C. K. L. Ng et al. / Bioorg. Med. Chem. 15 (2007) 3422–3429
3427
(50). Anal. Calcd for C24H40Br2N4Æ0.5H2O: C, 52.1; H,
7.3; N, 10.1. Found: C, 52.0; H, 7.5; N, 10.0.
at reflux for 24 h and the solvent was removed in vacuo.
The crude mixture was purified by flash chromatogra-
phy, eluting with 90:30:1 CH2Cl2/MeOH/NH3(aq) (Rf
0.63), and the combined fractions were concentrated un-
der reduced pressure. The residue was then passed
through a column of Lewatit MP-64 anion resin (ClÀ),
eluting with H2O. The resulting fractions were combined
and the solvent removed in vacuo to give 14 as an off-
4.1.9.
1,12-Bis(4-N,N-dimethylaminopyridinium)dode-
cane dibromide (11). 1,12-Dibromododecane (0.50 g,
1.52 mmol) was dissolved in methyl isobutyl ketone
(5 mL) and 4-N,N-dimethylaminopyridine (0.37 g,
3.05 mmol) was added. The mixture was stirred at reflux
for 24 h, then cooled and the resulting precipitate was col-
lected by filtration and recrystallised from MeOH/Et2O to
give 11 as a colourless solid (0.53 g, 84%); mp 268–271 ꢁC.
1H NMR (200 MHz, CD3OD): d 8.19 (4H, d, J = 8.0 Hz),
6.86 (4H, d, J = 6.0 Hz), 4.07 (4H, t, J = 7.3 Hz), 3.15
(12H, s), 1.78–1.72 (4H, m), 1.08 (16H, br s, CH2). 13C
NMR (75 MHz, CD3OD): 148.4, 141.9, 107.8, 57.9,
47.1 39.2, 30.9, 29.6, 29.1, 26.1. MS: m/z ESI (positive
ion) 206 [MÀ2BrÀ]2+ (100%), 411 [MÀ2BrÀÀH+]+ (15).
Anal. Calcd for C26H44Br2N4: C, 54.6; H, 7.8; N, 9.8.
Found: C, 54.8; H, 7.9; N, 9.7.
1
white solid (0.05 g, 8%). H NMR (200 MHz, CD3OD):
d 9.37 (2H, d, J = 5.7 Hz), 9.15 (2H, d, J = 8.3 Hz), 8.42
(2H, d, J = 9.0 Hz), 8.38 (2H, d, J = 8.2 Hz), 8.22 (2H,
dt, J = 8.0, 1.3 Hz), 8.08–7.91 (4H, m), 5.03 (4H, t,
J = 7.5 Hz), 2.05–1.91 (4H, m), 1.32–1.05 (16H, m).
MS: m/z ESI (positive ion) 213 [MÀ2ClÀ]2+ (100%),
461 [MÀ2ClÀÀH+]+ (87). Found: [MÀ2ClÀ]2+
213.1511, [C30H38N2]2+ requires 213.1535.
4.1.13. 1,8-Bis(4-aminoquinaldinium)octane dibromide
(15). 1,8-Dibromooctane (0.50 g, 1.84 mmol) was dis-
solved in methyl isobutyl ketone (5 mL) and 4-amino-
quinaldine (0.58 g, 3.67 mmol) was added. The mixture
was stirred at reflux for 24 h, at which time precipitate
was formed. The crude mixture was cooled, the precipi-
tate was filtered off and recrystallised from MeOH/Et2O
to give 15 as an off-white solid (0.21 g, 19%); mp 302–
313 ꢁC. 1H NMR (200 MHz, CD3OD): d 8.36–8.23 (2H,
m), 8.22–7.88 (4H, m), 7.76–7.56 (2H, m), 6.55 (2H, s),
4.43 (4H, t, J 8.1 Hz), 2.75 (6H, s), 1.78–1.74 (4H, m),
1.51–1.41 (8H, m, CH2), NH2 not observed. 13C NMR
(75 MHz, CD3OD): d 157.9, 156.2, 139.8, 134.6, 126.3,
124.2, 118.3, 104.4, 48.8, 29.3, 29.1, 26.3, 21.5, 21.1. MS:
m/z ESI (positive ion) 214 [MÀ2BrÀ]2+ (100%), 427
[MÀ2BrÀÀH+]+ (55). Anal. Calcd for C28H36Cl2N4Æ1-
H2O: C, 55.5; H, 6.0; N, 8.7. Found: C, 55.2; H, 6.5; N, 8.7.
