Leishmanicidal Activity of N-Oxide Derivatives
chloroform (4 times, 40 ml each). The organic phase was dried with so- C14H11N5O3: C, 56.56; H, 3.73; N, 23.56. Found: C, 56.77; H, 3.52; N,
23.80. LRMS: m/z 298.09 [M ϩ H]ϩ.
dium sulfate or magnesium sulfate. After filtration, the organic phase was
Data for 3-amino-N=-[(1E)-(3-oxido-2,1,3-benzoxadiazol-5-yl)
concentrated under reduced pressure to produce brown oil. The samples
methylene]benzohydrazide (compound 8b) are as follows: yield, 70%;
mp, 211 to 213°C. Rf, 0.76 (1:1 ethyl acetate-hexane). IR Vmax (cmϪ1; KBr
pellets): 3,431 (N-H aromatic), 3,082 (C-H aromatic), 1,654 (CAO
amide), 1,610 (CAN imine), 1,556 and 1,467 (CAC aromatic), 1,450
(N-O furoxan). 1H NMR (300 MHz, DMSOd6) ␦: 10.01 (1H; s; N-H), 8.82
(1H; s; C-Himine), 7.65 to 8.13 (6H; m), 6.73 to 7.15 (3H; m; N-Hamine).
13C NMR (75 MHz, DMSOd6) ␦: 164.7, 148.9, 147.2, 133.8, 133.3, 130.7,
130.2, 129.7, 129.4, 118.6, 117.9, 115.2, 114.4, 112.1 ppm. Analysis calcu-
lated for C14H11N5O3: C, 56.56; H, 3.73; N, 23.56. Found: C, 56.33; H,
3.59; N, 23.64. LRMS: m/z 298.09 [M ϩ H]ϩ.
were further purified with silica gel column chromatography, using
hexane-ethyl acetate (6:4) as the mobile phase, producing compound 3 as
an oil.
Data for 4-phenyl-1,2,5-oxadiazol-3-carbaldehyde 2-oxide (com-
pound 3) are as follows: yield, 45%; infrared (IR) Vmax (cmϪ1; KBr
pellets), 3,059 (C-H aromatic), 2,827 (C-Haldehyde), 1,696 (CAO
imidealdehyde), 1,620 and 1,548 (CAN furoxan), 1,600 and 1,460 (CAC aro-
matic), 1,358 (N-O). 1H NMR (400 MHz, acetoned6) ␦: 10.1 (1H; s), 7.97
(2H; m), 7.62 (3H; m) ppm. 13C NMR (100 MHz, acetoned6) ␦: 115.78,
126.94, 128.32, 129.98, 131.95, 157.8, and 178 ppm. Analysis calculated
for C9H6N2O3: C, 56.85; H, 3.18; N, 14.73. Found: C, 56.3; H, 3.19; N,
14.5. Low-resolution mass spectrometry (LRMS): m/z 191.05 [M ϩ H]ϩ.
General procedure for the synthesis of compounds 4a and b and 8a
to c. A mixture of 6-formyl-2,1,3-benzoxadiazol 1-oxide (compound 7)
(0.37 g, 2.25 mmol) or 4-phenyl-1,2,5-oxadiazol-3-carbaldehyde 2-oxide
(compound 3) (0.43 g, 2.25 mmol); 2-, 3-, or 4-aminobenzohydrazide
(0.32 g, 2.15 mmol); and 8 ml of anhydrous ethanol containing 5 drops of
glacial acetic acid was stirred at room temperature while protected from
light for 15 h. The reaction was monitored by TLC using hexane-ethyl
acetate (1:1) as the mobile phase. The compounds 4a and b or 8a to c were
isolated by filtration and purified by crystallization using ethanol to pro-
duce yellow solids.
Data for 4-amino-N=-[(1E)-(3-oxido-2,1,3-benzoxadiazol-5-yl)
methylene]benzohydrazide (compound 8c) are as follows: yield, 98%;
