Trypanothione Reductase Inhibitors
(30 mL), then N-methylpiperazine (5.5 mL, 49 mmol) and iPr2NEt
(53 mL, 307 mmol) were added, and the mixture was stirred at 258C
for 16 h. The mixture was concentrated, diluted with CH2Cl2
(30 mL), washed with NaOH (0.5 m in H2O, 10 mL) and H2O (2ꢀ
10 mL), dried (MgSO4), filtered, and concentrated. Purification by
column chromatography (SiO2; EtOAc/MeOH/NH3 (aq), 90:10:1)
yielded piperazine 1 (10 mg, 69%) as a yellow solid: Rf =0.25
methylamine, and concentrated. The residue was diluted in CH2Cl2
(10 mL), washed with H2O (3ꢀ20 mL), dried (MgSO4), filtered, and
concentrated. Purification by column chromatography (SiO2;
CH2Cl2/MeOH, 10:1) yielded 34 (101 mg, 18%) as a yellow solid:
Rf =0.30 (CH2Cl2/MeOH 10:1); mp: 107–1098C; 1H NMR (400 MHz,
CDCl3): d=1.23–1.53 (m, 4H), 1.70–1.78 (m, 2H), 1.99–2.20 (m, 4H),
2.20 (t, J=2.4 Hz, 1H), 2.58 (br. s, 8H), 3.22 (d, J=2.4 Hz, 2H), 7.07
(br. s, 1H), 7.24–7.32 (m, 2H), 7.70 (d, J=7.5 Hz, 1H), 7.76 ppm (d,
J=7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=22.4, 26.0, 29.7, 35.3,
45.1, 46.7, 52.9, 73.0, 79.1, 121.2, 121.9, 123.1, 123.7, 123.9, 139.0,
139.6, 147.5 ppm; IR (ATR): n˜ =2925, 2853, 1739, 1453, 1366, 1344,
1293, 1259, 1156, 1125, 1015 cmꢁ1; HRMS (MALDI): calcd for
1
(EtOAc/MeOH/NH3 (aq), 90:10:1); mp: 78–808C; H NMR (300 MHz,
CD3OD): d=2.29 (s, 3H), 2.58 (br. s, 8H), 3.64 (s, 2H), 6.91 (d, J=
7.9 Hz, 2H), 7.11 (s, 1H), 7.16 (dd, J=8.4, 7.5 Hz, 1H), 7.30–
7.36 ppm (m, 10H); 13C NMR (75 MHz, CD3OD): d=45.9, 52.9, 53.6,
55.6, 115.7, 128.9, 129.3, 130.7, 130.8, 131.5, 132.9, 134.2, 135.4,
137.2, 142.3 ppm; IR (ATR): n˜ =3056, 2925, 2800, 1668, 1582, 1552,
1476, 1438, 1282, 1195, 1139, 1085, 1024, 1001 cmꢁ1; HRMS
C21H26SN2 [M+H]+: 339.1889, found: 339.1890 (41%), calcd for
+
C7H13N2 [MꢁC14H13S]+: 125.1073, found: 125.1071 (100%).
+
(MALDI): calcd for C27H29N4S2 [M+H]+: 473.1828, found: 473.1835
+
(100%); calcd for C27H28N4S2 [M]+: 472.1755, found: 472.1736
1-(1-(Benzo[b]thiophen-2-yl)cyclohexyl)-4-tosylpiperazine (36):
+
(6%).
N,N-bis-(2-chloroethyl)-p-toluenesulfonamide
(35,
640 mg,
2.16 mmol), KI (719 mg, 4.32 mmol), and K2CO3 (594 mg,
4.32 mmol) were added to a solution of piperazine 31 (100 mg,
432 mmol) in DMF (7 mL) at 258C. The mixture was stirred at 1308C
for 24 h, then cooled, diluted with EtOAc (50 mL), and washed
with H2O (3ꢀ50 mL). The aqueous layers were extracted with
EtOAc (150 mL); the combined organic layers were washed with
water (3ꢀ150 mL), dried (MgSO4), filtered, and concentrated. Purifi-
cation by column chromatography (SiO2; CH2Cl2/MeOH, 100:0!
