A.K. Timiri et al. / Bioorganic Chemistry 62 (2015) 74–82
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2.4.11. N-(3-chlorophenyl)-4-(1,3-dioxoisoindolin-2-yl)benzene-
sulphonamide (11)
ArAH), 7.91 (m, 2H, ArAH), 8.02 (m, 4H, ArAH), 10.94 (s, 1H,
NH); 13CNMR (75 MHz, DMSO-d6)
118.19, 123.67, 125.81,
126.15, 126.76, 127.29, 127.50, 127.64, 130.91, 131.43, 134.96,
136.08, 138.25, 141.89, 142.07, 146.28, 166.50, 166.79; MS (ESI):
m/z 423 [M + H]+.
d
Yield: 81%; Buff white amorphous powder. Mp: 223–225 °C; 1H
NMR (400 MHz, DMSO-d6) d 7.140 (t, 2H, J = 8 Hz, ArAH), 7.172(s,
1H, ArAH), 7.30 (t, 1H, J = 7.6 Hz, ArAH), 7.70 (d, 2H, J = 8.4 Hz,
ArAH), 7.91 (m, 2H, ArAH), 7.93 (m, 2H, ArAH), 7.98(m, 2H,
ArAH), 10.7(s, 1H, NH); MS (ESI): m/z 412 [M]+.
2.4.19. 4-(1,3-Dioxoisoindolin-2-yl)-N-(naphthalen-1-yl)benzene-
sulphonamide (19)
2.4.12. N-(4-chlorophenyl)-4-(1,3-dioxoisoindolin-2-yl)benzene-
sulphonamide (12)
Yield = 88%; Pale purple colour amorphous powder. Mp: 198–
200 °C; 1H NMR (400 MHz, DMSO-d6) d 7.21(d, 1H, J = 8 Hz,
ArAH), 7.40–7.50(m, 3H, ArAH), 7.62(s, 1H, ArAH), 7.64 (s, 1H,
ArAH), 7.86(d, 1H, J = 8 Hz, ArAH), 7.89–7.99 (m, 7H, ArAH), 8.04
(d,1H, J = 8 Hz, ArAH), 10.37 (s, 1H, NH); MS (ESI): m/z 429
[M + H]+.
Yield: 83%; Pale white amorphous powder. Mp: 212–214 °C; 1H
NMR (400 MHz, DMSO-d6) d 7.16 (d, 2H, J = 9.2 Hz, ArAH), 7.32 (d,
2H, J = 8.8 Hz, ArAH), 7.68(d, 2H, J = 8 Hz, ArAH), 7.92 (m, 4H,
ArAH), 7.99 (m, 2H, ArAH), 10.57 (s, 1H, NH); MS (ESI): m/z 412
[M]+.
2.4.20. 4-(1,3-Dioxoisoindolin-2-yl)-N-phenethylbenzenesulphonamide
(20)
2.4.13. 4-(1,3-Dioxoisoindolin-2-yl)-N-o-tolylbenzenesulphonamide
(13)
Yield = 90%; Pale white amorphous powder. Mp: 170–172 °C;
1H NMR (400 MHz, DMSO-d6) d 2.78 (m, 2H, ACH2), 3.03 (m, 2H,
ACH2), 7.27(m, 5H, ArAH), 7.62 (m, 3H, ArAH), 7.76 (s, 1H,
ArAH), 7.91 (m, 5H, ArAH), 10.72 (s, 1H, NH); 13CNMR (75 MHz,
DMSO-d6) d 35.38, 44.18, 123.66, 126.33, 127.25, 127.66, 128.40,
128.75, 131.52, 134.95, 135.34, 138.69, 139.54, 166.66; MS (ESI):
m/z 407 [M + H]+.
Yield: 89%. Pale pink amorphous powder. Mp: 391–393 °C, 1H
NMR (DMSO-D6) d 2.03 (s, 3H, CH3), 7.01 (m, 1H, Ar), 7.14 (m,
3H, Ar), 7.67 (d, 2H, Ar, J = 8.4 Hz), 7.82 (d, 2H, Ar, J = 8.8 Hz),
7.92 (m, 2H, Ar), 7.99 (m, 2H, Ar), 9.72(s, 1H, NH); MS (ESI):
(m/z) 393 [M + H]+.
2.4.14. 4-(1,3-Dioxoisoindolin-2-yl)-N-m-tolylbenzenesulphonamide
(14)
2.5. X-ray crystallographic study of Compound 16
Yield = 90%; Pale pinkish white amorphous powder. Mp: 241–
243 °C; 1H NMR (400 MHz, DMSO-d6) d 2.21 (s, 3H, CH3), 6.86(d,
1H, J = 7.2 Hz, ArAH), 6.95(d, 2H, J = 6.8 Hz, ArAH), 7.13 (t, 1H,
J = 8 Hz, ArAH), 7.66 (d, 2H, J = 8.8 Hz, ArAH), 7.91 (m, 4H,
ArAH), 7.98 (m, 2H, ArAH), 10.33(s, 1H, NH); MS (ESI): m/z 393
[M + H]+.