mp, 225 to 227°C. Rf, 0.46 (1:1 ethyl acetate-hexane). IR Vmax (cmϪ1; KBr
pellets): 3,419 (N-H aromatic), 3,080 (C-H aromatic), 1,654 (CAO
amide), 1,627 (CAN imine), 1,550 and 1,461 (CAC aromatic), 1,450
(N-O furoxan). 1H NMR (300 MHz, DMSOd6) ␦: 11.80 (1H; s; N-H), 8.45
(1H; s; C-Himine), 7.72 to 8.03 (3H; m), 7.69 (2H; dd; Jortho ϭ 7.8 Hz/Jmeta ϭ
1.9 Hz), 6.50 (2H; dd; Jortho ϭ 7.8 Hz/Jmeta ϭ 1.9 Hz), 5.87 (2H; s; N-
H
amine). 13C NMR (75 MHz, DMSOd6) ␦: 163.7, 158.9, 152.1, 142.7,
137.9, 129.8, 128.8, 119.4, 115.7, 113.3, 112.4 ppm. Analysis calculated for
C14H11N5O3: C, 56.56; H, 3.73; N, 23.56. Found: C, 56.19; H, 3.88; N,
23.71. LRMS: m/z 298.09 [M ϩ H]ϩ.
General procedure for the synthesis of compounds 13a and -b. A
mixture of 3-hydroxybenzaldehyde or 4-hydroxybenzaldehyde (0.4 g, 3.3
mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 0.5 ml, 3.3 mmol),
and 10 ml of dichloromethane was stirred under nitrogen at room tem-
perature for 20 min. Then, 3,4-bis(phenylsulfonyl)-1,2,5-oxadiazole 2-N-
oxide (compound 12) (1.0 g, 2,73 mmol) was slowly added to the reaction
mixture. The reaction mixture was stirred under nitrogen at room tem-
perature for 2 to 2.5 h and monitored by TLC (1:1, dichloromethane-
hexane). The compounds 13a and -b were isolated by the addition of 50
ml of dichloromethane. Then, the organic phase was washed with satu-
rated potassium carbonate (5 times, 30 ml). The organic phase was dried
with sodium sulfate. After filtration, the organic phase was concentrated
under reduced pressure to produce a yellow solid. The samples were fur-
ther purified with silica gel column chromatography, using dichloro-
methane-hexane (5:4) as the mobile phase to give the compounds 13a and
-b as white powder.
Data for 3-{[5-oxido-4-(phenylsulfonyl)-1,2,5-oxadiazol-3-yl]oxy}
benzaldehyde (compound 13a) are as follows: yield, 57%; mp, 102 to
104°C. Rf, 0.1 (1:1 dichloromethane-hexane). IR Vmax (cmϪ1; KBr pel-
lets): 3,081 (C-H aromatic), 2,762 (C-H aldehyde), 1,697 (CAO alde-
hyde), 1,598 (CAN furoxan), 1,442 (N-O furoxan), 1,560 to 1,450 (CAC
aromatic), 1,357 and 1,165 (SAO sulfone). 1H NMR (300 MHz, CDCl3)
␦: 10.03 (1H; s; C-Haldehyde), 8.10 (2H; d, Jortho ϭ 8.0 Hz), 7.86 (1H; m),
7.83 (3H; t), 7.66 (3H; m) ppm. 13C NMR (75 MHz, CDCl3) ␦: 190.50,
157.80, 153.30, 138.20, 137.82, 135.87, 130.93, 129.87, 128.60, 128,32,
125.76, 119.82, 110.69 ppm. Analysis calculated for C15H10N2O6S: C,
52.02; H, 2.91; N, 8.09. Found: C, 52.06; H, 3.22; N, 7.91. LRMS: m/z
347.03 [M ϩ H]ϩ.
Data for 2-amino-N=-[(1E)-(2-oxido-4-phenyl-1,2,5-oxadiazol-3-yl)
methylene]benzohydrazide (compound 4a) are as follows: yield, 48%;
melting point (mp), 190 to 192°C. Rf, 0.07 (1:1 ethyl acetate-hexane). IR
Vmax (cmϪ1; KBr pellets): 3,369 (N-H amine), 3,079 (C-H aromatic),
1,647 (CAO amide), 1,606 (CAN imine), 1,600 and 1,460 (CAC aro-
matic), 1,450 (N-O furoxan). 1H NMR (300 MHz, DMSOd6) ␦: 11.97 (1H;
