Obesity is associated with a significantly increased risk of cardiovascular and metabolic diseases such as diabetes mellitus. Recently, a growing body of evidence shows that phytochemicals, especially many flavonoids, place an inhibitory regulatory effect on adipogenesis, obesity and diabetes. With computer-aided drug discovery, the action modes of more and more bioactive flavonoids are being identified and confirmed at the molecular level. Citrus fruit peels are particularly rich in bioactive flavonoids which have demonstrated strong therapeutic potentials in regulating lipid metabolisms. However, they are usually thrown away after consuming the flesh, sometimes even causing environmental problems. Thus, extraction of useful flavonoids from citrus fruit waste for pharmaceutical industry could be a profitable and environmentally friendly solution in the future, advocating the concepts of circular economy and sustainable society. The aim of this review is to summarize current evidence on the antiobesity and antidiabetic potentials of identified bioactive flavonoids extracted from the peels of citrus fruits. Our results suggest that various citrus fruit peels could be potential sources for novel drugs and nutraceuticals. Combining experimental data and artificial intelligence methods to study citrus flavonoids would facilitate the discovery of novel drugs against obesity and obesity-related metabolic diseases.

Cinnamoyl sucrose esters (CSEs) were evaluated as AGIs and their enzyme inhibition activity and potency were compared with gold standard acarbose. The inhibition activity of the CSEs against α-glucosidase and α-amylase depended on their structure including the number of the cinnamoyl moieties, their position, and the presence or absence of the acetyl moieties. The inhibitory values of the CSEs 2–9 generally increases in the order of mono-cinnamoyl moieties < di-cinnamoyl ≤ tri-cinnamoyl < tetra-cinnamoyl. This trend was supported from both in vitro and in silico results. Both tetra-cinnamoyl CSEs 5 and 9 showed the highest α-glucosidase inhibitory activities of 77 ± 5%, 74 ± 9%, respectively, against acarbose at 27 ± 4%, and highest α-amylase inhibitory activities of 98 ± 2%, 99 ± 1%, respectively, against acarbose at 93 ± 2%. CSEs 3, 4, 6, 7, 8 showed desired higher inhibition of α-glucosidase than α-amylase suggesting potential for further development as AGIs with reduced side effects. Molecular docking studies on CSEs 5 and 9 attributed the high inhibition of these compounds to multiple π-π interactions and favorable projection of the cinnamoyl moieties (especially O-3 cinnamoyl) in the enzyme pockets. This work proposes CSEs as new AGIs with potentially reduced side effects.