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

  • Bioorg Med Chem Lett. 2025 Dec 1:128:130333. doi: 10.1016/j.bmcl.2025.130333.
Grigoriy V Urakov  1 ,  Konstantin V Savateev  2 ,  Pavel A Slepukhin  3 ,  Vladimir L Rusinov  4 ,  Umida M Ibragimova  5 ,  Roman D Danilov  5 ,  Xenia I Zhukova  5 ,  Svetlana A Sorokina  5 ,  Violetta R Raiberg  5 ,  Roman A Litvinov  5 ,  Alexander A Spasov  5 ,  Denis A Babkov  5
Affiliations
  • 1. Ural Federal University named after the First President of Russia B.N. Eltsin, Mira St. 19, Yekaterinburg 620002, Russian Federation.
  • 2. Ural Federal University named after the First President of Russia B.N. Eltsin, Mira St. 19, Yekaterinburg 620002, Russian Federation. Electronic address: [email protected].
  • 3. Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, Sofii Kovalevskoy St. 22, Yekaterinburg 620137, Russian Federation.
  • 4. Ural Federal University named after the First President of Russia B.N. Eltsin, Mira St. 19, Yekaterinburg 620002, Russian Federation; Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, Sofii Kovalevskoy St. 22, Yekaterinburg 620137, Russian Federation.
  • 5. Volgograd State Medical University, Pavshikh Bortsov Sq. 1, Volgograd 400131, Russian Federation.
PMID: 40651538 DOI: 10.1016/j.bmcl.2025.130333
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.

Keywords
Antiglycation; Azido-tetrazole tautomerism; Azolopyrimidines; Diabetes; Dual-action; α-Glucosidase.
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