Discovery of Helminthosporin, an Anthraquinone Isolated from Jacq as a Dual Cholinesterase Inhibitor.

Natural products have extensively contributed toward the discovery of new leads for Alzheimer's disease. During our search for new inhibitors of cholinesterase enzymes from natural sources, the ethyl acetate (EtOAc) extract of Jacq was identified as a dual cholinesterase inhibitor with IC values of 2.7 and 11.4 μg/mL against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), respectively. The phytochemical investigation of the EtOAc extract has resulted in isolation of four anthraquinones, namely, helminthosporin, emodin, chrysophanol, and physcion, amongst which the helminthosporin has been isolated for the first time from sp. All isolated secondary metabolites have displayed significant inhibition of EeAChE with IC values of 2.63, 15.21, 33.7, and 12.16 μM, respectively. In addition, the helminthosporin was also found to inhibit BChE with an IC value of 2.99 μM. The enzyme kinetic study has indicated that helminthosporin inhibits AChE and BChE in a noncompetitive manner with values of 10.3 and 12.3 μM, respectively. The results of molecular modeling and propidium iodide displacement assay have revealed that helminthosporin occupies the peripheral anionic site of the active site gorge of AChE. In the PAMPA-BBB permeability assay, helminthosporin was found to possess high BBB permeability ( = 6.16 × 10 cm/s). In a nutshell, helminthosporin has been identified as a brain permeable dual cholinesterase inhibitor, and thus its further synthetic exploration is warranted for optimization of its potency.