JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
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(300 mL) and ammonia gas was added to the solution at 0 ꢁC. (t, J ¼ 7.4 Hz, 2H), 5.15 (t, J ¼ 7.4 Hz, 2H), 4.78 (t, J ¼ 7.7 Hz, 2H),
After 1 h, the reaction mixture was concentrated in vacuo, filtered 2.26–1.97 (m, 2H), 1.99–1.72 (m, 2H), and 1.68–1.35 (m, 2H). 13C
and washed with water to give the desired product (3.96 g, 66%).
1H NMR (500 MHz, DMSO-d6) d 8.97 (d, J ¼ 4.2 Hz, 1H), 8.26 (s, 1H),
8.22 (d, J ¼ 8.4 Hz, 1H), 8.08 (d, J ¼ 8.4 Hz, 1H), 7.93 (s, 1H), 7.81 (t,
J ¼ 7.6 Hz, 1H), 7.68 (t, J ¼ 7.6 Hz, 1H), 7.57 (d, J ¼ 4.2 Hz, 1H).
Quinoline-5-carboxamide (6) was purchased from AA blocks.
Quinoline-6-carboxamide (7): To a mixture of quinoline-6-carboxylic
acid (12.8 g, 74 mmol) in CH2Cl2 (740 mL) was added 20 drops of
DMF at 0 ꢁC, followed by oxalyl chloride (32 mL) dropwise. The
resulting reaction was stirred at r.t. overnight, and then concen-
trated in vacuo. The crude mixture was dissolved in THF (600 mL)
and ammonia gas was added to the solution at 0 ꢁC. After 1 h, the
reaction mixture was concentrated in vacuo, filtered and washed
with water to give the desired product (6.0 g, 47%). 1H NMR
(500 MHz, DMSO-d6) d 8.99 (dd, J ¼ 4.2, 1.7 Hz, 1H), 8.58 (d,
J ¼ 1.5 Hz, 1H), 8.52–8.43 (m, 1H), 8.29 (s, 1H), 8.22 (dd, J ¼ 8.8,
1.9 Hz, 1H), 8.07 (d, J ¼ 8.8 Hz, 1H), 7.62 (dd, J ¼ 8.3, 4.2 Hz, 2H).
Quinoline-7-carboxamide (8): To a mixture of quinoline-7-car-
boxylic acid (0.50 mg, 2.9 mmol) in CH2Cl2 (29 mL, 0.1 M) was
added one drops of DMF at 0 ꢁC, followed by oxalyl chloride
(0.4 mL, 5 mmol) dropwise. The resulting reaction was stirred at r.t.
for 1 h, and then concentrated in vacuo. The crude mixture was
dissolved in NH4OH (50 mL) and stirred at r.t. for 0.5 h. The reac-
tion mixture was concentrated in vacuo, added with NaHCO3 and
extracted with EA. The combined organic layers were washed with
brine, dried over Na2SO4, filtered and concentrated in vacuo to
NMR (125 MHz, DMSO-d6) d 163.14, 149.20, 146.75, 145.98, 145.81,
145.21, 141.44, 141.37, 137.85, 136.97, 131.74, 130.46, 128.76,
127.67, 127.45, 125.87, 57.51, 57.29, 29.64, 28.80, and 22.33. HRMS
2þ
calculated for C21H24N4O2
363.1881.
363.1888 [M–H]þ; found: m/z
4-Carbamoyl-1-(5-(2-((hydroxyimino)methyl)pyridin-1-ium-1-yl)pen-
tyl)quinolin-1-ium bromide (11). 1-(5-Bromopentyl)-2-((hydroxyimi-
no)methyl)pyridin-1-ium bromide (736 mg, 2.09 mmol) and
quinoline-4-carboxamide (300 mg, 1.74 mmol) were dissolved in
DMF (17 mL). The reaction mixture was stirred at 85 ꢁC for 144 h.
