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

Figures & data

Figure 1. Chemical structure (a) and binding mode of compound 1 in the active site of LeuRS M. tuberculosis (b). Hydrogen bond is indicated by green dotted line.

Table 1. Chemical structure of compounds and residual activity of M. tuberculosis LeuRS in the presence of compound at 100 μM.

Compound	Chemical structure	LeuRS residual activity, %	Compound	Chemical structure	LeuRS residual activity, %
2		2.3 (IC50 = 7.6 μM)	3		18 (IC50 = 7.2 μM)
4		40	5		100
6		100	7		55
8		100	9		67
10		71	11		72
12		64	13		70
14		57	15		70
16		72	17		45
18		70	19		70
20		69	21		55
22		38	23		71
24		40	25		72
26		42	27		72
28		44	29		73
30		37	31		65
32		28	33		42
34		57	35		39
36		52	37		36
38		100	39		100
40		36	41		100
42		36	43		86
44		36	45		93
46		26	47		100
48		70	49		100
50		36	51		37
52		26	53		100
54		29	55		94
56		83	57		70
58		70	59		71
60		51	61		61
62		100	63		56
64		100

Table 2. Compounds inhibitory activity toward M. tuberculosis LeuRS and human cytoplasmic LeuRS.

Compounds	M. tuberculosis IC50 (μM)	Human (cytoplasmic) IC50 (μM)	Selectivity index (IC50Hum/IC50Tub)
2	7.6	68.9	9
3	7.2	76.5	11

Figure 2. Binding modes of compounds 2 (a) and 3 (b) in the active site of LeuRS M. tuberculosis. Hydrogen bonds are shown by the green dotted lines.