Single crystals of compound 16 suitable for X-ray diffraction
were obtained by slow evaporation method. Three dimensional
intensity data were collected on a Bruker SMART APEX CCD [32]
diffractometer using graphite monochromatized Mo K
a radiation
(k = 0.71073 Å). The intensity data collection, frames integration,
Lorentz Polarization (LP) correction were done using SAINT soft-
ware [32]. Empirical absorption correction (multi-scan) was per-
formed using SADABS program [32]. The structure was solved by
direct methods using SHLEXS 97 and refined by full-matrix
least-squares procedures using SHELXL97 programs [33]. The
molecular geometry was calculated using PARST [32]. All
non-hydrogen atoms were first refined isotropically and then with
anisotropic displacement parameters. The hydrogen atoms were
included in the structure factor calculation at idealized positions
by using a riding model, but not refined. The final R-factor con-
verged to 4.3%. Table 2 summarizes the crystal data. Compound
16, C22H18N2O4S1 crystallizes in monoclinic P 21/c space group.
The ORTEP plot [34] of the molecule is shown in Fig. 2. The isoin-
dole ring adopts a planar conformation and cyclobenzene rings
(C9AC14) and (C15AC20) also adopt a planar conformation. The
isoindole ring makes a dihedral angle of 48.16 (1)° with the
cyclobenzene ring (C9AC14) and 84.28 (1)° with the cyclobenzene
ring (C15AC20).
2.4.15. 4-(1,3-Dioxoisoindolin-2-yl)-N-p-tolylbenzenesulphonamide
(15)
Yield = 84%; Off white amorphous powder. Mp: 224–226 °C; 1H
NMR (400 MHz, DMSO-d6) d 2.19 (s, 3H, CH3), 7.04 (dd, 4H,
J = 13.2 Hz, 8.8 Hz, ArAH), 7.65 (d, 2H, J = 8 Hz, ArAH), 7.91 (m,
4H, ArAH), 7.98 (m, 2H, ArAH), 10.24 (s, 1H, NH); MS (ESI): m/z
393 [M + H]+.
2.4.16. 4-(1,3-Dioxoisoindolin-2-yl)-N-(4-ethylphenyl)benzene-
sulphonamide (16)
Yield = 88%; Pale pinkish white amorphous powder. Mp 212–
214 °C; 1H NMR (400 MHz, DMSO-d6)
d 1.19 (t, 3H, ACH3,
J = 7.2 Hz), 2.59 (q, 2H, ACH2A, J = 7.4 Hz), 7.01 (d, 2H, J = 8.4 Hz,
ArAH), 7.09 (d, 2H, J = 8.0 Hz, ArAH), 7.63 (d, 2H, J = 8.4 Hz,
ArAH), 7.84 (m, 4H, ArAH), 7.96 (m, 4H, ArAH); 13CNMR
(75 MHz, DMSO-d6)
d 15.45, 27.46, 120.43, 123.66, 127.40,
127.52, 128.56, 131.44, 134.96, 135.11, 135.68, 138.64, 139.80,
166.56; MS (ESI): m/z 406 [M]+.
In the crystal, the molecular structure is stabilized by inter-
molecular of NAHꢀ ꢀ ꢀO hydrogen bonds, generating the R22 (8) ring
motifs [35] and intramolecular CAHꢀꢀꢀO hydrogen bonds. (Fig. 3
and Table 3). Selected bond lengths and bond angles are given in
supplementary information.
2.4.17. 4-(1,3-Dioxoisoindolin-2-yl)-N-(4-nitrophenyl)benzene-
sulphonamide (17)
Yield = 75%; Pale yellow colour amorphous powder. Mp: 244–
246 °C; 1H NMR (400 MHz, DMSO-d6) d 7.37 (d, 2H, J = 9.2 Hz,
ArAH), 7.72 (d, 2H, J = 8.8 Hz, ArAH), 7.91 (d, 2H, J = 3.2 Hz,
ArAH), 7.98 (d, 2H, J = 3.2 Hz, ArAH), 8.05 (d, 2H, J = 8.4 Hz,
ArAH), 8.17 (d, 2H, J = 9.2 Hz, ArAH), 11.43 (s, 1H, NH); MS (ESI):
m/z 423 [M]+.
2.6. DENV2 protease assay [36]
To measure the inhibitory activities of the compounds, the
DENV2 NS2B–NS3 protease activities were measured in the pres-
ence of the compounds using Bz-Nle-Lys-Arg-Arg-AMC as a sub-
strate. The enzyme concentration in the assay was 125 nM, and
2.4.18. 4-(4-(1,3-Dioxoisoindolin-2-yl)phenylsulphonamido)benzoic
acid (18)
Yield = 76%; Pale pinkish white amorphous powder. Mp: 263–
265 °C; 1H NMR (400 MHz, DMSO-d6) d 7.26 (d, 2H, J = 8.4 Hz,
ArAH), 7.70 (d, 2H, J = 9.2 Hz, ArAH), 7.83 (d, 2H, J = 8.8 Hz,
the substrate concentration was 20
8.5, 20% Glycerol, and 1 mM CHAPS. The inhibitor concentrations
were 100 M for the first round and between 3.125 and 400
for the compounds 16 and 19 in the second round. Before adding
lM in 10 Mm Tris–HCl pH
l
lM