Synthesis and bioactivities evaluation of oleanolic acid oxime ester derivatives as α-glucosidase and α-amylase inhibitors

Abstract

Different oleanolic acid (OA) oxime ester derivatives (3a-3t) were designed and synthesised to develop inhibitors against α-glucosidase and α-amylase. All the synthesised OA derivatives were evaluated against α-glucosidase and α-amylase in vitro. Among them, compound 3a showed the highest α-glucosidase inhibition with an IC₅₀ of 0.35 µM, which was ∼1900 times stronger than that of acarbose, meanwhile compound 3f exhibited the highest α-amylase inhibitory with an IC₅₀ of 3.80 µM that was ∼26 times higher than that of acarbose. The inhibition kinetic studies showed that the inhibitory mechanism of compounds 3a and 3f were reversible and mixed types towards α-glucosidase and α-amylase, respectively. Molecular docking studies analysed the interaction between compound and two enzymes, respectively. Furthermore, cytotoxicity evaluation assay demonstrated a high level of safety profile of compounds 3a and 3f against 3T3-L1 and HepG2 cells.

Highlights

1. Oleanolic acid oxime ester derivatives (3a–3t) were synthesised and screened against α-glucosidase and α-amylase.

2. Compound 3a showed the highest α-glucosidase inhibitory with IC50 of 0.35 µM.

3. Compound 3f presented the highest α-amylase inhibitory with IC50 of 3.80 µM.

4. Kinetic studies and in silico studies analysed the binding between compounds and α-glucosidase or α-amylase.

Graphical abstract

Keywords:

• Oleanolic acid
• structural modification
• α-glucosidase
• α-amylase
• enzyme inhibition

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was financially supported by the National Natural Science Foundation of China [No. 81803390], Natural Science Foundation of Guangdong Province [No. 2021A1515010221], Special Fund Project of Science and Technology Innovation Strategy of Guangdong Province 2018 and 2020 [No. Jiangke (2018)352 and Jiangke (2020)182], Department of Education of Guangdong Province [Nos. 2017KSYS010, 2019KZDXM035, 2021KCXTD044, 2021KTSCX135], Special Funds for the Cultivation of Guangdong College Students’ Scientific and Technological Innovation (“Climbing Program” Special Funds, pdjh2021a0504) and Jiangmen City Science and Technology Basic Research Project [No. 2020030101030005457].