New antibacterial tetrameric QACs
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 3, March, 2021
547
positive Staphylococcus aureus and gram-negative Escher-
ichia coli. This compound is superior in the antibacterial
activity to Chlorhexidine Digluconate and Octenidine
Hydrochloride currently administered in medical practice.
Either elongation or shortening the length of alkyl sub-
stituent led to a decreased antibacterial activity.
J = 7.3 Hz); 1.20—1.46 (m, 48 H, 24 CH2); 1.96—2.10 (m, 8 H,
+
4
4
CH ); 4.60 (t, 8 Н, 4 N CH , J = 8.0 Hz); 4.84 (s, 8 Н,
2
2
OCH ); 7.96 (dd, 4 H, 4 CH , J = 6.6 Hz, J = 2.2 Hz); 8.35
2
Py
1
2
(
dd, 4 H, 4 CHPy, J1 = 6.6 Hz, J2 = 1.5 Hz); 8.62 (d, 4 H,
1
3
4
CHPy, J = 6.6 Hz); 9.10 (br.s, 4 H, 4 CHPy). C NMR
(
CD OD-d ), : 14.4, 23.6, 27.3, 29.9, 30.1, 30.2, 30.4, 32.6,
3 4
3
2.8, 63.6, 69.9, 129.7, 132.8, 134.6, 138.6, 159.1. IR (KBr),
–
1
/cm : 3102, 2955, 2926, 2855, 1580, 1491, 1276, 1201, 827,
Experimental
682. Found (%): С, 57.52; H, 7.97; N, 4.38. С H Br N О .
61 100 4 4 4
Calculated (%): С, 57.55; H, 7.92; N, 4.40.
1H and 13C NMR spectra were recorded on a Bruker AM-300
spectrometer operating at the frequencies of 300.13 and 75.47 MHz,
respectively. IR spectra were recorded on a Specord M82 Fourier
spectrometer in KBr pellets, using Soft Spectra software. Melting
points were recorded on a Gallenkamp apparatus. Elemental
analysis was performed using a Vario EL cube CHNS analyzer.
Thin layer chromatography was performed on DC Kieselgel 60
F254 silica gel on an aluminum plate.
1-Decyl-3-(3-[(1-decylpyridinium-3-yl)oxy]-2,2-bis{[(1-
decylpyridium-3-yl)oxy]methyl}propoxy)pyridinium tetrakis-
bromide (3d). The yield was 0.56 g (85%), white powder, m.p.
l
121—124 C. H NMR (CD OD-d ), : 0.90 (t, 12 Н, 4 CH ,
3
4
3
J = 7.3 Hz); 1.22—1.52 (m, 56 H, 28 CH ); 2.02—2.18 (m, 8 H,
2
+
4 CH ); 4.68 (t, 8 Н, 4 N CH , J = 8.0 Hz); 4.90 (s, 8 Н,
2
2
4 OCH ); 8.04 (dd, 4 H, 4 CH , J = 6.7 Hz, J = 2.3 Hz); 8.41
2
Py
1
2
(dd, 4 H, 4 CHPy, J1 = 6.7 Hz, J2 = 1.5 Hz); 8.64 (d, 4 H,
1
3
3
-{3-(Pyridin-3-yloxy)-2,2-bis[(pyridin-3-yloxy)methyl]-
4 CHPy, J = 6.7 Hz); 9.21 (br.s, 4 H, 4 CHPy). C NMR
(CD OD-d ), : 14.6, 23.5, 27.1, 29.9, 30.1, 30.2, 30.4, 30.6,
propoxy}pyridine (5) was obtained in two steps according to the
3
4
known procedures.15
32.5, 33.1, 63.6, 69.6, 129.8, 133.0, 134.3, 138.3, 159.1. IR (KBr),
–
1
Synthesis of tetrakispyridinium salts 3а—f (general procedure).
A mixture of compound 5 (0.222 g, 0.5 mmol) and the corre-
sponding alkyl bromide (2.2 mmol) was refluxed in 4-methyl-
pentan-2-one (3 mL) for 48 h. The completion of reaction was
monitored by TLC (hexane—ethyl acetate, 3 : 1) as disappearance
of 5. The mixture was cooled down and kept at 0 C for 30 min.
