Identification of Mycobacterium tuberculosis leucyl-tRNA synthetase (LeuRS) inhibitors among the derivatives of 5-phenylamino-2H-[1,2,4]triazin-3-one

Abstract

The increase of antibiotic resistance amongst Mycobacterium tuberculosis strains has become one of the most pressing problems of modern medicine. Therefore, the search of antibiotics against M. tuberculosis with novel mechanisms of action is very important. We have identified inhibitors of M. tuberculosis leucyl-tRNA synthetase (LeuRS) among the derivatives of 5-phenylamino-2H-[1,2,4]triazin-3-one. The most active compounds 5-(5-chloro-2-hydroxy-phenylamino)-6-methyl-2H-[1,2,4]triazin-3-one and 5-(5-chloro-2-hydroxy-phenylamino)-2H-[1,2,4]triazin-3-one inhibit M. tuberculosis LeuRS with IC₅₀ of 7.6 μМ and 7.2 μМ, respectively. It was established that the inhibitory activity of compounds against pathogenic LeuRS is 10-fold better, than for human enzyme.

Keywords:

• Aminoacylation assay
• inhibitor
• leucyl-tRNA synthetase
• Mycobacterium tuberculosis
• virtual screening

Acknowledgements

We thank Dr. Stephen Cusack and Dr. Andres Palencia (EMBL Grenoble Outstation, France) for the gift of clone for expression and purification of M. tuberculosis LeuRS. We thank Dr. Michael Alley (Anacor Pharmaceuticals, USA) for the gift of plasmid for expression and purification of human cytoplasmic LeuRS.

Declaration of interest

There is no declaration of interest for this work.

This work was supported by the Science and Technology Center in Ukraine (contract No. 5218), the National Agency of Science, Innovation and Informatization of Ministry of Education and Science of Ukraine (contract No. DP/337-2013).