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. 2022 Aug 12;13(9):1510–1516. doi: 10.1021/acsmedchemlett.2c00309

Table 1. SAR of Trisubstituted 4,5-Dihydropyrazoles 1–44.

graphic file with name ml2c00309_0004.jpg

compda Ar1 Ar2 R IC50 (μM)b
1 4-MePh 2-furyl SO2Me 15.9 ± 0.8
2 4-FPh 2-furyl SO2Me 12.66 ± 0.22
3 4-ClPh 2-furyl SO2Me 2.72 ± 0.11
4 4-BrPh 2-furyl SO2Me 2.47 ± 0.36
5 4-CF3Ph 2-furyl SO2Me 2.88 ± 0.06
6 4-NO2Ph 2-furyl SO2Me 1.97 ± 0.12
7 4-CNPh 2-furyl SO2Me 7.44 ± 0.21
8 4-MeOPh 2-furyl SO2Me 10.11 ± 0.30
9 Ph 2-furyl SO2Me inactive
10 3-MePh 2-furyl SO2Me inactive
11 3-FPh 2-furyl SO2Me inactive
12 2-furyl 2-furyl SO2Me inactive
13 4-MePh 2-furyl SO2CF3 inactive
14 4-MePh 2-furyl C(O)Me inactive
15 4-MePh 2-furyl H inactive
16 4-MePh 2-furyl CO2tBu 3.29 ± 0.16
17 4-BrPh 2-furyl CO2tBu 1.26 ± 0.03
18 4-BrPh 3-furyl CO2tBu 3.82 ± 0.09
19 4-BrPh thiazol-2-yl CO2tBu 1.61 ± 0.01
20 4-BrPh thiazol-5-yl CO2tBu 4.36 ± 0.08
21 4-BrPh 2-pyridinyl CO2tBu 0.65 ± 0.04
22 4-BrPh 3-pyridinyl CO2tBu 1.63 ± 0.11
23 4-BrPh 4-pyridinyl CO2tBu 2.78 ± 0.13
24 4-BrPh Ph CO2tBu 0.262 ± 0.039
25 4-NO2Ph Ph CO2tBu 0.439 ± 0.016
26 4-MeSO2Ph Ph CO2tBu inactive
27 4-MeC(O)Ph Ph CO2tBu inactive
28 4-tBuPh Ph CO2tBu inactive
29 4-CF3C(O)Ph Ph CO2tBu inactive
30 2-pyridinyl Ph CO2tBu inactive
31 3-pyridinyl Ph CO2tBu 14.5 ± 3.7
32 4-pyridinyl Ph CO2tBu inactive
33 4-BrPh Ph CO2Me 2.10 ± 0.07
34 4-BrPh Ph CO2Et 0.0328 ± 0.0006
35 4-BrPh Ph CO2iPr 0.0044 ± 0.0002
36 4-BrPh Ph CO2cPr 0.0441 ± 0.0028
37 4-BrPh Ph CO2iBu 0.164 ± 0.033
38 4-BrPh Ph CO2allyl 0.0318 ± 0.0028
39 4-BrPh Ph CO2(CH2)2C2H 0.065 ± 0.022
40 4-BrPh Ph C(O)NHMe 5.53 ± 0.12
41 4-BrPh Ph C(O)NMe2 2.41 ± 0.03
42 4-BrPh Ph C(O)pyrrolidine inactive
43 4-BrPh Ph C(O)NHiPr 0.350 ± 0.009
44 4-BrPh Ph C(O)NHtBu 9.22 ± 0.51
a

All compounds are racemates.

b

IC50 values represent the half maximal (50%) inhibitory concentration for the Bcl-2–Beclin 1 BH3 interaction as determined in the AlphaLISA assay. Error represents SD (n = 3). All compounds were inactive (at 10 μM) against the Bcl-2–Bax BH3 interaction except compounds 34 (IC50 = 6.62 ± 0.27 μM), 35 (IC50 = 0.88 μM ± 0.04 μM), 36 (IC50 = 15.1 ± 0.04 μM), and 38 (IC50 = 8.83 ± 0.39 μM).