The precipitate was filtered and dried in order to isolate pure
products 3a—f.
/cm : 2957, 2923, 2852, 1495, 1473, 1274, 1205, 829, 811,
679. Found (%): С, 58.74; H, 8.23; N, 4.19. С H Br N О .
6
5
108
4
4
4
Calculated (%): С, 58.73; H, 8.19; N, 4.22.
1-Undecyl-3-(3-[(1-undecylpyridinium-3-yl)oxy]-2,2-bis-
{[(1-undecylpyridium-3-yl)oxy]methyl}propoxy)pyridinium tetra-
kisbromide (3e). The yield was 0.60 g (88%), white powder, m.p.
l
128—131 C. H NMR (CD OD-d ), : 0.88 (t, 12 Н, 4 CH ,
3
4
3
J = 7.3 Hz); 1.20—1.54 (m, 64 H, 32 CH ); 2.00—2.18 (m, 8 H,
2
+
1
-Heptyl-3-(3-[(1-heptylpyridinium-3-yl)oxy]-2,2-bis{[(1-
4 CH ); 4.66 (t, 8 Н, 4 N CH , J = 7.8 Hz); 4.90 (s, 8 Н,
2
2
heptylpyridium-3-yl)oxy]methyl}propoxy)pyridinium tetrakis-
bromide (3а). The yield was 0.44 g (76%), white powder, m.p.
4 OCH ); 8.06 (dd, 4 H, 4 CH , J = 6.7 Hz, J = 2.3 Hz); 8.43
2 Py 1 2
(dd, 4 H, 4 CHPy, J1 = 6.7 Hz, J2 = 1.5 Hz); 8.64 (d, 4 H,
l
13
1
18—120 C. H NMR (CD OD-d ), : 0.84 (t, 12 Н, 4 CH ,
4 CHPy, J = 6.6 Hz); 9.16 (br.s, 4 H, 4 CHPy). C NMR
3
4
3
J = 7.3 Hz); 1.22—1.44 (m, 32 H, 16 CH ); 1.92—2.06 (m, 8 H,
(CD OD-d ), : 14.5, 23.5, 27.2, 29.8, 30.1, 30.2, 30.3, 30.5,
2
3 4
+
4
4
CH ); 4.63 (t, 8 Н, 4 N CH , J = 7.9 Hz); 4.83 (s, 8 Н,
30.6, 32.5, 33.1, 63.6, 69.6, 129.8, 133.0, 134.3, 138.3, 159.1.
2
2
–1
OCH ); 7.94 (dd, 4 H, 4 CH , J = 6.6 Hz, J = 2.3 Hz); 8.33
IR (KBr), /cm : 2956, 2924, 2854, 1581, 1492, 1278, 1202, 843,
815, 681. Found (%): С, 59.76; H, 8.48; N, 3.99. С H Br N О .
2
Py
1
2
(
dd, 4 H, 4 CHPy, J1 = 6.6 Hz, J2 = 1.5 Hz); 8.60 (d, 4 H,
69
116
4
4 4
1
3
4
CHPy, J = 6.6 Hz); 9.12 (br.s, 4 H, 4 CHPy). C NMR
Calculated (%): С, 59.82; H, 8.44; N, 4.04.
(
CD OD-d ), : 14.3, 23.6, 27.4, 30.1, 30.2, 32.6, 32.8, 63.6,
1-Dodecyl-3-(3-[(1-dodecylpyridinium-3-yl)oxy]-2,2-bis-
{[(1-dodecylpyridium-3-yl)oxy]methyl}propoxy)pyridinium tetra-
kisbromide (3f). The yield was 0.64 g (90%), white powder, m.p.
3
4
–
1
7
2
0.0, 129.3, 132.3, 134.2, 138.1, 159.2. IR (KBr), /cm : 3134,
960, 2927, 2850, 1729, 1488, 1460, 1401, 1385, 1275. Found (%):
l
С, 54.80; H, 7.34; N, 4.80. С H Br N О . Calculated (%):
127—130 C. H NMR (CD OD-d ), : 0.91 (t, 12 Н, 4 CH ,
5
3
84
4
4
4
3
4
3
С, 54.84; H, 7.29; N, 4.83.
