Synthesis and biological evaluation of novel ursolic acid analogues as potential α-glucosidase inhibitors

Abstract

Ursolic acid (UA) is a major pentacyclic triterpenoid in plants, vegetables and fruits, which has been reported to have a potential anti-diabetic activity. Despite various semi-synthetic ursolic acid derivatives already described, new derivatives still need to be designed and synthesized to further improve the anti-diabetic activity. In the present study, two series of novel UA derivatives, were synthesized and their structures were confirmed. The enzyme inhibition activities of semi-synthesized analogues against α-glucosidase were screened in vitro. The results indicated that most of UA derivatives showed a significant inhibitory activity, especially analogues UA-O-i with the IC50 values of 0.71 ± 0.27 μM, which was more potential than other analogues and the positive control. Furthermore, molecular docking studies were also investigated to verify the in vitro study. Structure modification at the C-3 and C-2 positions of UA was an effective approach to obtain the desired ligand from UA, whose structure was in accordance with the active pocket. Besides, suitable hydrophobic group at the position of C-2 might play an important role for the docking selectivity and binding affinity between the ligand and the homology modelling protein. These results could be helpful for designing more potential α-glucosidase inhibitors from UA in the future.

Dietary ursolic acid improves health span and life span in male Drosophila melanogaster

“…C) in UA‐administered flies compared to controls, improving the energy resources and hence the climbing ability of aged male w 1118 flies. Although UA exhibits inhibitory effects on porcine α‐amylase and yeast α‐glucosidase activity in vitro glucose levels were not lowered but enhanced by UA intake in male fruit flies, indicating srl ‐mediated glucose upregulation by UA.…”

“…Similarly, UA-triggered longevity in C. elegans is similarly genetically controlled as dietary restriction-mediated longevity [56]. UA was reported to inhibit glucosidase activity in vitro [50]. Although sucrose represents the major carbohydrate source in the experimental diet, a potential UA-dependent decrease in carbohydrate digestion did not appear to have led to the apparent DR-mimicking effect, as both the quantity of ingested food ( Fig.…”

“…UA stimulates protein synthesis in myotubes, suppresses protein degradation, induces muscle fiber rejuvenation, increases exercise capacity in vitro and in vivo in mice and counteracts age‐related weakness and muscle loss in mice . UA slightly but significantly increased protein levels in male fruit flies by 9%, which may indicate increased muscle mass and may have contributed to the UA‐dependent climbing activity enhancement as well.…”

“…Additionally, UA induces autophagy in multiple cell culture models [44,45] and in vivo [46]. Both in vitro studies and rodent in vivo studies indicate the anticatabolic activity of UA which counteracts age-related deficits in skeletal muscle strength, quality, and mass and promotes an increase in muscle fiber rejuvenation [47][48][49][50]. All of the abovementioned properties make UA a very promising secondary plant metabolite that may be able to improve life span and health span in several species.…”

Semisynthesis of ursolic acid‐2‐(2‐thienylidene)‐oxadiazole hybrid molecule and an evaluation of its COX inhibition property

“…Compound 3 obtained was then subjected to Claisen-Schmidt condensation with various heterocyclic aldehydes a to f. The reaction was conducted in the presence of methanolic potassium hydroxide by refluxing the mixture for 8 hours [13] as shown in Scheme 2.…”