Azolo[5′,1′,2,3]pyrimido[5,4-e]tetrazolo[1,5-c]pyrimidines as dual-action antiglycators and α-glucosidase inhibitors

Abstract

The novel chemotype, azolo[5′,1′:2,3]pyrimido[5,4-e]tetrazolo[1,5-c]pyrimidines 12, with promising dual action antiglycating and α-glucosidase inhibiting activities was developed basen on reaction of 6-(tetrazol-5-yl)-7-aminoazolo[1,5-a]pyrimidines 3 with (het)aroyl chlorides. The conditions for this process were optimized to achieve high yields of heterocycles 12 upon mild conditions whereas azido-tetrazole tautomerism was revealed for these products 12 and it was shown that the equilibrium is shifted towards azide tautomer. The obtained azolo[5′,1′:2,3]pyrimido[5,4-e]tetrazolo[1,5-c]pyrimidines 12 inhibited the glycation reaction in the BSA-glucose assay more strongly than pyridoxamine as a reference compound, which is promising in terms of preventing AGEs assosiated pathologies such as long-term complication of diabetes and cancer. Furthermore, some heterocycles 12 inhibited α-glucosidase in the mid-micromolar range - more effectively than acarbose, with an IC₅₀ 17.52 μM for the lead compound 12k.