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. 2016 Jan 15;26(2):355–360. doi: 10.1016/j.bmcl.2015.12.003

Table 1.

Inhibitory activities of isobenzofuran-1(3H)-ones with various A-subunits

graphic file with name fx2.jpg

Number Scheme Xa Inhibition of Jurkat cell lysis IC50b (μM)
6 1 Ph >20
7 1 2-Me Ph >20
8 1 3-Me Ph >20
9 1 4-Me Ph >20
10 1 2-Cl Ph >20
11 1 3-Cl Ph >20
12 1 4-Cl Ph >20
13 1 2-OMe Ph >20
14 1 3-OMe Ph >20
15 1 4-OMe Ph 9.36
16 1 3-NH2 Ph 13.97
17 1 4-NH2 Ph 11.82
18 1 3-OH Ph 5.89
19 1 4-OH Ph >20
20 1 3-CN Ph 20
21 1 4-CN Ph 6.87
22 1 3-CONH2 Ph 2.97
23 1 4-CONH2 Ph 0.18
23ac 1 4-CONH2 Ph 6.04
23bd 1 4-CONH2 Ph >20
29 2 4-CONHMe Ph 10.7
30 2 4-CONMe2 Ph >20
31e 1 graphic file with name fx3.gif >20
32 1 4-CONH(CH2)3NMe2 Ph >20
39 3 4-COOEt Ph 10.97
40 3 3-OH, 4-COOEt Ph >20
46 3 3-NH2, 4-COOH Ph 5.84
48 3 3-OH, 4-CONH2 Ph 0.67
49e 3 graphic file with name fx4.gif 12.75
50e 3 3-OH, 4-CONH(CH2)2NMe2 Ph >20
51 3 3-OH, 4-CONHCH2CH2OH Ph 3.31
52 3 3-OH, 4-CONHCH2CH(OH)CH3 Ph >20
53 3 3-OH, 4-CONHCH2CONH2 Ph 2.65
54 3 3-OH, 4-CONHCH2CH2CONH2 Ph 7.12
55 3 3-NH2, 4-CONH2 Ph 1.20
56e 3 graphic file with name fx5.gif 14.71
57e 3 3-NH2, 4-CONH(CH2)2NMe2 Ph >20
58 1 4-SMe Ph >20
59 1 4-CH2OH Ph 0.90
60 1 4-SO2Me Ph >20
61 1 3-SO2NH2 Ph 4.85
62 1 4-SO2NHtert-Bu Ph 6.09
63 1 4-NHSO2Me Ph 1.09
67 4 4-CONH2, 3-pyridyl 0.92
70 1 4-Pyridyl 4.53
71 1 5-Isobenzofuran-1(3H)-one 6.24
a

Structure of the A-subunit.

b

Testing was carried out over a range of doses, with the IC50 being equal to the concentration at which 50% inhibition of the lysis of Jurkat cells by perforin was observed, as measured by 51Cr release. Values are the average of at least two independent IC50 determinations.

c

Isobenzofuran-1(3H)-one C-subunit replaced with an isoindolin-1-one.

d

Isobenzofuran-1(3H)-one C-subunit replaced with an 2-methylisoindolin-1-one.

e

Detailed structures for compounds, 31, 49, 50, 56 and 57 can be found in the Supplementary information (Experimental Section).