Journal of Enzyme Inhibition and Medicinal Chemistry (Dec 2024)

Novel hybrids of 1,2,3-triazole-benzoxazole: design, synthesis, and assessment of DprE1 enzyme inhibitors using fluorometric assay and computational analysis

  • Manisha Singh,
  • Sarah M. Batt,
  • Christian S. C. Canales,
  • Fernando R. Pavan,
  • Sethu Arun Kumar,
  • Handattu S. Akshatha,
  • Meduri Bhagyalalitha,
  • Karthik G. Pujar,
  • Durgesh Bidye,
  • Gurubasavaraj V. Pujar,
  • Gurdyal S. Besra

DOI
https://doi.org/10.1080/14756366.2024.2403744
Journal volume & issue
Vol. 39, no. 1

Abstract

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Decaprenylphosphoryl-β-D-ribose-oxidase (DprE1), a subunit of the essential decaprenylphosphoribose-2′-epimerase, plays a crucial role in the synthesis of cell wall arabinan components in mycobacteria, including the pathogen responsible for tuberculosis, Mycobacterium tuberculosis. In this study, we designed, synthesised, and evaluated 15 (BOK-1–BOK-10 and BOP-1–BOP-5) potential inhibitors of DprE1 from a series of 1,2,3-triazole ligands using a validated DprE1 inhibition assay. Two compounds, BOK-2 and BOK-3, demonstrated significant inhibition with IC50 values of 2.2 ± 0.1 and 3.0 ± 0.6 μM, respectively, whereas the standard drug (TCA-1) showed inhibition at 3.0 ± 0.2 μM. Through molecular modelling and dynamic simulations, we explored the structural relationships between selected 1,2,3-triazole compounds and DprE1, revealing key features for effective drug–target interactions. This study introduces a novel approach for designing ligands against DprE1, offering a potential therapeutic strategy for tuberculosis treatment.

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