M.F. Maleki et al.
Bioorganic Chemistry 109 (2021) 104684
4
.4.3. 3-((methyl(5-((2-oxo-1,2-dihydroquinolin-6-yl)oxy)pentyl)amino)
4.4.7. 3-((methyl(3-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)propyl)amino)
methyl)phenyl (2-ethylhexyl)carbamate (3j)
methyl)phenyl (4-phenylbutyl)carbamate (3n)
◦
1
◦
1
C
31
H
43
N
3
O
4
(521.33); mp: 71–74 C; Rf = 0. 7 (methanol); H NMR
C
31
H
35
N
3
O
4
(513.26); mp: 67–69 C; Rf = 0. 69 (methanol); H NMR
(300 MHz, DMSO‑d
) δ (ppm) 1.43–1.68 (m, 4H) 1.83–1.93 (m, 2H,
CH ), 2.27 (s, 3H, N CH NH CH Ph,
), 2.44–2.57 (m, 4H, CH
CH CH NH CO), 3.44 (s, 2H,
Ph), 3.23 (q, J = 6.3 Hz, 2H, CH
NH(Me) CH
(
(
300 MHz, DMSO‑d
6
) δ (ppm) 0.78–83 (m, 6H, 2 ×
CH ), 2.11 (s, 3H, N
Ph), 3.11 (q,
CO), 3.40 (s, 2H, NH(Me) CH
Ph), 3.91 (t, J = 6.3 Hz,
Ar), 5.01 (t, J = 6.3, 1H, NH), 6.64 (d, J = 9.5 Hz, 1H, Ar),
.87–7.32 (m, 7H, Ar), 7.67 (d, J = 9.5 Hz, 1H, Ar), 12.59 (s, 1H, NH-
–
CH
CH
6.5 Hz, 2H,
3
), 1.18–1.51
6
m, 13H), 1.71–1.75 (m, 2H,
–
2
–
2
–
3
), 2.32 (t, J
–
2
–
–
–
3
2
– –
2
=
6.8 Hz, 2H, CH
2
NH
–
CH
–
J
=
2
2
–
–
2
– –
2
CH
–
2
NH
–
–
–
2
2
–
Ph), 3.92 (t, J = 6.2 Hz, 2H, CH O Ar), 5.48 (t, J =
– –
2
6
H, CH
–
2
O
–
6.1 Hz, 1H), 6.68 (d, J = 9.4 Hz, 1H, Ar), 7.07–7.23 (m, 10H, Ar),
7.29–7.59 (m, 2H, Ar), 7.61 (d, J = 9.5 Hz, 1H,Ar), 12.13 (s, 1H, NH-
1
3
13
ring); C NMR (75 MHz, DMSO‑d
6
) δ (ppm) 11.3, 14.4, 23.0, 23.0, 24.0,
6
ring); C NMR (75 MHz, DMSO‑d ) δ (ppm) 27.0, 30.3, 34.6, 41.5, 58,
2
1
1
7
7.0, 29.0, 29.1, 30.7, 31.0, 42.2, 44.0, 57.1, 61.6, 68.3, 110.5, 116.8,
62, 67.7, 109, 117, 120.4, 120.5, 120.8, 122.3, 122.7, 125.4, 127, 129.5,
20.2, 120.3, 122.0, 122.7, 125.3, 129.2, 133.8, 140.2, 141.4, 151.7,
130.6 135, 144.3, 145.7, 147.8, 153.2, 156.0, 158.9, 158.7, 164.1; (ESI,
+
+
54.0, 155.0, 158.9, 162.8; (ESI, m/z): 522 [M+1] ; Anal. calcd: C,
m/z): 514 [M+1] ; Anal. calcd: C, 72.49; H, 6.87; N, 8.18; found: C,
1.37; H, 8.31; N, 8.05; found: C, 71.33; H, 8.27; N, 8.13.
72.43; H, 6.83; N, 8.21.