4.1.10. 1,12-Bis(2-aminopyridinium)dodecane dibromide
(12). 1,12-Dibromododecane (0.50 g, 1.52 mmol) was
dissolved in methyl isobutyl ketone (5 mL) and 2-amino-
pyridine (0.29 g, 3.05 mmol) was added. The mixture
was stirred at reflux for 24 h, then cooled and the result-
ing precipitate was collected by filtration. The crude pre-
cipitate was recrystallised from MeOH/Et2O to afford 12
as a beige powder (0.22 g, 28%); mp 226–234 ꢁC (lit.
mp27 230–232 ꢁC). 1H NMR (200 MHz, CD3OD):
d 8.00 (2H, d, J = 6.5 Hz), 7.89 (2H, dd, J = 8.4,
6.9 Hz), 7.12 (2H, d, J = 8.9 Hz), 6.95 (2H, dd, J = 6.9,
6.9 Hz), 4.21 (4H, t, J = 7.6 Hz), 1.87–1.82 (4H, m),
1.44–1.41 (16H, br s), NH2 not observed. 13C NMR
(75 MHz, CD3OD):154.5, 142.5, 139.8, 115.2, 113.4,
65.8, 54.0, 29.5, 29.3, 26.1, 14.4. MS: m/z ESI (positive
ion) 178 [MÀ2BrÀ]2+ (100%), 355 [MÀ2BrÀÀHÀ]+
(25). Anal. Calcd for C22H36Br2N4: C, 51.2; H, 7.0; N,
10.9. Found: C, 51.5; H, 7.3; N, 10.6.
4.1.14. 1,12-Bis(4-aminoquinaldinium)dodecane dichlo-
ride (16). 1,12-Dibromododecane (0.50 g, 1.52 mmol)
was dissolved in methyl isobutyl ketone (5 mL) and
4-aminoquinaldine (0.48 g, 3.05 mmol) was added. The
mixture was stirred at reflux for 24 h and the solvent
was removed in vacuo. The crude mixture was purified
by flash chromatography, eluting with 90:30:1 CH2Cl2/
MeOH/NH3(aq) (Rf 0.68), and the combined fractions
were concentrated under reduced pressure. The residue
was then passed through a column of Lewatit MP-64
anion resin (ClÀ), eluting with H2O. The resulting frac-
tions were combined and the solvent removed under
reduced pressure to give 16 as an off-white solid (0.04 g,
4.1.11. 1,10-Bis(quinolinium)decane dibromide (13). To
1,10 dibromodecane (0.25 g, 0.83 mmol) in methyl
isobutyl ketone (1 mL) was added quinoline (0.43 g,
3.33 mmol). The mixture was deoxygenated by freeze/
thaw and refluxed for 18 h, then cooled to room temper-
ature and the resulting precipitate was collected by fil-
tration. The crude product was recrystallised from
MeOH/Et2O to yield 13 as a beige powder (0.16 g,
1
35%); mp 264–272 ꢁC. H NMR (200 MHz, CDCl3): d
1
9.58 (2H, d, J = 5.8 Hz), 8.96 (2H, d, J = 8.4 Hz),
8.29–8.08 (6H, m), 8.08–7.82 (4H, m), 4.99 (4H, t,
J = 7.6 Hz), 2.02–1.87 (4H, m), 1.33–1.08 (12H, m).
13C NMR (75 MHz, CDCl3): d 153.7, 151.9, 142.2,
135.4, 134.8, 126.6, 122.6, 62.7, 34.4, 33.0, 32.9, 30.5, 2
signals obscured or overlapping. MS: m/z ESI (positive
ion) 199 [MÀ2BrÀ]2+ (100%), 477 [MÀ2BrÀÀH+]+
(87). Found: [MÀ2BrÀ]2+ 199.1357, [C28H34N2]2+ re-
quires 199.1355 Anal. Calcd for C28H34Br2N2Æ2H2O:
C, 56.6; H, 6.4; N, 4.7. Found: C, 56.7; H, 6.4; N, 4.8.
4%); mp: 159–165 ꢁC. H NMR (200 MHz, CD3OD): d
8.45–8.33 (2H, m), 8.12–7.97 (4H, m), 7.80–7.66 (2H,
m), 6.78 (2H, s), 4.52 (4H, t, J = 7.5 Hz), 2.78 (6H, s),
1.87–1.79 (4H, m), 1.32–1.05 (16H, m), NH2 not
observed. 13C NMR (75 MHz, CD3OD): d 156.9, 141.3,
136.1, 128.0, 127.8, 125.7, 119.7, 105.8, 50.3, 31.1, 30.8,
30.1, 29.7, 28.5, 27.3, 22.5. MS: m/z ESI (positive ion)
242 [MÀ2ClÀ]2+ (100%). Found: [MÀ2ClÀ]2+ 242.1778,
[C32H44N4]2+ requires 242.1778.
4.2. Antifungal susceptibility testing
4.1.12. 1,12-Bis(quinolinium)dodecane dichloride (14).
1,12-Dibromododecane (0.50 g, 1.52 mmol) was dis-
solved in methyl isobutyl ketone (5 mL) and quinoline
(0.39 g, 3.05 mmol) was added. The mixture was stirred
The antifungal activity of the compounds was measured
by standard broth microdilution methods of the US Na-
tional Committee for Clinical Laboratory Standards for