Trypanocidal Activity of N-Hydroxy Imidazolines
(10-g prepacked cartridge) eluting with CH2Cl2-MeOH (9:1) and 0.1% 136.6 (2ϫC), 132.2 (2ϫC), 124.9 (2ϫC), 124.2 (4ϫC), 123.9 (2ϫC),
Et3N yielded the product as an 8:2 mixture of 17a and 18a as a brown solid
(389 mg; 72%). HPLC (UV), Ͼ90%; mp, 110 to 112°C. H NMR (300
118.7 (4ϫC), 104.9 (2ϫC), 64.0 (2ϫC), 52.0 (4ϫC), 40.6 (4ϫC), 28.3
(2ϫC), 24.3 (2ϫC), 19.7 (2ϫC). LRMS (ESIϩ) m/z ϭ 1,017.91 (M ϩ H).
(iv) N,N=-(((((ethane-1,2-diylbis(4,1-phenylene))bis(azanediyl))
bis(carbonothioyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(N-ethoxy-
2-nitrobenzenesulfonamide) (12b). The reaction was carried out by fol-
lowing the general procedure with compounds 7 (740 mg; 2.5 mmol) and
9b (1.81 g; 6.23 mmol). The product was purified by precipitation from
MeOH as a light yellow solid (1.98 g; 91%). HPLC (UV), 95%; mp, 198
to 200°C. 1H NMR (400 MHz, DMSO) ␦ 9.66 (br s, 2H, NH), 8.05 (m,
6H, ArH), 7.97 to 7.89 (m, 2H, ArH), 7.80 (br s, 2H, NH), 7.29 (d, J ϭ
8.5, 4H, ArH), 7.22 (d, J ϭ 8.5, 4H, ArH), 4.09 (q, J ϭ 7.0, 4H,
OCH2CH3), 3.75 (m, 4H, NCH2), 3.25 (m, 4H, NCH2), 2.84 (s, 4H,
PhCH2), 1.18 (t, J ϭ 7.0, 6H, OCH2CH3). 13C NMR (101 MHz,
DMSO) ␦ 180.5 (2ϫC), 149.2 (2ϫC), 137.8 (2ϫC), 136.7 (2ϫC),
136.4 (2ϫC), 132.0 (2ϫC), 132,0 (2ϫC), 128.6 (4ϫC), 124.1 (2ϫC),
123.7 (2ϫC), 123.3 (4ϫC), 73.4 (2ϫC), 51.8 (2ϫC), 41,0 (2ϫC), 36.5
(2ϫC), 13.3 (2ϫC). LRMS (ESIϩ) m/z ϭ 875.69 (M ϩ H).
(v) N,N=-(((((ethane-1,2-diylbis(4,1-phenylene))bis(azanediyl))
bis(carbonothioyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(2-nitro-N-
((tetrahydro-2H-pyran-2-yl)oxy)benzenesulfonamide)(12c). Thereac-
tion was carried out by following the general procedure with 7 (722 mg;
2.44 mmol) and 9c (2.1 g; 6.26 mmol). The product was purified by pre-
cipitation from cold CH2Cl2. Recrystallization in cold CH2Cl2 yielded
12c as a white solid (1.25 g; 52%). HPLC (UV), 92%; mp, 104 to 105°C.
1H NMR (400 MHz, DMSO) ␦ 9.76 (br s, 2H, NH), 8.13 to 8.00 (m, 6H,
ArH), 7.98 to 7.90 (m, 2H, ArH), 7.39 (br s, 2H, NH), 7.25 (s, 8H,
ArH), 5.01 to 4.97 (m, 2H, OCH), 4.08 to 3.98 (m, 2H, OCH2), 3.76 to
3.65 (m, 4H, NCH2), 3.58 to 3.49 (m, 2H, NCH2), 3.34 to 3.30 (m, 2H,
NCH2), 2.84 (s, 4H, PhCH2), 2.83 to 2.76 (m, 2H), 1.88 to 1.77 (m,
2H), 1.67 (s, 2H), 1.56 to 1.34 (m, 8H). 13C NMR (101 MHz, DMSO)
␦ 180.2 (2ϫC), 149.0 (2ϫC), 138.3 (2ϫC), 136.6 (2ϫC), 136.3 (2ϫC),
132.2 (2ϫC), 128.9 (2ϫC), 124.3 (2ϫC), 123.9 (2ϫC), 123.8, 104.9
(2ϫC), 64.0 (2ϫC), 52.0 (2ϫC), 40.6 (2ϫC), 36.6 (2ϫC), 28.3 (2ϫC),
24.3 (2ϫC), 19.7 (2ϫC). LRMS (ESIϩ) m/z ϭ 988 (M ϩ H).
1
MHz, CDCl3) ␦ 7.36 (s, 2H, ArH), 7.12 (s, 4H, ArH), 3.82 (s, 4H, CH2),
3.78 (s, 6H, OCH3), 3.63 to 3.51 (m, 4H, NCH2), 3.50 to 3.34 (m, 4H,
NCH2). 13C NMR (75 MHz, CDCl3) ␦ 158.6 (2ϫC), 137.6 (2ϫC), 131.3
(2ϫC), 127.8 (2ϫC), 124.9 (2ϫC), 118.8 (2ϫC), 117.7 (2ϫC), 63.0
(2ϫC), 51.5 (2ϫC), 46.0 (2ϫC), 35.5 (2ϫC). LRMS (ESIϩ) m/z ϭ 407.11
(M ϩ H).
