Spacered With Tetrazole Oleanolic and Ursolic Indolo-Acids Are Strong Inhibitors of α-Glucosidase

A series of oleanane and ursane-type derivatives conjugated with a tetrazole cycle were obtained by 2 + 3 cycloaddition of C28-cyanoalkyl esters with sodium azide in the presence of NH₄Cl. It was shown that 2,3-indolo-oleanolic and ursolic acids with a tetrazole moiety exhibited strong inhibitory activity against α-glucosidase with IC₅₀ values of 1.15 and 1.28 μM, respectively, being more active than the marketed drug acarbose (IC₅₀ 649.94 μM). It was also established that the NH of the tetrazole moiety forms a hydrogen bond with the backbone of Ser308, which allowed an explanation for the drastically improved activity of the tetrazolyl derivatives. The tetrazole derivative of 2,3-indolo-oleanolic acid was also identified as a potential inhibitor of NLRP3 activation, reducing the area of LPS + ATP-stimulated macrophages by 33%, not much less than glibenclamide (51%).