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

ABSTRACT 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 (SA 1–4 ) and therapeutic targets are not clearly clarified. To unravel the neuroprotective roles and underlying mechanisms of SA 1–4 against oxidative injury and healthy longevity crosstalk, a combination of in vitro experiments, in silico modeling, and network pharmacology was employed. Pretreatment with SA 1–4 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 SA 1–4 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 SA 1–4 and key targets‐regulated SIRTs in neurodegeneration, including non‐amyloidogenic cascade, tau phosphorylation, calcium homeostasis, insulin‐mediated glucose uptake, and neuroinflammation. Therefore, SA 1–4 exert promising multi‐target therapeutic strategies against oxidative damage, potentially offering alternative anti‐Alzheimer candidates for further clinical neurodegenerative and anti‐aging therapeutics. image