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Pyrazole and Triazole Derivatives as Mycobacterium tuberculosis UDP-Galactopyranose Inhibitors

Dalia M Ahmed1,2, Jeffrey M Chen3,4,5, David A R Sanders1

  • 1Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, SK S7N 5C9, Canada.

Pharmaceuticals (Basel, Switzerland)
|February 26, 2022
PubMed

Insights

Researchers explored pyrazole and triazole analogues targeting Mycobacterium tuberculosis UDP-galactopyranose mutase (MtbUGM). While most compounds inhibited MtbUGM, none showed significant antituberculosis activity, highlighting challenges in developing new anti-TB drugs.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Microbiology

Background:

  • UDP-galactopyranose mutase (UGM) is crucial for bacterial cell wall synthesis and absent in mammals, making it a potential drug target.
  • Mycobacterium tuberculosis UGM (MtbUGM) is a promising target for novel antituberculosis agents.
  • Previous research identified MS208 as a mixed inhibitor of MtbUGM, targeting an allosteric site.

Purpose of the Study:

  • To investigate the structure-activity relationship of pyrazole and triazole analogues based on the MS208 scaffold as MtbUGM inhibitors.
  • To evaluate the antituberculosis activity of these synthesized compounds against Mycobacterium tuberculosis.

Main Methods:

  • Synthesis of thirteen pyrazole and triazole analogues.
  • In vitro testing of compounds against MtbUGM enzyme activity.
  • In vitro evaluation of compounds against Mycobacterium tuberculosis growth.

Main Results:

  • Most synthesized analogues exhibited MtbUGM inhibitory activity.
  • The pyrazole derivative DA10 demonstrated competitive inhibition of MtbUGM with a Ki of 51 ± 4 µM.
  • Structural modifications to MS208 did not enhance antituberculosis activity; DA10 did not inhibit M. tuberculosis growth.

Conclusions:

  • The study provides insights into the structure-activity relationship of MtbUGM inhibitors.
  • Developing effective antituberculosis agents targeting MtbUGM requires further optimization beyond simple enzyme inhibition.
  • Novel strategies are needed to translate MtbUGM inhibition into bacterial growth inhibition.
Keywords:
UDP-galactopyranose mutaseantituberculosisenzyme kineticsinhibitorspyrazolestriazoles

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