Table 1.

Inhibition of trypanothione synthetase (TryS) by N⁵-substituted, 3-chlorokenpaullones.

				% TryS inhibition at 30 μMa or IC50 value (µM)b,c
N5-linker chain	Compound	N5-substitution		LiTryS
None	1	H		NA
	2	CH2CH2OH		∼30
CH2CO-OR1	3	R1 = H		NA
	4	R1 = CH3		3.0 ± 0.7
	5	R1 = CH2CH3		36.2 ± 3.6
	6	R1 = tert-butyl		2.4 ± 0.3
CH2CO-NR1,R2	7	R1 = H,	R2 = H	5.1 ± 0.5
	8	R1 = H,	R2 = NH2	4.0 ± 0.5
	9	R1 = H,	R2 = CH3	0.8 ± 0.1
	10	R1 = CH3,	R2 = CH3	0.5 ± 0.0
	11	R1 = H,	R2 = CH2CH3	1.5 ± 0.2
	12	R1 = CH2CH3,	R2 = CH2CH3	0.5 ± 0.1
	13	R1 = H,	R2 = (CH2)2OH	2.3 ± 0.3
	14	R1 = H,	R2 = C-(CH2OH)3	5.2 ± 0.4
	15	R1 = H,	R2 = tert-butyl	2.3 ± 0.4
	16	R1 = H,	R2 = 1,3,4-thiadiazol-2-yl	∼30
	17	R1 = H,	R2 = 4,5-dihydro-1,3,thiazol-2-yl	∼30
	18	R1 = H,	R2 = 1,3-oxazol-2-yl	20.1 ± 1.5
	19	R1 = H,	R2 = phenyl	∼30
CH2CO-R1	20	R1 = piperazin-1-yl, hydrochloride		0.3 ± 0.0
	21	R1 = 4-methylpiperazin-1-yl		0.4 ± 0.1
	22	R1 = 4-BOC-piperazin-1-yl		∼30
	23	R1 = 4-(pyrimidin-2-yl)piperazin-1-yl		12.5 ± 0.2
	24	R1 = piperidin-1-yl		38.6 ± 1.3
	25	R1 = pyrrolidin-1-yl		0.5 ± 0.2
	26	R1 = morpholin-4-yl		2.8 ± 0.7
CH2CO-NH-CH2-CH2-NR1,R2	MOL2008d	R1 = H,	R2 = CH3	0.15 ± 0.06
	27	R1 = H,	R2 = H, hydrochloride	0.3 ± 0.0
	28	R1 = CH2CH3,	R2 = CH2CH3	0.5 ± 0.1
	29	R1 = H,	R2 = BOC	36.7 ± 5.9
CH2CO-NH-CH2-CH2-R1	30	R1 = morpholin-4-yl		3.3 ± 0.1
	31	R1 = piperidin-1-yl		0.8 ± 0.1
	32	R1 = piperazin-1-yl, dihydrochloride		0.6 ± 0.1
	33	R1 = 4-methylpiperazin-1-yl		1.1 ± 0.3
	34	R1 = 4-BOC-piperazin-1-yl		∼30
CH2CO-NH(CH2)4-NH-R1	35	R1 = H, hydrochloride		0.4 ± 0.1
	36	R1 = BOC		∼30

^aEnzyme inhibition is expressed as % TryS inhibition ± 2σ^n-1.

^bIC₅₀ values with their corresponding standard deviation (± 2σ^n-1) are highlighted in bold italics.

^cFor compounds inhibiting Leishmania infantum TryS by 50 ± 5% at 30 μM, an IC₅₀ of ∼30 µM is assumed.

^dData published in Ref. 20. NA, not active (enzyme activity at 30 μM is > 95%). BOC, refers to a tert-butyloxycarbonyl group.