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

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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%).