Poliothrysoside and its derivatives as novel insulin sensitizers potentially driving AMPK activation and inhibiting adipogenesis

•Poliothrysoside (1), a phenolic glycoside was identified as an antidiabetic lead.•It was chemically modified to give fifteen derivatives 2–16.•They were analyzed for glucose uptake potential in resistant 3T3-L1 adipocytes.•2 significantly increased insulin sensitivity in concentration dependent manner.•It activated AMPK signaling and also inhibited adipogenesis in 3T3-L1 adipocytes.

In our efforts to develop safe and active chemical entities from nature, we first identified poliothrysoside (1), a phytoconstituent isolated from Flacourtia indica, possessing antidiabetic potential. Subsequently, fifteen derivatives (2–16) were synthesized to assess the activity profile of this class. All the compounds were analyzed for their glucose uptake potency in chronic insulin-induced insulin resistant 3T3-L1 adipocytes. Interestingly, compound 2 exhibited strong ability to increase the insulin sensitivity, primarily activating the AMPK signaling pathway and also inhibited the adipogenesis in 3T3-L1 adipocytes, in concentration dependent manner. Overall, these studies suggest the potential of poliothrysoside and its derivatives as promising leads for non-insulin dependent type 2 diabetes (T2D).

Graphical abstractPoliothrysoside derivative 2 increased the insulin sensitivity in resistant cells by activating the AMPK signaling pathway and it also inhibited the adipogenesis in 3T3-L1 adipocytes.Figure optionsDownload full-size imageDownload as PowerPoint slide