic amino acid residues. In conclusion, the current study showed that FA/GA derivatives could be further exploited for their multitarget role in oxidative stress-related AD therapies.