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Design and synthesis of amino acids-conjugated heterocycle derived ureas/thioureas as potent inhibitors of protein glycation

Abstract

Protein glycation is believed to play an important role in the development of long-term disorders associated with diabetic complications. In view of the wide occurrence of advanced glycation end products (AGE’s) and the oxidative stress derived from them in a variety of diabetic complications, it would be of great interest to identify and develop AGE inhibitors. In this study, synthesis and in vitro antiglycation activity of a small library of forty urea/thiourea derivatives of Phe/Tyr/Glu/Lys-benzisoxazole hybrids are reported. Structures of the compounds were confirmed by IR, NMR, mass spectrometry, and elemental analysis. Most of the title compounds exhibited promising activity. Best antiglycation activity was found for Tyr analogue with methoxy group as a substituent particularly at the para position with IC50 value of 1.9 μM against the positive control, Rutin, with IC50 = 41.9 μM. Thus, the title compounds represent novel class of potent antiglycating agents.

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Abbreviations

AGE’s:

advanced glycation end products

BSA:

bovine serum albumin

EDCI:

1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide

Het:

[3-(4-piperidyl)-6-fluoro-1,2-benzisoxazole]

HOBt:

1-hydroxybenzotriazole

NMM:

N-methyl morpholine

TCA:

trichloroacetic acid

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Correspondence to D. Channe Gowda.

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Shantharam, C.S., Suyoga Vardhan, D.M., Suhas, R. et al. Design and synthesis of amino acids-conjugated heterocycle derived ureas/thioureas as potent inhibitors of protein glycation. Russ J Bioorg Chem 40, 443–454 (2014). https://doi.org/10.1134/S1068162014040128

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  • DOI: https://doi.org/10.1134/S1068162014040128

Keywords

  • amino acids
  • conjugation
  • heterocycle
  • urea/thiourea
  • antiglycation