Unraveling Network Pharmacology‐Based Therapeutics of Anthranilate Sulfonamides via Sirtuins/ <scp>FOXO3a</scp> Cascade in Alzheimer's Disease

Sulfonamide-based compounds have been a clinically attractive scaffold for drug development and proven as antioxidant and antimicrobial agents, but their pharmacological derivatives containing anthranilates (SA1-4) and therapeutic targets are not clearly clarified. To unravel the neuroprotective roles and underlying mechanisms of SA1-4 against oxidative injury and healthy longevity crosstalk, a combination of in vitro experiments, in silico modeling, and network pharmacology was employed. Pretreatment with SA1-4 in human neuronal SH-SY5Y cells significantly regulated sirtuins (SIRTs)/forkhead box class O 3a (FOXO3a)-mediated longevity signaling pathway via targeting endogenous antioxidant enzymes (i.e., superoxide dismutase 2 [SOD2] and catalase [CAT]), apoptotic cascades (i.e., Bcl-2-associated X-protein [BAX] and B-cell lymphoma-2 [BCL-2]), mitochondrial balance, and ultimately led to the neuronal rescue. Molecular docking simulations support the possibility of the SA1-4 modulatory effect within the active binding site of SIRT1. Importantly, in silico predictions of pharmacokinetic profiles suggested that the synthetic compounds possessed preferable drug-like properties, good oral bioavailability, and safety profiles. Network pharmacology also revealed the involvement of SA1-4 and key targets-regulated SIRTs in neurodegeneration, including non-amyloidogenic cascade, tau phosphorylation, calcium homeostasis, insulin-mediated glucose uptake, and neuroinflammation. Therefore, SA1-4 exert promising multi-target therapeutic strategies against oxidative damage, potentially offering alternative anti-Alzheimer candidates for further clinical neurodegenerative and anti-aging therapeutics.