5-Phenylamino-2H-[1,2,4]triazin-3-ones

The increasing 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 μM and 7.2 μM, respectively. It was established that the inhibitory activity of compounds against pathogenic LeuRS is ten-fold better, than for human enzyme. These inhibitors demonstrate low antibacterial activity against M. tuberculosis H37Rv and need further structural optimization to improve physicochemical properties and antibiotic potency.   

Figure 1. The binding mode of compound 5-(5-Chloro-2-hydroxy-phenylamino)-6-methyl-2H-[1,2,4]triazin-3-one in the active site of LeuRS M. tuberculosis. Hydrogen bonds are shown by the dotted lines.

• Identification of Mycobacterium tuberculosis leucyl-tRNA synthetase (LeuRS) inhibitors among the derivatives of 5-phenylamino-2H-[1,2,4]triazin-3-one. Gudzera OI, Golub AG, Bdzhola VG, Volynets GP, Kovalenko OP, Boyarshin KS, Yaremchuk AD, Protopopov MV, Yarmoluk SM, Tukalo MA. J Enzyme Inhib Med Chem. 2016, 31(2): 201-207.