Table 1. Aminoguanidine Halogen Series and Antimalarial Drugs^a.

compound	R1	R2	IC50 D6 (nM)	IC50 Dd2 (nM)	IC50 Tm90–C2B (nM)	IC50 A6 (nM)	IC50 cytotoxicity (μM)	IVTI
2	2-F	H	2866	4593	>5000	1893	>200	>100
3	3-F	H	767	>5000	>5000	426	49	64
4	4-F	H	1016	3792	4904	369	24	24
5	2-Cl	H	334	961	1219	348	>200	>100
6	3-Cl	H	202	567	664	237	35	>100
robenidine	4-Cl	H	324	814	1317	410	30	93
7	2-Br	H	280	715	974	876	94	>100
8	3-Br	H	572	1516	1838	502	62	>100
9	4-Br	H	277	876	899	269	38	>100
atovaquone	N/A	N/A	<1	<1	>5000	>5000	72	>100
chloroquine	N/A	N/A	10	70	297	16	181	>100

^aSee Scheme 1 for the aminoguanidine scaffold and sites of modification. P. falciparum IC₅₀ values are the average of two to four determinations, each carried out in quadruplicate (a more granular view of this data is provided in the Supporting Information). D6, P. falciparum pan-sensitive strain; Dd2, multidrug-resistant P. falciparum strain; Tm90–C2B, multidrug-resistant P. falciparum clinical isolate that is also resistant to atovaquone; A6, P. falciparum in-house derived mutant line resistant to respiratory antagonists.⁴⁰ Cytotoxicity assays were carried out with human hepatoma derived HepG2 cells and performed in quadruplicate. IVTI = in vitro therapeutic index, defined as cytotoxicity/D6 IC₅₀. N/A = not applicable.