J = 7.3 Hz); 1.24—1.50 (m, 72 H, 36 CH ); 2.00—2.16 (m, 8 H,
2
+
1
-Octyl-3-(3-[(1-octylpyridinium-3-yl)oxy]-2,2-bis{[(1-
4 CH ); 4.68 (t, 8 Н, 4 N CH , J = 7.7 Hz); 4.90 (s, 8 Н,
2
2
octylpyridium-3-yl)oxy]methyl}propoxy)pyridinium tetrakis-
bromide (3b). The yield was 0.50 g (82%), white powder, m.p.
4 OCH ); 8.04 (dd, 4 H, 4 CH , J = 8.8 Hz, J = 5.8 Hz); 8.40
2 Py 1 2
(dd, 4 H, 4 CHPy, J1 = 8.8 Hz, J2 = 2.2 Hz); 8.65 (d, 4 H,
l
13
1
15—118 C. H NMR (CD OD-d ), : 0.84 (t, 12 Н, 4 CH ,
4 CHPy, J = 5.8 Hz); 9.21 (br.s, 4 H, 4 CHPy). C NMR
3
4
3
J = 7.3 Hz); 1.21—1.41 (m, 40 H, 20 CH ); 1.94—2.08 (m, 8 H,
(CD OD-d ), : 14.2, 23.6, 27.2, 29.7, 29.9, 30.0, 30.2, 30.8,
2
3 4
+
4
4
CH ); 4.61 (t, 8 Н, 4 N CH , J = 8.0 Hz); 4.84 (s, 8 Н,
31.0, 31.2, 32.6, 32.7, 63.4, 69.8, 129.6, 132.6, 134.6, 138.4,
2
2
–
1
OCH ); 7.96 (dd, 4 H, 4 CH , J = 6.6 Hz, J = 2.2 Hz); 8.35
159.0. IR (KBr), /cm : 2956, 2922, 2852, 1495, 1471, 1274,
2
Py
1
2
(
dd, 4 H, 4 CHPy, J1 = 6.6 Hz, J2 = 1.5 Hz); 8.59 (d, 4 H,
1205, 829, 811, 679. Found (%): С, 60.79; H, 8.52; N, 3.87.
1
3
4
CHPy, J = 6.6 Hz); 9.14 (br.s, 4 H, 4 CHPy). C NMR
С H Br N О . Calculated (%): С, 60.83; H, 8.67; N, 3.89.
73 124 4 4 4
(
CD OD-d ), : 14.4, 23.6, 27.3, 30.0, 30.1, 30.2, 32.6, 32.7,
Evaluation of antibacterial activity in vitro (general procedure).
3
4
–
1
–1
6
3
3.4, 69.8, 129.6, 132.6, 134.6, 138.6, 159.0. IR (KBr), /cm
:
Test samples were prepared at the concentration of 20000 g mL
with ethanol. Aliquots (150 L) were transferred using an
Eppendorf tube, and a two-step dilution with a liquid nutrient
134, 2957, 2925, 2852, 1494, 1473, 1274, 1205, 829, 811.
Found (%): С, 56.23; H, 7.65; N, 4.58. С H Br N О . Calcul-
5
7
92
4
4
4
–
1
ated (%): С, 56.25; H, 7.62; N, 4.60.
medium (final concentration of 256—0.25 g mL ) was carried
out. The aliquot (150 L) was added into a 96 well plate.
Then, aliquots (150 L) of bacteria were added, brought to
1
-Nonyl-3-(3-[(1-nonylpyridinium-3-yl)oxy]-2,2-bis{[(1-
nonylpyridium-3-yl)oxy]methyl}propoxy)pyridinium tetrakis-
6
–1
bromide (3с). The yield was 0.54 g (85%), white powder, m.p.
~10 CFU mL , and incubated for 24 h at 37 C. The MIC was
l
1
18—121 C. H NMR (CD OD-d ), : 0.84 (t, 12 Н, 4 CH ,
determined visually according to the turbidity.
3
4
3