Marine algae-derived polyamines and phlorotannins as cholinesterase inhibitors: In vitro and in silico analysis

The limitations of conventional cholinesterase inhibitors in Alzheimer's disease (AD) therapy namely, their short half-lives and adverse side effects—necessitate the exploration of natural alternatives. This investigation examined the inhibitory potential of selected polyamines (putrescine and spermidine) and a phlorotannin derivative (phloroglucinol), naturally present in the macroalgae species Cystoseira crinita and Stypopodium schimperi, against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using in vitro and in silico approaches. Additionally, radical scavenging potentials of each sample were determined. Enzyme activity assays employing the Ellman method revealed that putrescine and spermidine reached similar inhibition levels (approximately 32 %), while Cystoseira crinita acetone extract demonstrated superior potency with an IC50 of 0.085 mg/mL, indicating robust enzyme modulation. Complementary molecular docking studies conducted with Schrödinger Maestro 2020 elucidated the formation of stable enzyme-ligand complexes through hydrogen bonding and π-π interactions with critical residues including HIS447, TYR337, and TRP86 within the AChE active site. Moreover, crude macroalgal extracts, particularly those derived from C. crinita and S. schimperi, exhibited marked AChE inhibition, further substantiating the therapeutic potential of these marine-derived compounds. Collectively, these findings demonstrate that the polyamines and phlorotannin derivative studied not only effectively regulate cholinesterase activity but also offer naturally derived structural frameworks for the development of novel AD treatments. Phloroglucinol showed a high scavenging of DPPH (85%) and ABTS (98%) radicals, close to the activity of the reference compound trolox (96% for DPPH and 94% for ABTS). Further pharmacokinetic and toxicological evaluations are warranted to ascertain their clinical viability in AD management. © 2026 Elsevier Ltd