Acetone was poured into the reaction mixture and keep in
refrigerator overnight. The solid was filtered and washed with
acetone to give the desired product (65 mg, 7%). 1H NMR
(500 MHz, DMSO-d6) d 13.14 (s, 1H), 10.07 (s, 1H), 9.80 (s, 1H), 9.14
(d, J ¼ 6.2 Hz, 1H), 8.79 (s, 1H), 8.75–8.65 (m, 2H), 8.57 (q,
J ¼ 8.1 Hz, 2H), 8.45–8.32 (m, 2H), 8.22 (s, 1H), 8.13 (t, J ¼ 7.4 Hz,
2H), 5.15 (t, J ¼ 7.4 Hz, 2H), 4.78 (t, J ¼ 7.7 Hz, 2H), 2.26–1.97 (m,
2H), 1.99–1.72 (m, 2H), and 1.68–1.35 (m, 2H). 13C NMR (125 MHz,
DMSO-d6) d 165.89, 151.76, 149.98, 146.91, 145.91, 145.21, 141.36,
137.88, 135.71, 130.61, 127.93, 127.46, 126.04, 125.80, 119.63,
119.41, 57.51, 57.30, 29.64, 28.85, and 22.34. HRMS calculated for
2þ
C21H24N4O2 363.1888 [M–H]þ; found: m/z 363.1880.
5-Carbamoyl-1-(5-(2-((hydroxyimino)methyl)pyridin-1-ium-1-yl)pen-
tyl)quinolin-1-ium bromide (12). 1-(5-Bromopentyl)-2-((hydroxyimi-
no)methyl)pyridin-1-ium bromide (736 mg, 2.09 mmol) and
quinoline-4-carboxamide (300 mg, 1.74 mmol) were dissolved in
DMF (17 mL). The reaction mixture was stirred at 85 ꢁC for 144 h.
Acetone was poured into the reaction mixture and keep in
refrigerator overnight, then filtered. The solid was put in MeCN at
85 ꢁC for overnight to get the desired product (147 mg, 13%). 1H
1
give the desired product (371 mg, 74%). H NMR (500 MHz, DMSO-
d6) d 8.99 (dd, J ¼ 4.2, 1.7 Hz, 1H), 8.58 (s, 1H), 8.43 (dd, J ¼ 8.3,
0.9 Hz, 1H), 8.29 (s, 1H), 8.05 (d, J ¼ 1.0 Hz, 2H), 7.62 (dd, J ¼ 8.3,
4.2 Hz, 2H).
2.1.2.2. Synthesis of monoquaternary precursor. 1-(5-Bromopentyl)- NMR (500 MHz, DMSO-d6) d 13.20 (s, 1H), 9.64 (dd, J ¼ 5.9, 1.4 Hz,
2-((hydroxyimino)methyl)pyridin-1-ium
bromide
(9).
1,5-
1H), 9.55–9.48 (m, 1H), 9.07 (dd, J ¼ 6.3, 1.4 Hz, 1H), 8.76 (s, 1H),
8.72 (d, J ¼ 9.1 Hz, 1H), 8.56 (td, J ¼ 7.9, 1.4 Hz, 1H), 8.47 (s, 1H),
8.40 (dd, J ¼ 8.2, 1.6 Hz, 1H), 8.32–8.25 (m, 1H), 8.22 (dd, J ¼ 8.8,
5.8 Hz, 1H), 8.18 (d, J ¼ 7.1 Hz, 1H), 8.13–8.01 (m, 2H), 5.10 (t,
J ¼ 7.5 Hz, 2H), 4.74 (t, J ¼ 7.6 Hz, 2H), 2.12–1.97 (m, 2H), 1.93–1.85
(m, 2H), and 1.55–1.42 (m, 2H). 13C NMR (125 MHz, DMSO-d6) d
168.30, 150.44, 147.23, 146.53, 145.74, 145.50, 141.92, 138.08,
136.62, 135.12, 129.34, 127.97, 127.44, 126.41, 123.26, 121.47,
Dibromopentane (84 mL, 615 mmol) was dissolved in MeCN
(373 mL, 0.55 M) and added 2-pyridinealdoxime (25 g, 205 mmol).