92:8) afforded 36 (112 mg, 57%) as a white solid: Rf =0.07 (CH2Cl2);
1-(2-(2,6-Bis(phenylthio)phenyl)-1H-imidazol-5-yl)-N-(3,4-dichlo-
robenzyl)-N,N-dimethylmethanaminium formate (26) and 1-(2-
(2,6-Bis(phenylthio)phenyl)-1H-imidazol-5-yl)-N-((2-(2,6-bis(phe-
nylthio)phenyl)-1H-imidazol-5-yl)methyl)-N,N-dimethylmethana-
minium formate (27): 3,4-dichlorobenzylbromide (25, 8 mL,
55 mmol) was added to a solution of amine 22 (23 mg, 55 mmol) in
Et2O (6 mL) and acetone (6 mL) at 258C, and the mixture was
stirred at 258C for 18 h. Concentration and purification by reverse
phase HPLC (C18; 0.1% HCO2H in H2O/CH3CN, 90:10!0:100,
60 min) yielded quaternary amines 26 and 27:
1
mp: 178–1808C; H NMR (300 MHz, CDCl3): d=1.22–2.07 (m, 10H),
2.42 (s, 3H), 2.59 (t, J=4.6 Hz, 4H), 2.97 (br. s, 4H), 7.05 (s, 1H),
7.16–7.35 (m, 4H), 7.60 (d, J=8.2 Hz, 2H), 7.71 (br. d, Jꢂ6.7 Hz,
1H), 7.77 ppm (br. d, Jꢂ7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
14.8, 22.2, 23.6, 29.7, 35.8, 45.5, 49.5, 122.2, 122.7, 124.0, 128.6,
129.0, 129.7, 130.3, 133.5, 140.2, 144.2, 147.9 ppm; IR (ATR): n˜ =
2933, 2846, 1595, 1451, 1355, 1332, 1304, 1291, 1276, 1164, 1129,
1105, 1069, 1022 cmꢁ1; HRMS (MALDI): calcd for C25H30N2O2S2Na+
[M+Na]+: 477.1641, found: 477.1641 (38%), calcd for C11H17N2O2S+
[MꢁC14H13S]+: 241.1005, found: 241.1005 (100%).
26 (8 mg, 25%) as a white solid: Rf =0.01 (EtOAc/MeOH/NH3 (aq),
90:10:2); mp: 97–1008C; 1H NMR (300 MHz, CD3OD): d=2.84 (s,
6H), 4.38 (d, J=9.2 Hz, 2H), 5.15 (s, 2H), 6.94 (d, J=8.0 Hz, 2H),
7.05 (d, J=7.9 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.23–7.34 (m, 10H),
7.40 (d, J=8.1 Hz,1H), 7.57 (s, 1H), 7.76 ppm (s, 1H); 13C NMR
(75 MHz, CD3OD): d=50.9, 61.6, 63.9, 115.3, 127.6, 129.2, 130.1,
130.7, 130.9, 131.7, 132.1, 132.8, 133.4, 133.5, 133.8, 135.3, 136.1,
138.1, 141.5, 146.2 ppm; IR (ATR): n˜ =3052, 2924, 2851, 1582, 1553,
1475, 1431, 1393, 1196, 1132, 1068, 1024, 1000 cmꢁ1; HRMS
1-(1-(Benzo[b]thiophen-2-yl)cyclohexyl)piperazine (37): A solu-
tion of tosylamine 36 (100 mg, 220 mmol) was dissolved in HBr
(48% in H2O, 5 mL) and stirred at 1008C for 1 h. The solution was
cooled, poured into saturated aq NaHCO3 (50 mL), extracted with
CH2Cl2/iPrOH (3:1, 3ꢀ50 mL), dried (MgSO4), filtered, and concen-
trated. Purification by column chromatography (SiO2; EtOAc/
MeOH/NH3 (aq), 100:0:0!90:10:1) yielded 37 (40 mg, 60%) as a
brown solid: Rf =0.35 (EtOAc/MeOH/NH3(aq), 90:10:1); mp: 1938C
(decomp); 1H NMR (300 MHz, CDCl3): d=1.33–1.55 (m, 4H), 1.56–
1.75 (m, 2H), 1.97–1.99 (m, 4H), 2.75 (br. s, 4H), 3.11 (br. s, 4H),
5.58 (br. s, 1H), 7.07 (s, 1H), 7.23–7.33 (m, 2H), 7.69 (dd, J=6.7,
1.8 Hz, 1H), 7.75 ppm (dd, J=7.1, 1.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=22.3, 25.7, 29.7, 34.7, 42.8, 44.3, 121.8, 122.2, 123.4,
124.2, 124.2, 139.0, 139.3, 147.7 ppm; IR (ATR): n˜ =3327, 2934,
2840, 2796, 2161, 1593, 1476, 1456, 1434, 1377, 1296, 1248, 1175,
1144, 1112, 1088, 1067, 1011 cmꢁ1; HRMS (EI): calcd for C18H24N2S+
[M]+: 300.1660, found: 300.1653 (45%), calcd for C14H14S+
[MꢁC4H10N2]+: 214.0816, found: 214.0810 (100%).
