Table 1.

Structure and activity of the triazolopyrimidine-based series against PfDHODH and P. falciparum in whole cell assays

compd	R	R1	R2	R3	IC50PfDHODH	EC50(μM) Pf3D7 cells
7	CH3	H	H		0.047±0.022	0.079±0.045
8	CF3	H	H		0.21±0.07	3.3±0.0
9	C2H5	H	H		0.19±0.073	0.31±0.32
10	CH3	CH3	H		0.16±0.096	0.55±0.22
11	CH3	H	CH3		3.0±0.84	16±4.0
12	CH3	H	C6H5CH2		93±9	35±35
13	CH3	H	H		>200	>50
14	CH3	H	H		1.7±0.49	1.6±0.35
15	CH3	H	H		1.2±0.28	2.2±0.5
16	CH3	H	H		0.33 ±0.1	1.7±0.56
17	CH3	H	H		2.0±0.07	0.41±0.18
18	CH3	H	H		45±6.0	4.4±1.8
19	CH3	H	H		>100	>100
20	CH3	H	H		0.056±0.024	0.19±0.12

Errors represent the standard error of the mean. The IC₅₀ for inhibition of human DHODH was >200 μM for all listed compounds. Enzyme data were collected with the DCIP assay. Growth inhibition by compound 7 was also tested on additional P. falciparum cell lines (EC₅₀ values for FCR3, K1, Dd2, HB3 and D6 were 0.18±0.018, 0.14±0.008, 0.14±0.05, 0.10±0.044 and 0.058±0.001 respectively).