Natural Product-Derived Acyl-Tryptamine Conjugates: A Systematic Series of Sixty-Nine Novel Dual-Release Prodrug Candidates Targeting Neuroinflammation, Senescence, Neuroprotection, and Serotonergic Modulation

A novel series of sixty-nine N-acyl tryptamine conjugates is presented, organised into twentythree structural classes derived from natural product scaffolds: ergolin-8-oyl, berberin-9-oyl, resveratrol-3-oyl, pterostilben-3-oyl, hesperetin-2-oyl, naringenin-2-oyl, eriodictyol-2-oyl, taxifolin-2-oyl, quercetin-2-oyl, isorhamnetin-2-oyl, tamarixetin-2-oyl, rhamnetin-2-oyl, fisetin-2-oyl, kaempferol-2-oyl, galangin-2-oyl, apigenin-2-oyl, luteolin-2-oyl, diosmetin-2-oyl, baicalein-2-oyl, wogonin-2-oyl, chrysin-2-oyl, curcumin-4-oyl, and silibinin-oyl. All compounds share a secondary amide bond linking the acyl moiety to substituted tryptamine scaffolds bearing 4-hydroxy, 5-methoxy, or 4-acetoxy substitution, with enzymatic hydrolysis proposed to simultaneously release a pharmacologically active tryptamine and a bioactive natural product-derived acyl fragment. The twenty-three classes introduce mechanistically distinct secondary hypotheses including SIRT1/AMPK activation, Nrf2 induction, AhR modulation, NF-κB inhibition, MAO-B inhibition, senolytic activity, D2 receptor modulation, aromatase inhibition, and mitochondrial redox support. All sixty-nine compounds are new chemical entities; no synthesis or biological testing has been performed. SMILES strings, predicted physicochemical properties, and hypothetical pharmacological profiles are provided to stimulate further investigation. This series constitutes the fourth instalment of a systematic acyl-tryptamine prodrug platform, complementing three preceding publications describing heteroaromatic, endogenous, and phytochemical acyl classes across fifty-five additional compounds.