Table 1. Structure–Activity Relationships^a.

			IC50 (μM)
compd	R	Ar/R1	PfDHODH	PvDHODH	hDHODH	EC50 (μM) Pf3D7 cellsd
1	CF2CH3	4-SF5–Ph	0.0089 (0.0073–0.011)	0.027 (0.023–0.032)	>100	0.0043–0.0078
2	H	2-naphthyl	0.047	0.23	>100	0.068
3	H	4-CF3–Ph	0.28	2.6	>100	0.34
5	CF2CH3	H	0.021 (0.019–0.024)	0.035 (0.030- 0.041)	ND	0.0028 (0.0022–0.0037)
6	CF2CH3	6-F	0.024 (0.021–0.027)	0.056 (0.048–0.066)	>100	0.0075 (0.0063–0.0089)
7	CF2CH3	6-Cl (E-I)	0.0037 (0.0021–0.0066)	0.029 (0.019–0.042)	>100	0.0038 (0.0030–0.0049)
8	CF2CH3	6-Cl (E-II)	1.34 (1.1–1.7)	ND	>100	0.42 (0.37–0.47)
9	CF2CH3	7-Cl (E-I, S)	0.0063 (0.005–0.008)	0.010 (0.0083- 0.013)	>100	0.0012 (0.0011–0.0013)
10	CF2CH3	7-Cl (E-II, R)	0.79 (0.70–0.94)	ND	>100	2.8 (1.0–7.8)
11	CF2CH3	6-Br (E-I)b	0.0046 (0.0038- 0.0056)	0.024 (0.021–0.027)	>100	0.0026 (0.0016–0.0042)
12	CF2CH3	6-Br (E-II)c	0.79 (0.59–1.1)	2.1 (1.8–2.5)	>100	0.14 (0.090–0.21)
13	CF2CH3	7-Br (E-I)	0.0046 (0.0036–0.006)	0.012 (0.010–0.013)	>100	0.00039 (0.00034–0.00044)
14	CF2CH3	7-Br (E-II)	0.64 (0.53–0.77)	ND	>100	1.4 (1.2–1.5)
15	CF2CH3	6-OMe	0.14 (0.11–0.16)	0.22 (0.20–0.25)	>100	0.017 (0.014–0.019)
16	CF2CH3	7-OMe (E-I)	0.021 (0.018–0.024)	0.13 (0.11–0.15)	>100	0.025 (0.023–0.026)
17	CF2CH3	7-OMe (E-II)	1.0 (0.86–1.2)	ND	ND	0.64 (0.56–0.75)
18	CF2CH3	6,7-di-F (E-I)	2.3 (1.9–2.8)	ND	ND	>2.5
19	CF2CH3	6,7-di-F (E-II)	0.060 (0.049–0.072)	0.071 (0.066–0.076)	ND	0.022 (0.018–0.026)
20	CF2CH3	6-F,7- CF3	0.089 (0.078–0.10)	0.39 (0.34–0.44)	>100	0.097 (0.080–0.12)
21	CF2CH3	6- CF3, 7-F	0.087 (0.067–0.11)	0.82 (0.69–0.96)	>100	3.3 (2.97–3.63)
22	CF3	H	0.17 (0.12–0.23)	ND	>100	0.021 (0.017–0.025)
23	CF3	6-F	0.077 (0.066–0.089)	0.28 (0.25–0.33)	ND	0.066 (0.062–0.07)
24	CF3	7-Cl (E-I)	0.015 (0.012–0.018)	ND	>50	0.033 (0.030–0.035)
25	CF3	7-Cl (E-II)	1.1 (0.98–1.2)	ND	ND	1.5 (1.2–1.7)
26	CF2CH3	H	0.048 (0.040–0.059)	ND	>100	0.036 (0.031–0.042)
27	CF2CH3	5-Br	0.11 (0.083–0.14)	ND	ND	0.59 (0.25–1.4)
28	CF2CH3	5-Cl	0.085 (0.075–0.097)	ND	ND	0.12 (0.0.045–0.20)
29	CF2CH3	5,6-di-Cl	0.14 (0.11–0.17)	ND	ND	0.58 (0.22–1.5)
30	CF2CH3	5-SO2Me	4.0 (2.7–6.1)	ND	ND	6.5 (4.9–8.1)
31	CF2CH3	5-SO2NMe2	8.0 (6.7–9.7)	ND	ND	ND
32	CF2CH3	4,7-di-Me	0.014 (0.012- 0.017)	0.024 (0.022- 0.027)	>100	0.00039 (0.00021–0.00075)
33	CF2CH3	4,7-di-F	0.065 (0.057–0.075)	0.15 (0.14–0.16)	>100	0.046 (0.002–0.0048)
34	CF2CH3	4-F	0.052 (0.041–0.066)	0.3 (0.26–0.34)	>100	0.064 (0.061–0.066)
35	CF2CH3	5,6-di-F	0.052 (0.042–0.064)	0.37 (0.28–0.50)	>100	0.040 (0.035–0.044)
36	CF2CH3	4-CF3	0.066 (0.054–0.080)	0.28 (0.22–0.34)	>100	0.0043 (0.0029–0.0056)
37	CF3	5,6-di-F	0.12 (0.11–0.14)	ND	ND	0.15 (0.092–0.23)

^aDHODH IC₅₀ and P. falciparum EC₅₀ values were determined from triplicate data points at each concentration in the dose titration. Values in parentheses represent the 95% confidence interval of the fit.

^bEnantiomer-I is the second eluted on the chiral column.

^cEnantiomer-II is the first eluted on the chiral column.

^dData were collected using albumax unless otherwise stated. Data for 2(15) and 3(16) were taken from previous reports. Compound 1 has been previously profiled in these assays, and parasite data were previously reported.^11,12 Enzyme data were recollected herein to serve as a direct comparator.