General procedure for the synthesis of 1-(2-(alkoxyamino)ethyl)-3-
arylthioureas 10c, 11a, 11c, 12b and 12c, and 13b and c. A suspension of
isothiocyanates 5 to 8 (2.4 mmol; 1 equiv) in dry DMF (5 ml) was added
dropwise to a stirred solution of compounds 9a to 9c (6 mmol; 2.5 equiv)
in dry DMF (5 ml) under an argon atmosphere. The flask containing the
isothiocyanate suspension was rinsed with approximately 20 ml of dry
DMF that was added subsequently to the reaction mixture. The reaction
mixture was stirred at room temperature for 12 h. The solvent was re-
moved under high vacuum, and the crude product was treated with meth-
anol. Trituration with a spatula yielded a crude solid that was filtered and
washed with MeOH. The compounds were purified as specified below.
(i) 4-(3-(2-(2-Nitro-N-((tetrahydro-2H-pyran-2-yl)oxy)phenylsul
fonamido)ethyl)thioureido)-N-(4-(3-(2-(2-nitro-N-((tetrahydro-2H-
pyran-2-yl)oxy)phenylsulfonamido)ethyl)thioureido)phenyl)benz-
amide (10c). The reaction was carried out by following the general pro-
cedure described above with compounds 5 (750 mg; 2.4 mmol) and 9c
(2.07 g; 6.0 mmol). The product was purified by precipitation from
MeOH. Compound 10c was obtained as a light yellow solid (1.18 g; 41%).
HPLC (UV), Ͼ95%; mp, 132 to 133°C. 1H NMR (300 MHz, CDCl3) ␦
8.01 to 7.78 (m, 6H), 7.74 (m, 4H), 7.62 (m, 2H), 7.35 (d, J ϭ 8.2, 2H),
7.21 (d, J ϭ 8.2, 2H), 4.96 (d, J ϭ 6.8, 1H, OCH), 4.88 (d, J ϭ 7.2, 1H,
OCH), 4.37 to 4.19 (m, 2H, OCH2), 3.99 to 3.83 (m, 2H, NCH2), 3.73 to
3.56 (m, 2H, NCH2), 3.50 to 3.32 (m, 2H, NCH2), 3.20 to 3.02 (m, 2H,
NCH2), 2.76 (m, 2H, OCH2), 1.94 to 1.61 (m, 4H, CH2), 1.56 to 1.28 (m,
8H, CH2). 13C NMR (75 MHz, CDCl3) ␦ 180.3, 179.9, 165.2, 149.8, 149.7,
140.3, 137.2, 135.8, 135.6, 132.54, 132.51, 132.4, 132.0 (2ϫC), 131.5,
131.4, 129.2 (2ϫC), 126.2 (2ϫC), 125.4, 124.24, 124.21, 123.7 (2ϫC),
121.9, 105.9, 105.8, 65.8, 65.6, 52.8, 52.6, 41.6, 41.5, 28.9 (2ϫC), 24.6
(2ϫC), 21.2 (2ϫC). LRMS (ESIϩ) m/z ϭ 1002.45 (M ϩ H).
(ii) 1,3-Bis(4-(3-(2-N-methoxy-2-nitrophenylsulfonamido)ethyl)
thioureido)phenylurea (11a). The reaction was carried out by following
the general procedure with compounds 6 (750 mg; 2.4 mmol) and 9a (2.07
g; 6.0 mmol). Purification by silica chromatography (10-g prepacked car-
tridge) eluting with hexane-ethyl acetate (EtOAc) (100:0¡0:100) yielded
11a as a light green solid (774 mg; 91%). HPLC (UV), Ͼ95%; mp, Ͼ182°C
(decompose). 1H NMR (400 MHz, DMSO) ␦ 9.60 (br s, 2H, NH), 8.69 (br
s, 2H, NH), 8.14 to 7.98 (m, 6H, ArH), 7.97 to 7.87 (m, 2H, ArH), 7.73 (br
s, 2H, NH), 7.42 (d, J ϭ 8.6, 4H, ArH), 7.24 (d, J ϭ 8.6, 4H, ArH), 3.83 (s,
6H, OCH3), 3.75 (m, 4H, NCH2), 3.29 to 3.17 (m, 4H, NCH2). 13C NMR
(101 MHz, DMSO) ␦ 180.6 (2ϫC), 152.5, 149.3 (2ϫC), 136.8 (2ϫC),
136.5 (2ϫC), 132.6, 132.0, 131.9 (2ϫC), 124.7 (2ϫC), 124.1 (4ϫC), 123.7
(2ϫC), 118.5 (2ϫC), 65.4 (2ϫC), 51.8 (4ϫC), 41.1 (4ϫC). LRMS (ESIϩ)
m/z ϭ 877.65 (M ϩ H).
