In Vitro and In Silico Investigation of Polyacetylenes from (Spreng.) Dandy as Potential COX-2, 5-LOX, and BchE Inhibitors.

Diverse secondary metabolites are biosynthesized by plants via various enzymatic cascades. These have the capacity to interact with various human receptors, particularly enzymes implicated in the etiology of several diseases. The -hexane fraction of the whole plant extract of the wild edible plant, (Spreng.) Dandy was purified by column chromatography. Five polyacetylene derivatives were identified, including (3,8)-deca-8-en-4,6-diyne-1,3-diol (), (3)-deca-4,6,8-triyne-1,3-diol (), (3)-(6,12)-tetradecadiene-8,10-diyne-1,3-diol (), bidensyneoside (), and (3)-(6,12)-tetradecadiene-8,10-diyne-1-ol-3--β-D-glucopyranoside (). These compounds were investigated for their in vitro inhibitory activity against enzymes involved in neuroinflammatory disorders, including cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and butyrylcholinesterase (BchE) enzymes. All isolates recorded weak-moderate activities against COX-2. However, the polyacetylene glycoside () showed dual inhibition against BchE (IC 14.77 ± 1.55 μM) and 5-LOX (IC 34.59 ± 4.26 μM). Molecular docking experiments were conducted to explain these results, which showed that compound exhibited greater binding affinity to 5-LOX (-8.132 kcal/mol) compared to the cocrystallized ligand (-6.218 kcal/mol). Similarly, showed a good binding affinity to BchE (-7.305 kcal/mol), which was comparable to the cocrystallized ligand (-8.049 kcal/mol). Simultaneous docking was used to study the combinatorial affinity of the unresolved mixture / to the active sites of the tested enzymes. Generally, the individual molecules showed lower docking scores against all the investigated targets compared to their combination, which was consistent with the in vitro results. This study demonstrated that the presence of a sugar moiety (in and ) resulted in dual inhibition of 5-LOX and BchE enzymes compared to their free polyacetylenes analogs. Thus, polyacetylene glycosides could be suggested as potential leads for developing new inhibitors against the enzymes involved in neuroinflammation.