Table 2.

Biological activity of N⁵-substituted, 3-chlorokenpaullones.

N5-linker	Compound	N5-substitution	Macrophages		EC50 (µM) and [SI]c
			% infection by L. braziliensis at 10 µMa	% cytotoxicity at 100 µMb or CC50 (µM)	Amastigotes
					L. braziliensis	L. infantum
none	1	H	ND	0 at 200 µM
CH2CO-OR1	6	R1 = tert-butyl	89 ± 13	64 ± 0
CH2CO-NR1,R2	9	R1 = H, R2 = CH3	107 ± 2	93 ± 4
	10d	R1, R2 = CH3	72 ± 4 at 5 µM	21 ± 1
	12	R1, R2 = CH2CH3	82 ± 14	24 ± 8
	15	R1 = H, R2 = tert-butyl	104 ± 1	48 ± 8
CH2CO-R1	20	R1 = piperazin-1-yl, hydrochloride	15 ± 1 at 5 µM	8.1 ± 0.1	0.2-0.4e [≥21]	0.9 ± 0.1 [9]
	21	R1 = 4-methylpiperazin-1-yl	65 ± 7	35.5 ± 0.1	7.0 ± 1.3 [5]	1.0 ± 0.5 [35]
	25	R1 = pyrrolidin-1-yl	68 ± 8	69 ± 0
	26	R1 = morpholin-4-yl	29 ± 3	10.2 ± 0.2	1.6 ± 0.6 [6]	0.5 ± 0.1 [20]
CH2CO-NH-CH2-CH2-NR1,R2	MOL2008	R1 = H, R2 = CH3	52 ± 10	10.3 ± 0.1	∼ 4 [2.5]	∼ 10 [1]
	27	R1, R2 = H, hydrochloride	68 ± 1	36 ± 1
	28	R1, R2 = CH2CH3	38 ± 1 at 5 µM	6.0 ± 1.0	3.0 ± 0.5 [2]
CH2CO-NH-CH2-CH2-R1	31	R1 = piperidin-1-yl	49 ± 3 at 5 µM	9.0 ± 1.0	4.1 ± 0.6 [2]
	32	R1 = piperazin-1-yl, dihydrochloride	139 ± 2	24 ± 3
CH2CO-NH(CH2)4-NH-R1	35	R1 = H, hydrochloride	116 ± 3	0
	Amphotericin B			8.9 ± 0.5	0.2 ± 0.0 [59]	0.1 ± 0.0 [100]

^aPercentage of Leishmania braziliensis-infected macrophages treated with the corresponding paullone at, unless otherwise stated, 10 µM. The values are expressed relative to infected and non-treated macrophages. ND: not determined.

^bPercentage cytotoxicity against non-infected macrophages of paullones at, unless otherwise stated, 100 µM. The values are expressed relative to non-treated macrophages. CC₅₀ and the corresponding standard deviation (±σ^n–1) are highlighted in bold italics.

^cSI, selectivity index determined as the ratio EC₅₀ for amastigotes/CC₅₀ for macrophages.

^dThe CC₅₀ could not be determined because this compound induced macrophage detachment from the culture surface.

^eEC₅₀ interval with 95% confidence.