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Synthesis and characterization of novel acyl hydrazones derived from vanillin as potential aldose reductase inhibitors

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Abstract

In the polyol pathway, aldose reductase (AR) catalyzes the formation of sorbitol from glucose. In order to detoxify some dangerous aldehydes, AR is essential. However, due to the effects of the active polyol pathway, AR overexpression in the hyperglycemic state leads to microvascular and macrovascular diabetic problems. As a result, AR inhibition has been recognized as a potential treatment for issues linked to diabetes and has been studied by numerous researchers worldwide. In the present study, a series of acyl hydrazones were obtained from the reaction of vanillin derivatized with acyl groups and phenolic Mannich bases with hydrazides containing pharmacological groups such as morpholine, piperazine, and tetrahydroisoquinoline. The resulting 21 novel acyl hydrazone compounds were investigated as an inhibitor of the AR enzyme. All the novel acyl hydrazones derived from vanillin demonstrated activity in nanomolar levels as AR inhibitors with IC50 and KI values in the range of 94.21 ± 2.33 to 430.00 ± 2.33 nM and 49.22 ± 3.64 to 897.20 ± 43.63 nM, respectively. Compounds 11c and 10b against AR enzyme activity were identified as highly potent inhibitors and showed 17.38 and 10.78-fold more effectiveness than standard drug epalrestat. The synthesized molecules’ absorption, distribution, metabolism, and excretion (ADME) effects were also assessed. The probable-binding mechanisms of these inhibitors against AR were investigated using molecular-docking simulations.

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Acknowledgements

This work was supported by the Research Fund of Ardahan University (Grant Number 2019-008), the Research Fund of Erzincan Binali Yıldırım University (Grant Number FBA-2017-501), and the Research Fund of Anadolu University (Grant Number 2102S003).

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Authors and Affiliations

  1. Department of Pharmacy Services, Nihat Delibalta Göle Vocational High School, Ardahan University, 75700, Ardahan, Turkey

    Yeliz Demir

  2. Department of Material and Material Processing Technologies, Kars Vocational School, Kafkas University, 36100, Kars, Turkey

    Feyzi Sinan Tokalı & Erbay Kalay

  3. Department of Biochemistry, Faculty of Pharmacy, Erzincan Binali Yıldırım University, 24002, Erzincan, Turkey

    Cüneyt Türkeş

  4. Department of Veterinary Physiology, Faculty of Veterinary Medicine, Kafkas University, 36100, Kars, Turkey

    Pelin Tokalı

  5. East Anatolian High Technology Application and Research Center, Atatürk University, 25240, Erzurum, Turkey

    Osman Nuri Aslan

  6. Department of Chemistry, Faculty of Arts and Science, Kafkas University, 36100, Kars, Turkey

    Kıvılcım Şendil

  7. Department of Biochemistry, Faculty of Pharmacy, Anadolu University, 26470, Eskisehir, Turkey

    Şükrü Beydemir

  8. The Rectorate of Bilecik Şeyh Edebali University, 11230, Bilecik, Turkey

    Şükrü Beydemir

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Demir, Y., Tokalı, F.S., Kalay, E. et al. Synthesis and characterization of novel acyl hydrazones derived from vanillin as potential aldose reductase inhibitors. Mol Divers 27, 1713–1733 (2023). https://doi.org/10.1007/s11030-022-10526-1

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