(vi) N,N=-(((((9,10-dihydroanthracene-2,6-diyl)bis(azanediyl))
bis(carbonothioyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(N-ethoxy-
2-nitrobenzenesulfonamide) (13b). The reaction was carried out by fol-
lowing the general procedure with 8 (0.61 g; 2.08 mmol) and 9b (1.49 g;
5.2 mmol). The product was purified by silica chromatography with
hexane-EtOAc (80:20¡0:100) and yielded 13b as a light brown solid (562
1
mg; 32%). HPLC (UV), 95%; mp, 126 to 127°C. H NMR (400 MHz,
DMSO) ␦ 9.67 (br s, 2H), 8.16 to 7.98 (m, 6H), 7.98 to 7.90 (m, 2H), 7.77
(br s, 2H), 7.33 (m, 2H), 7.27 (d, J ϭ 8.0, 2H), 7.14 (d, J ϭ 8.0, 2H), 4.11
(q, J ϭ 7.1, 4H), 3.87 (s, 4H), 3.79 to 3.67 (m, 4H), 3.30 to 3.17 (m, 4H),
1.18 (t, J ϭ 7.1, 6H). 13C NMR (101 MHz, DMSO) ␦ 180.6 (2ϫC), 149.2
(2ϫC), 137.2, 136.7, 136.4 (2ϫC), 132.9, 132.25, 132.19, 127.5 (2ϫC),
124.1 (2ϫC), 123.8 (2ϫC), 122.5 (2ϫC), 121.5 (2ϫC), 73.4 (2ϫC),
51.8 (2ϫC), 41.0 (2ϫC), 35.0 (2ϫC), 13.3 (2ϫC). (ESIϩ) m/z ϭ 873.7
(M ϩ H).
(vii) N,N=-(((((9,10-dihydroanthracene-2,6-diyl)bis(azanediyl))
bis(carbonothioyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(2-nitro-N-
((tetrahydro-2H-pyran-2-yl)oxy)benzenesulfonamide)(13c). Thereac-
tion was carried out by following the general procedure with compounds
8 (0.722 g; 2.44 mmol) and 9c (2.1 g; 6.26 mmol). Purification by silica
chromatography with hexane-EtOAc (100:0¡0:100) yielded 13c as a
brown solid (846 mg; 35%). HPLC (UV), Ͼ90%; mp, 116 to 118°C. 1H
NMR (400 MHz, DMSO) ␦ 9.79 (br s, 2H), 8.14 to 8.01 (m, 6H), 7.99 to
7.91 (m, 2H), 7.37 to 7.25 (m, 4H), 7.17 to 7.05 (m, 2H), 4.92 to 4.88 (m,
2H), 4.14 to 4.06 (m, 2H), 3.89 (s, 4H), 3.80 to 3.64 (m, 2H), 3.61 to 3.44
(m, 4H), 3.14 to 3.06 (m, 2H), 2.81 (m, 2H), 1.76 (m, 2H), 1.61 (m, 2H),
1.32 (m, 8H). 13C NMR (101 MHz, DMSO) ␦ 180.2 (2ϫC), 149.8 (2ϫC),
137.5, 136.6, 136.2, 133.6, 132.25, 132.19, 127.7 (2ϫC), 124.2 (2ϫC),
(iii) 1,3-Bis(4-(3-(2-(N-tetrahydro-2H-pyran-2-yl)oxy-2-nitrophe
nylsulfonamido)ethyl)thioureido)phenylurea (11c). The reaction was
carried out by following the general procedure with compounds 6 (722
mg; 2.44 mmol) and 9c (2.1 g; 6.26 mmol). Purification by silica chroma-
tography eluting with hexane-EtOAc (100:0¡0:100) yielded 11c as a light
yellow solid (806 mg; 32%). HPLC (UV), Ͼ95%; mp, 164 to 166°C. 1H
NMR (400 MHz, DMSO) ␦ 9.68 (br s, 2H, NH), 8.70 (br s, 2H, NH), 8.12
to 8.00 (m, 6H, ArH), 7.97 to 7.89 (m, 2H, ArH), 7.43 (d, J ϭ 8.8, 4H,
ArH), 7.31 (br s, 2H, NH), 7.21 (d, J ϭ 8.8, 4H, ArH), 5.11 to 4.75 (m, 2H,
OCH), 4.13 to 3.93 (m, 2H, OCH2), 3.79 to 3.62 (m, 4H, NCH2), 3.59 to
3.46 (m, 2H, OCH2), 3.42 to 3.35 (m, 2H, OCH2), 2.91 to 2.75 (m, 2H,
NCH2), 1.88 to 1.60 (m, 4H, CH2), 1.58 to 1.24 (m, 8H, CH2). 13C NMR
(101 MHz, DMSO) ␦ 180.3 (2ϫC), 152.5, 148.9 (2ϫC), 137.0 (2ϫC), 123.8 (2ϫC), 122.9 (2ϫC), 122.0 (2ϫC), 104.9 (2ϫC), 64.0 (2ϫC), 52.0
February 2015 Volume 59 Number 2
Antimicrobial Agents and Chemotherapy