The reaction mixture was stirred at 85 ꢁC for 75 h. The reaction
mixture was cooled to r.t. and removed the solvent. The crude
mixture was dissolved in MeOH and silica gel (10 g) was added to
the crude mixture. The solution was stirred at r.t. for 30 min and
concentrated in vacuo. The solid was packing with silica gel and
purified by silica gel column chromatography. After further purifi-
cation by silica gel column chromatography and recrystallisation
in acetone/MeOH to give the desired product (7.46 g, 13.4%). 1H
NMR (500 MHz, DMSO-d6) d 13.14 (s, 1H), 9.10 (d, J ¼ 6.0 Hz, 1H),
8.89–8.71 (m, 1H), 8.56 (t, J ¼ 7.9 Hz, 1H), 8.41 (dd, J ¼ 8.2 Hz, 1H),
8.12 (t, J ¼ 6.2 Hz, 1H), 4.89–4.66 (m, 2H), 3.53–3.52 (m, 2H),
2.00–1.65 (m, 4H), 1.60–1.37 (m, 2H). 13C NMR (125 MHz, DMSO-d6)
d 146.77, 146.00, 145.62, 141.46, 127.48, 125.93, 57.57, 34.81,
31.45, 29.40, and 24.02. HRMS calculated for C11H16BrN2Oþ
271.0441 [M–H]þ; found: m/z 271.0451.
2þ
57.99, 30.13, 29.33, and 22.77. HRMS calculated for C21H24N4O2
363.1888 [M–H]þ; found: m/z 363.1879.
6-Carbamoyl-1-(5-(2-((hydroxyimino)methyl)pyridin-1-ium-1-yl)pen-
tyl)quinolin-1-ium bromide (13). 1-(5-Bromopentyl)-2-((hydroxyimi-
no)methyl)pyridin-1-ium bromide (500 mg, 1.42 mmol) and
quinoline-6-carboxamide (196 mg, 1.14 mmol) were dissolved in
DMF (14 mL). The reaction mixture was stirred at 85 ꢁC for 144 h.
Acetone was poured into the reaction mixture and keep in
refrigerator overnight. The solid was filtered and washed with
acetone to give the desired product (40 mg, 6.7%). 1H NMR
(500 MHz, DMSO-d6) d 13.16 (s, 1H), 9.68 (d, J ¼ 5.6 Hz, 1H), 9.37
(d, J ¼ 8.3 Hz, 1H), 9.09 (d, J ¼ 6.1 Hz, 1H), 9.00 (s, 1H), 8.78 (s,
1H), 8.72 (d, J ¼ 9.3 Hz, 1H), 8.63 (d, J ¼ 9.2 Hz, 1H), 8.57 (t, J
¼ 7.8 Hz, 1H), 8.51 (s, 1H), 8.42 (d, J ¼ 7.7 Hz, 1H), 8.32–8.23 (m,
1H), 8.12 (t, J ¼ 6.6 Hz, 1H), 7.91 (s, 1H), 5.10 (t, J ¼ 7.2 Hz, 2H),
4.75 (t, J ¼ 7.4 Hz, 2H), 2.16–1.98 (m, 2H), 1.97–1.81 (m, 2H), and
1.61–1.35 (m, 2H). 13C NMR (125 MHz, DMSO-d6) d 165.75, 150.77,
148.30, 146.77, 145.20, 141.38, 138.45, 134.82, 133.52, 130.36,
129.32, 127.45, 125.84, 122.84, 119.42, 57.49, 57.06, 29.64, 28.82,
2.1.2.3. Synthesis of final bisquaternary salts. 3-Carbamoyl-1-(5-(2-
((hydroxyimino)methyl)pyridin-1-ium-1-yl)pentyl)quinolin-1-ium brom-
ide (10). 1-(5-Bromopentyl)-2-((hydroxyimino)methyl)pyridin-1-ium
bromide (736 mg, 2.09 mmol) and quinoline-3-carboxamide
(300 mg, 1.74 mmol) were dissolved in DMF (17 mL). The reaction
mixture was stirred at 85 ꢁC for 144 h. Acetone was poured into
the reaction mixture and keep in refrigerator overnight. The solid
was filtered and washed with acetone to give the desired product
and 22.27. HRMS calculated for C21H24N4O22þBr– 521.0188
1
(170 mg, 17%). H NMR (500 MHz, DMSO-d6) d 13.14 (s, 1H), 10.07
2
(s, 1H), 9.80 (s, 1H), 9.14 (d, J ¼ 6.2 Hz, 1H), 8.79 (s, 1H), 8.75–8.65 [M–H]–; found: m/z 521.0189. HRMS calculated for C21H24N4O2
2þ
(m, 2H), 8.57 (q, J ¼ 8.1 Hz, 2H), 8.45–8.32 (m, 2H), 8.22 (s, 1H), 8.13 363.1888 [M–H]þ; found: m/z 363.1886.