Molecular Mechanisms and Network Pharmacology Revealing Therapeutic Potential of Acetamidosulfonamides against Parkinsonian Model.

Parkinson's disease (PD) is the second most common age-related motor neurodegenerative disease (ND) that has critically posed a global health burden since the 18th century. There is also no full therapy for the clinical syndrome, nor halts the progression of the disease. This study aimed to investigate multidisciplinary potentials of the acetamidosulfonamides (1-16) in PD via systematic biology-based in vitro, in silico, and network pharmacology assessments. The biological effects of the synthetic compounds, especially 8, 13, 14, and 16, provided potent neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced Parkinsonian SH-SY5Y model through the modulation of antioxidant defenses, antiapoptotic signaling, mitochondrial balance, and the regulation of both acetylcholinesterase (AChE) and sirtuin 1 (SIRT1). Molecular docking confirmed that these synthetic compounds interact favorably with the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE, as well as the active binding pocket of SIRT1. The network pharmacology and target enrichment analysis also revealed a close correlation with APP, MAOA, MAOB, SLC6A3, and DRD1, governing the regulation of neurotransmitters. In summary, this research highlights four acetamidosulfonamides as promising candidates to be further developed as multitarget anti-PD agents for PD prevention and management.