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ORIGINAL RESEARCH article

Front. Endocrinol.

Sec. Diabetes: Molecular Mechanisms

Volume 16 - 2025 | doi: 10.3389/fendo.2025.1638013

This article is part of the Research TopicFuture Horizons in Diabetes: Integrating Gut Microbiota, AI, and Personalized CareView all 5 articles

Future Horizons in Diabetes Treatment: Hypoglycemic Activity Of [1,2,4]Triazino[2,3-c]Quinazoline Derivatives

Provisionally accepted
Serhii  TrzhetsynskyiSerhii Trzhetsynskyi1Inna  NosulenkoInna Nosulenko1Anna  KinichenkoAnna Kinichenko1Dmytro  SkorynaDmytro Skoryna1Halyna  BerestHalyna Berest1Volodymyr  ShvetsVolodymyr Shvets1Oleksii  VoskoboinikOleksii Voskoboinik2Serhii  KovalenkoSerhii Kovalenko3Pavlo  PetakhPavlo Petakh4*Oleksandr  KamyshnyiOleksandr Kamyshnyi5*
  • 1Zaporizkij Derzhavnij Medichnij Universitet, Zaporizhzhia, Ukraine
  • 2Nacional'nij universitet Zaporiz'ka politehnika, Zaporizhzhia, Ukraine
  • 3Dniprovs'kij nacional'nij universitet imeni Olesa Goncara, Dnipro, Ukraine
  • 4Uzhhorod National University, Uzhhorod, Ukraine
  • 5Ternopil's'kij nacional'nij medicnij universitet imeni I A Gorbacevs'kogo, Ternopil, Ukraine

The final, formatted version of the article will be published soon.

Abstract Type 2 diabetes mellitus (T2DM) remains a significant and multifaceted challenge for modern healthcare. This issue becomes even more pressing during times of armed conflict and the subsequent recovery period, as research indicates an increased incidence of T2DM among combat veterans, largely due to post-traumatic stress disorder. Although numerous antidiabetic drugs are currently available, achieving optimal control of hyperglycemia continues to be problematic. In this context, and as part of a focused search for biologically active substances within the class of substituted and condensed [1,2,4]triazino[2,3-c]quinazolines, we explored the hypoglycemic effects of a newly synthesized series of such compounds. The study involved 21 synthesized compounds bearing the [1,2,4]triazino[2,3-c]quinazoline core. Experiments were conducted using white Wistar rats weighing between 260 and 280 grams. Prescreening of hypoglycemic activity was evaluated based on changes in blood glucose levels before and after compound administration by rats with normoglycemia. Compounds that demonstrated the most pronounced activity were selected for extended pharmacological evaluation using oral glucose tolerance test, adrenaline test, and rapid insulin tests in rats with dexamethasone-induced insulin resistance. Initial pharmacological screening under normoglycemic conditions showed that seven studied compounds significantly lowered blood glucose levels. Follow-up investigations validated the high hypoglycemic effect of 1,2,2-trimethyl-3-(3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)cyclopentane-1-carboxylic acid. Among the tested substances, compound 3-phenyl-6-(phenylamino)-2H-[1,2,4]triazino[2,3-c]quinazolin-2-one was the only one to exhibit moderate activity in the adrenaline tolerance test. None of the compounds enhanced insulin sensitivity in the liver or peripheral tissues. The findings suggest that substituted [1,2,4]triazino[2,3-c]quinazolines constitute a promising scaffold for the development of new hypoglycemic agents. 11β-Hydroxysteroid dehydrogenase is the most likely molecular target for lead-compound 1,2,2-trimethyl-3-(3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)cyclopentane-1-carboxylic acid.

Keywords: [1,2,4]triazino[2,3-c]quinazolines, Hypoglycemic activity, Diabetes Mellitus, Insulinresistance, molecular docking

Received: 30 May 2025; Accepted: 05 Sep 2025.

Copyright: © 2025 Trzhetsynskyi, Nosulenko, Kinichenko, Skoryna, Berest, Shvets, Voskoboinik, Kovalenko, Petakh and Kamyshnyi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Pavlo Petakh, Uzhhorod National University, Uzhhorod, Ukraine
Oleksandr Kamyshnyi, Ternopil's'kij nacional'nij medicnij universitet imeni I A Gorbacevs'kogo, Ternopil, Ukraine

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