Table 1 Correlation between the kinetics of inactivation of Mtb-DprE1 with cellular potency by BTZs and BOZs.


A series of Nitrobenzothiazinones (Nitro-BTZs)

k_inact/K_i (M⁻¹ s⁻¹)	39 ± 2	17 ± 2	240 ± 16	340 ± 50
CLND Solubility (μM)	370	≥450	90	11
MIC Mtb-H37Rv (n = 3)	3.3 μM 1.2 μg/ml	5.9 μM 2.1 μg/ml	0.8 μM 0.31 μg/ml	1.6 μM 0.6 μg/ml
MIC M. vaccae 10670 (n = 1)	1.1 μM 0.4 μg/ml	8.6 μM 3.1 μg/ml	<0.13 μM <0.05 μg/ml	0.5 μM 0.2 μg/ml
A series of Nitrobenzoxacinone (Nitro-BOZs) analogues of the Nitro-BTZs (above)

k_inact/K_i (M⁻¹ s⁻¹)	5.6 ± 0.1	4.2 ± 0.1	7.7 ± 0.3
CLND Solubility (μM)	≥510	≥510	130
MIC Mtb-H37Rv (n = 3)	16 μM 5.3 μg/ml	3.9 μM 1.4 μg/ml	6.5 μM 2.4 μg/ml
MIC M. vaccae 10670 (n = 1)	4.6 μM 1.6 μg/ml	18 μM 6.2 μg/ml	0.5 μM 0.2 μg/ml
The most potent Nitro-BTZs and Nitro-BOZ

k_inact/K_i (M⁻¹ s⁻¹)	720 ± 20	N.A.^c	300 ± 40
CLND Solubility (μM)	32	32	12
MIC Mtb-H37Rv (n = 3)	2.3 nM 1 ng/ml	0.42 nM 0.19 ng/ml	310 nM 0.14 μg/ml
MIC M. vaccae 10670 (n = 1)	1 nM 0.4 ng/ml	N.D.	<110 nM <0.05 μg/ml
Reduced forms of nitro-BTZs

Redox status relative to Nitro-BTZs	2-electron reduced	4-electron reduced	2-electron reduced
k_inact/K_i (M⁻¹ s⁻¹)	N.A.^a	N.A.^b	39 ± 1
CLND Solubility (μM)	250	10	210
Mtb-H37Rv MIC (n = 3)	82% Inhibition at 80 μM	>80 μM	67% Inhibition at 0.16 μM
M. vaccae 10670 MIC (n = 1)	73 μM 25 μg/ml	18 μM 6.2 μg/ml	0.06 μM 0.03 μg/ml

^ak_inact/K_i value for 1 could not be obtained because the time-courses only mildly deviate from linearity in the first 100 min of reaction making fitting to Eq. 1 difficult; the IC₅₀ decreases from 5 to 3 μM during the first 100 min of reaction (see Fig. S1A).
^bk_inact/K_i value for 2 could not be obtained because the k_obs versus inhibitor concentration relationship was concave up; the IC₅₀ decreases from 3.5 to 0.8 μM during the first 100 min of reaction.
^ck_inact/K_i value for 13 could not be obtained using the present assay due to tight-binding limit considerations¹⁹; the 10–170 nM inhibitor concentration range where inhibition is observed is less than or equal to the concentration of DprE1 in the assay resulting in inhibitor depletion over time (see Fig. S1A).

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