Das_2018_Bioorg.Chem_81_340

Synthesis of natural products has speeded up drug discovery process by minimizing the time for their purification from natural source. Several diseases like Alzheimer's disease (AD) demand exploring multi targeted drug candidates, and for the first time we report the multi AD target inhibitory potential of synthesized dihydroactinidiolide (DA). Though the activity of DA in several solvent extracts have been proved to possess free radical scavenging, anti bacterial and anti cancer activities, its neuroprotective efficacy has not been evidenced yet. Hence DA was successfully synthesized from beta-ionone using facile two-step oxidation method. It showed potent acetylcholinesterase (AChE) inhibition with half maximal inhibitory concentration (IC50) 34.03nM, which was further supported by molecular docking results showing strong H bonding with some of the active site residues such as GLY117, GLY119 and SER200 of AChE. Further it displayed DPPH and (.NO) scavenging activity with IC50 value 50nM and metal chelating activity with IC50 >270nM. Besides, it significantly prevented amyloid beta25-35 self-aggregation and promoted its disaggregation at 270nM. It did not show cytotoxic effect towards Neuro2a (N2a) cells up to 24h at 50 and 270nM while it significantly increased viability of amyloid beta25-35 treated N2a cells through ROS generation at both the concentrations. Cytotoxicity profile of DA against human PBMC was quite impressive. Hemolysis studies also revealed very low hemolysis i.e. minimum 2.35 to maximum 5.61%. It also had suitable ADME properties which proved its druglikeness. The current findings demand for further in vitro and in vivo studies to develop DA as a multi target lead against AD.