In vitro and in silico neuroprotective evaluation of new biotransformation metabolites of (-)-α-bisabolol

Abstract

Biotransformation of (-)-α-bisabolol (1) was investigated by screening twenty-two fungal strains in an effort to produce new more polar and potentially bioactive metabolites. Three fungi were selected for scale-up biotransformation: Cordyceps sinensis, Alternaria alternata and Aspergillus flavus. Five metabolites were isolated: 10β,11-dihydroxy-α-bisabolol (2), Hamanasic acid A (3), 2,3-dihydro-α-bisabolol (4), 7-dehydroxy-10,11-epoxy-3-methylcarboxy-α-bisabolol (5) and 10β,11,15-trihydroxy-α-bisabolol (6), with metabolites 4, 5, and 6 being newly identified. Structural elucidation was performed using spectroscopic methods. α-bisabolol and its metabolites were evaluated for their cyclooxygenase (COX) and acetylcholinesterase (AChE) inhibitory activities, as well as neuroprotective effects against H₂O₂ and Aβ_1-42-induced toxicity in SH-SY5Y cells. In vitro results showed that metabolite 5 exhibited the strongest COX-2 inhibition (IC₅₀ = 2.508 µM), while 2 showed AChE inhibition (IC₅₀ = 12.94 µM), These outcomes were more confirmed by molecular docking. Metabolites 6 and 2 demonstrated superior neuroprotective effects against H₂O₂ and Aβ_1-42-induced toxicity compared to α-bisabolol. Importantly, metabolite 2 showed pronounced AChE inhibitory activity alongside favorable ADMET attributes. These findings suggest that α-bisabolol and its metabolite 2 are potential candidates for the modulation of neurodegenerative diseases involving inflammation, neurotoxicity, or cholinergic dysfunction. Further in vivo investigations are mandatory to ensure the study outcomes.

Keywords: Biotransformation; Bisabolol; COX inhibitors; Cholinesterase inhibitors; Hamanasic acid A; Neuroprotective.

Fig. 1

Schematic presentation of the bioconversion of α-bisabolol (1) to its metabolites using three different fungal strains.

Fig. 2

Two-dimensional (2D) binding mode and residues involved in the recognition of (a) celecoxib, (b) bisabolol, the most potent compounds; (c) metabolite 4, (d) metabolite 5 and (e) metabolite 6 docked and minimized in the COX-2 binding pocket.

Fig. 3

Neuroprotection of bisabolol and its metabolites against H₂O₂-induced neurotoxicity in SH-SY5Y cells. Results were represented as means ± standard deviations (SD), with n = 5. * Indicates a statistically significant difference compared to the cell viability of H₂O₂-treated cells at p < 0.001. Statistical significance was determined using one-way ANOVA followed by Dunnett’s post-hoc test in GraphPad Prism® 10. Metabolites 2 and 6 showed more potent neuroprotection than the parent compound and other metabolites.

Fig. 4

Expected radical scavenging activity of α-bisabolol (1) by binding to fatty acid peroxyl radicals (LOO·) and stopping the lipid peroxidation chain reaction in the cell membrane.

Fig. 5

Neuroprotection against Aβ_1-42 induced-neurotoxicity in SH-SY5Y cells. ECG: Epigallocatechin-3-gallate was used as a positive control. Values were represented as means ± standard deviations (SD), n = 5. * Indicates a statistically significant difference compared to the cell viability of Aβ_1-42 -treated cells at p < 0.001. Statistical significance was determined using one-way ANOVA followed by Dunnett’s post-hoc test in GraphPad Prism® 10. Metabolites 2 and 6 were more neuroprotective than α-bisabolol and other metabolites.

Fig. 6

Dose–response curve of AChE inhibition by metabolite 2.

Fig. 7

2D binding mode and residues involved in the recognition of (a) galanthamine, (b) α-bisabolol and (c) the most potent compound (metabolite 2) docked and minimized in the AChE binding pocket.