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

## TL;DR

Anthranilate sulfonamides may protect neurons in Alzheimer's by activating longevity pathways and reducing oxidative stress.

## Contribution

The study reveals the neuroprotective mechanisms of anthranilate sulfonamides through SIRTs/FOXO3a signaling in Alzheimer's disease.

## Key findings

- SA1–4 compounds regulate SIRTs/FOXO3a pathways and antioxidant enzymes in neuronal cells.
- Molecular docking suggests SA1–4 can bind to SIRT1's active site.
- Network pharmacology links SA1–4 to neurodegeneration targets like tau phosphorylation and neuroinflammation.

## 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 (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.

Anthranilates sulfonamides (SA1–4) showed neuroprotective activity against human neuronal SH‐SY5Y cells under oxidative stress. The data represented significantly regulated sirtuins (SIRTs)/forkhead box class O 3a (FOXO3a)‐mediated longevity signaling pathway via targeting endogenous antioxidant enzymes, including superoxide dismutase 2 (SOD2) and catalase (CAT), apoptotic cascades (BAX and BCL‐2), and mitochondrial balance. Additionally, in silico investigation of pharmacokinetic profiles indicated that the synthetic compounds revealed preferable drug‐like properties, good oral bioavailability, and safety profiles. Network pharmacology also showed the involvement of SA1–4 and key targets‐regulated SIRTs in neurodegeneration.