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. Author manuscript; available in PMC: 2022 Mar 11.
Published in final edited form as: J Med Chem. 2021 Feb 23;64(5):2739–2761. doi: 10.1021/acs.jmedchem.0c02022

Table 2.

SAR of the Amide sub-series

graphic file with name nihms-1682557-t0006.jpg
Cmpd R R1 R2 R3 B-ring P. falciparum EC50 (μM) Cytotox CC50 (μM)
Pf3D7 PfDd2 HepG2
22 H CF3 cPr Me 3-Py 0.34±0.044 (3) 0.59±0.067 (3) >30
23 H CF3 cPr Me 5-Pyr 0.40±0.015 (3) 0.79±0.19 (3) >30
24 H SCF3 cPr Me 3-Py 0.31±0.078 (3) 0.39±0.045 (3) >30
25 H SCF3 cPr Me 5-Pyr 0.26±0.046 (3) 1.0±0.55 (5) >30
26 H OCF3 cPr Me 3-Py 0.32±0.035 (3) 0.52 ±0.055 (3) >30
27 H OCF3 cPr Me 5-Pyr 0.24±0.044 (3) 0.59±0.17 (5) >30
28 H CF3 cPr Et 3-Py 0.19±0.025 (3) 0.48±0.084 (3) >20
29 H CF3 cPr Et 5-Pyr 0.24±0.042 (3) 0.57±0.14 (3) >25
30 H CF3 cPr H 5-Pyr 0.72±0.021 (3) *EC50.1;EC50.2 2.0±1.4; 16±5.4 (4) >30
31 H CF3 cPr Me 2-Me, 5-Pyr 8.1, 7.5 9.8, 7.7 >30
32 F CF3 cPr Me 3-Py 0.31±0.026 (3) 0.46±0.046 (3) >30
33 H CF3 nPr Me 3-Py 0.21±0.021 (3) 0.33±0.035 (3) >15
34 H CF3 cPr C* 3-Py 1.8±0.15 (3) 4.2 ±0.84 (3) >20

Concentration response data were collected with technical triplicates at each inhibitor concentration and data were fitted in GraphPad Prism to determine the EC50 as described in the Table 1 footnote. Data are the EC50 mean ± std dev with the number of independent biological replicates shown in parenthesis.

*

C-ring replaced with piperidine.