(MALDI): calcd for C31H28Cl2N3S2 [MꢁHCO2]+: 576.1096, found:
+
+
576.1102 (46%); calcd for C22H17N2S2
373.0833, found: 373.0825 (4%).
[MꢁC10H12Cl2NO2]+:
27 (14 mg, 60%) as a white solid: Rf =0.01 (EtOAc/MeOH/NH3 (aq),
90:10:2); mp: 111–1138C; 1H NMR (300 MHz, CDCl3): d=2.84 (s,
6H), 4.28 (s, 4H), 6.92 (d, J=7.7 Hz, 4H), 7.09 (dd, J=8.5, 7.3 Hz,
2H), 7.18–7.31 (m, 20H), 7.54 (s, 2H), 8.68 ppm (s, 1H, HCOO);
13C NMR (75 MHz, CD3OD): d=50.2, 63.9, 115.3, 129.2, 130.2, 130.7,
132.1, 133.1, 133.4, 134.0, 135.3, 141.3, 146.5 ppm; IR (ATR): n˜ =
3052, 2663, 1580, 1574, 1552, 1475, 1435, 1372, 1342, 1257, 1195,
1148, 1111, 1085, 1068, 1023, 1001 cmꢁ1; HRMS (MALDI): calcd for
C46H40N5S4 [MꢁHCO2]+: 790.2161, found: 790.2164 (100%); calcd
+
for C24H24N3S2 [MꢁC23H17N2O2S2]+: 418.1406, found: 418.1403
+
(66%); calcd for C22H17N2S2 [MꢁC25H24N3O2S2]+: 373.0833, found:
+
373.0821 (10%).
1-(1-(Benzo[b]thiophen-2-yl)cyclohexyl)-4-(prop-2-ynyl)piper-
azine (34): Bis-(2-hydroxyethyl)-propyn-2-yl-amine[30] (250 mg,
1.7 mmol) was added to a solution of SOCl2 (610 mL, 8.50 mmol) in
CH2Cl2 (5 mL) at 258C. The mixture was heated to reflux and stirred
for 3 h, cooled to 08C, and concentrated. To a solution of amine 31
(430 mg, 1.70 mmol) in CH3CN/DMF (10:2, 12 mL), KI (300 mg,
1.7 mmol), and iPr2EtN (0.5 mL, 3.0 mmol) was added to toxic mus-
tard compound 33, which had been dissolved in CH3CN (5 mL) at
258C. The mixture was stirred at 708C for 5 d, quenched with
(2-Nitro-1,3-phenylene)bis(phenylsulfane)
(40):
Thiophenol
(2.57 mL, 25.1 mmol) and nitrobenzene 38 (2.00 g, 12.6 mmol)
were added to a suspension of K2CO3 (5.20 g, 37.7 mmol) in dry
DMF (15 mL) at 08C. The solution was stirred at 258C for 16 h,
then cooled to 08C, filtered, washed with H2O and saturated aq
NaHCO3, dried (MgSO4), filtered again, and concentrated. Purifica-
tion by column chromatography (SiO2; heptane/EtOAc/CH2Cl2,
7:1:1!1:1:1) afforded pure 40 (4.12 g, 90%) as a yellow powder:
ChemMedChem 2011, 6, 292 – 301
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
299