Abstract
Plant secondary metabolites have a long history of potential use in managing human diseases by inhibiting enzymes that are highly expressed due to various pathogenic conditions. Prostaglandins (PGs) and leukotrienes (LTs) are proinflammatory mediators synthesized from arachidonic acid (AA) by the action of cyclooxygenases (COXs) and lipoxygenases (LOXs), respectively. Particularly, COX-2/5-LOX enzymes play a significant role in inflammatory processes and the pain associated with them. Butyrylcholinesterase (BchE) was recently suggested as a more reliable potential target for sustaining normal cholinergic function. In an attempt to identify new potential COX-2/5-LOX and BchE inhibitors, a phytochemical investigation of Launaea capitata (Spreng.) Dandy (Asteraceae) was executed. This investigation led to the isolation of a new digalactosyldiacylglycerol isomer, namely 1,2-dilinolenoyl-3-O-(alpha-galactopyranosyl-(1,6)-O-alpha-D-galactopyranosyl)-sn-glycerol (1) in addition to 1-myristoyl-2-palmitoyl-3-O-(alpha-galactopyranosyl-(1,6)-O-beta-D-galactopyranosyl)-sn-glycerol (2), which was isolated herein for the first time from nature. The structures of the two isolates were elucidated by using 1D-, 2D-NMR, and ESI-MS spectroscopy. Compounds 1 and 2 exhibited good in vitro inhibitory activities against 5-LOX (59.01 and 21.67 mu g/mL) and BchE (13.37 and 24.32 mu g/mL), respectively. However, they exhibited weak inhibition of COX-2 (110.44 and 179.63 mu g/mL, respectively). These inhibitory activities were explained in silico using a computational docking study. The docking results were consistent with the in vitro enzyme inhibitory activity. The lowest binding affinity for 1 and 2 was observed against COX-2 (-7.360 and -5.723 kcal/mol), whereas they exhibited greater binding affinity to 5-LOX (-8.124 and -8.634 kcal/mol), respectively, compared to its natural substrate, AA (-5.830 kcal/mol). Additionally, 1 and 2 exhibited remarkable binding affinity to BchE (-8.313 kcal/mol and -7.502 kcal/mol, respectively), which was comparable to the co-crystallized ligand, thioflavin T (-8.107 kcal/mol). This was related to the multiple and crucial hydrogen bonding interactions of these compounds with the amino acid residues in the active sites of the investigated enzymes. This study demonstrated the role of plant galactolipids as potential leads in the development of new drugs that alleviate the neuroinflammatory conditions associated with various diseases, such as Alzheimer's disease and Type 2 diabetes mellitus.