s; N-H), 8.44 (1H; s; C-Himine), 7.76 (2H; dd; Jortho ϭ 7.8 Hz and Jmeta ϭ
1.5 Hz), 7.61 (2H; d; Jortho ϭ 7.8 Hz), 7.56 (1H; dt; Jortho ϭ 7.8 Hz and
J
meta ϭ 1.5 Hz), 7.48 (1H; d; Jortho ϭ 7.9 Hz), 7.22 (1H; dd; Jortho ϭ 7.9 Hz
and Jmeta ϭ 1.9 Hz), 6.77 (1H; dd; Jortho ϭ 7.9 Hz and Jmeta ϭ 1.9 Hz), 6.58
(1H; d; Jortho ϭ 7.9 Hz), 6.45 (2H; s; N-Hamine) ppm. 13C NMR (75 MHz,
DMSOd6) ␦: 165.2, 156.58, 148.7, 132.90, 131.76, 129.62, 129.31, 128.30,
126.90, 124.92, 121.7, 118.82, 116.40, 113.7 ppm. Analysis calculated for
C16H13N5O3: C, 59.44; H, 4.05; N, 21.66. Found: C, 59.38; H, 4.27; N,
21.53. LRMS: m/z 324.10 [M ϩ H]ϩ.
Data for 4-amino-N=-[(1E)-(2-oxido-4-phenyl-1,2,5-oxadiazol-3-yl)
methylene]benzohydrazide (compound 4b) are as follows: yield, 50%;
mp, 209 to 212°C. Rf, 0.3 (1:1 ethyl acetate-hexane). IR Vmax (cmϪ1; KBr
pellets): 3,470 (N-H amine), 3,082 (C-H aromatic), 1,635 (CAO amide),
1,602 (CAN imine), 1,597 and 1,458 (CAC aromatic), 1,450 (N-O fu-
roxan). 1H NMR (300 MHz, DMSOd6) ␦: 11.98 (1H; s; N-H), 8.31 (1H; s;
C-Himine), 7.77 (2H; dd; Jortho ϭ 7.9 Hz and Jmeta ϭ 2 Hz), 7.60 (2H; d;
J
ortho ϭ 7.9 Hz), 7.56 (1H; dt; Jortho ϭ 7.9 Hz and Jmeta ϭ 2 Hz), 7.22 (2H;
dd; Jortho ϭ 8.2 Hz), 6.59 (2H; dd; Jortho ϭ 8.2 Hz), 5.89 (2H; s; N-Hamine
)
ppm. 13C NMR (75 MHz, DMSOd6) ␦: 164.70, 157.21, 149.87, 131.02,
130.07, 129.70, 129.42, 126.92, 125.02, 121.8, 115.33, 113.41 ppm. Anal-
ysis calculated for C16H13N5O3: C, 59.44; H, 4.05; N, 21.66. Found: C,
59.70; H, 4.19; N, 21.85. LRMS: m/z 324.10 [M ϩ H]ϩ.
Data for 4-{[5-oxido-4-(phenylsulfonyl)-1,2,5-oxadiazol-3-yl]oxy}
benzaldehyde (compound 13b) are as follows: yield, 33%; mp, 118 to
120°C. Rf, 0.2 (1:1 dichloromethane-hexane). IR Vmax (cmϪ1; KBr pel-
lets): 3,078 (C-H aromatic), 2,744 (C-H aldehyde), 1,707 (CAO alde-
hyde), 1,599 (CAN furoxan), 1,450 (N-O furoxan), 1,537 to 1,450 (CAC
aromatic), 1,357 and 1,161 (SAO sulfone). 1H NMR (300 MHz, CDCl3)
␦: 10.03 (1H; s; C-Haldehyde), 8.03 (4H; m), 7.92 (1H; tt; Jortho ϭ 9 Hz and
Data for 2-amino-N=-[(1E)-(3-oxido-2,1,3-benzoxadiazol-5-yl)
methylene]benzohydrazide (compound 8a) are as follows: yield, 96%;
mp, 202 to 203°C. Rf, 0.57 (1:1 ethyl acetate-hexane). IR Vmax (cmϪ1; KBr
pellets): 3,421 (N-H aromatic), 3,078 (C-H aromatic), 1,622 (CAO
amide), 1,612 (CAN imine), 1,560 and 1,464 (CAC aromatic), 1,450
(N-O furoxan). 1H NMR (300 MHz, DMSOd6) ␦: 10.97 (1H; s; N-H), 8.44
(1H; s; C-Himine), 7.66 to 8.22 (3H; m), 7.58 (1H; d; Jortho ϭ 8 Hz), 7.22
(1H; dd; Jortho ϭ 8 Hz/Jmeta ϭ 2 Hz), 6.78 (1H; d; Jortho ϭ 8 Hz), 6.58 (1H;
dd; Jortho ϭ 8 Hz/Jmeta ϭ 2Hz), 6.45 (2H; s; N-Hamine). 13C NMR (75
MHz, DMSOd6) ␦: 165.2, 149.1, 147.2, 133.0, 132.7, 131.0, 129.7, 129.4,
J
meta ϭ 2.9 Hz), 7.75 (2H; tt; Jortho ϭ 9 Hz), 7.66 (2H; d; Jortho ϭ 9 Hz)
ppm. 13C NMR (75 MHz, CDCl3) ␦: 193.50, 158.90, 158.65, 138.20,
137.80, 135.60, 133.20, 131.60, 130.10, 121.30, 112.90 ppm. Analysis cal-
culated for C15H10N2O6S: C, 52.02; H, 2.91; N, 8.09. Found: C, 51.88; H,
129.2, 128.5, 119.6, 116.7, 115.2, 114.4 ppm. Analysis calculated for 2.73; N, 8.27. LRMS: m/z 347.03 [M ϩ H]ϩ.
August 2014 Volume 58 Number 8