Design, Synthesis And Bioactivities Study Of Novel Pyrrole Alkaloids And Aloe-Emodin Derivatives

In this study, a series of novel pyrrole alkaloids and aloe-emodin derivatives were designed and synthesized. The acetylcholinesterase, xanthine oxidase, and acetolactatesynthase inhibitory activities of these compounds were screened. Their structure-active relationships and mechanisms of enzyme-inhibition were also investigated.Twelve pyrrole alkaloids were synthesized with the commercial available reagents. Three series of26aloe-emodin derivatives were synthesized starting from aloe-emodin.The12pyrrole alkaloids showed weak acetylcholinesterase-inhibition activities with the inhibitory rats below50%at the concentration of100μg/mL. Among the26aloe-emodin derivatives,5compounds showed remarkable acetylcholinesterase inhibitory activities with the inhibitory rate above80%at the concentration of100Lg/mL. The compound C3which has a pyridinium substituent possessed the best inhibitory activity of acetylcholinesterase (IC50=0.09μM). The coumpound can inhibite acetylcholinesterase dose-dependently. The compound C3was a mixed-type acetylcholinesterase inhibitor with the Ki value of0.279μM. The docking study demonstrated that C3could interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) of acetylcholinesterase. The structure-activity study and the docking results both showed that the free8-OH and the quaternary ammonium fragment are important for the activity of the compound. So, compound C3was a novel acetylcholinesterase and may be a candidate chemical for the treatment of AD.The12pyrrole alkaloids possessed weak xanthine oxidase inhibitory activities. None of the12compounds could inhibit the xanthine oxidsase acitvity more than50%at the concentration of50μM. Four of the26aloe-emodin derivatives showed significant xanthine oxidase inhibitory activities with IC50of2.79μM,3.87μM,8.43μM and18.67μM respectively, which were compared with the positive control of allopurinol (IC50=11.23μM). Among them, the compound B1possessed the best xanthine oxidase-inhibition activity with IC50of2.79μM. The Lineweaver-Burk plot revealed that B1was a mixed-type xanthine oxidase inhibitor. The docking study demonstrated that B1 could interact with the catalyze site of xanthine oxidase. The structure-activity study and the docking results both showed that the free1,8-OH and the side chain are important for the xanthine oxidase inhibitory activity of the compounds. Therefor, compound B1was a novel non-purine xanthine-oxidase inhibitor and may be a leading compound for the development of anti-gout drugs.The anti-acetolactatesynthase activities of26aloe-emodin derivatives were studied by the virtual screening approach with the Dock Ligands (LibDock) program in Discovery Studio. Eighteen of26aloe-emodin derivatives and aloe-emodin itself could docked with acetolactatesynthase. Among the19compounds, compound C11possessed the hightest LibDockScore values and the compound B3and B4possessed the lowest LibDockScore values which are lower than that of the Chlorimuron ethyl. Among the18aloe-emodin derivatives,13compounds docked better with acetolactatesynthase than aloe-amodin with higher LibDockScore values. These result showed that it maybe an effective method to develop novel acetolactatesynthase inhibitors as herbicides by modification of aloe-amodin.