4
.4.4. 3-((methyl(5-((2-oxo-1,2-dihydroquinolin-6-yl)oxy)pentyl)amino)
4.4.8. 3-((methyl(5-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)pentyl)amino)
methyl)phenyl (4-phenylbutyl)carbamate (3k)
(541.29); mp: 83–86; Rf = 0. 75 (methanol); 1H NMR
300 MHz, DMSO‑d
) δ (ppm) 1.35–1.59 (m, 8H), 1.70–1.75 (m, 2H,
CH2 ), 2.11 (s, 3H, N CH Ph,
CH ), 2.47–2.59 (m, 4H, CH NH
CH CH CO), 3.39 (s, 2H, NH
Ph), 3.06 (q, J = 6.1, 2H, CH
CH Ar), 5.08 (t, J = 5.9,
Ph), 3.90 (t, J = 6.4 Hz, 2H, CH
H, NH), 6.61 (d, J = 9.5 Hz, 1H, Ar), 6.60–7.28 (m, 12H, Ar), 7.64 (d, J
9.5 Hz, 1H, Ar), 12.36 (s, 1H, NH-Ar); 13C NMR (75 MHz, DMSO‑d
) δ
ppm) 27.0, 28.7, 29.4, 30.3, 35.3, 41.5, 42.2, 57.2, 61.6, 68.3, 110.5,
methyl)phenyl heptylcarbamate (3o)
◦
1
C
33
H
39
N
3
O
4
C
30
H
41
N
3
O
4
(507.3); mp: 82–84 C; Rf = 0. 60 (methanol); H NMR
(
–
6
(300 MHz, DMSO‑d CH
6
) δ (ppm) 0.78 (t, J = 6.3 Hz,3H,
CH ), 2.13 (s, 3H, N
Ph), 3.05 (q,
CO), 3.41 (s, 2H, NH(Me) CH
–
3
),1.18–1.51
CH ), 2.31 (t, J
–
–
–
–
(m, 14H), 1.68–1.79 (m, 2H,
–
2
–
–
3
2
2
2
3
–
2
–
–
2
NH
–
=
6.8 Hz, 2H, CH
NH
NH
–
CH
–
J
=
5.9 Hz, 2H,
2
2
2
(
Me)
–
–
2
–
O
–
CH
–
2
–
–
2
–
Ph), 3.92 (t, J = 6.3 Hz,
1
2H, CH
Ar), 6.68–6.95 (m, 4H, Ar), 7.09–7.22 (m, 2H, Ar), 7.34 (dd, J = 8.6, 4.0
2
O Ar), 5.46 (t, J = 5.7 Hz, 1H, NH), 6.48 (d, J = 9.5 Hz, 1H,
– –
=
6
1
3
(
Hz, 1H, Ar), 7.65 (d, J = 9.4 Hz, 1H, Ar), 12.44 (s, 1H, NH-ring);
C
1
1
16.9, 120.2, 120.5, 122.1, 122.7, 125.4, 126.1, 128.7, 129.3, 133.8,
NMR (75 MHz, DMSO‑d ) δ (ppm) 11.4, 20.0, 21.0, 21.8, 22.5, 23.2, 27,
6
40.3, 141.4, 142.5, 142.7, 151.7, 154.0, 154.9, 162.1; (ESI, m/z): 542
31, 31.3, 41, 44.0, 52.1, 59.3, 65.3, 100.7, 110.4, 113.8, 120.5, 120.8,
121.7, 122.8, 128.3, 129.7, 133.8, 140, 141.3, 147.5, 151.0, 152.0,
+
+
[
M+1] ] ; Anal. calcd: C, 73.17; H, 7.26; N, 7.76; found: C, 73.15; H,
+
7
.28; N, 7.73.
162.8; (ESI, m/z): 508 [M+1] ; Anal. calcd: C, 70.98; H, 8.14; N, 8.28;
found: C, 70.90; H, 8.16; N, 8.24.
4
.4.5. 3-((methyl(3-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)propyl)amino)
methyl)phenyl heptylcarbamate (3l)
4.4.9. 3-((methyl(5-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)pentyl)amino)
◦
1
C
28
H
37
N
3
O
4
(479.62); mp: 83–85 C; Rf = 0. 6 (methanol); H NMR
300 MHz, DMSO‑d CH ), 1.41–1.50
) δ (ppm) 0.86 (t, J = 6.1 Hz, 3H,
CH ), 2.15 (s, 3H, N CH ), 2.51 (t, J
CH Ph), 3.05 (q, 6.3 Hz, 2H
CO), 3.49 (s, 2H, NH(Me) CH
Ph), 4.06 (t, J = 6.4 Hz,
methyl)phenyl (2-ethylhexyl)carbamate (3p)
(
(
6
–
3
C
31
H
43
N
3
O
4
(521.33); 82–84 ◦C; R
f
=
0. 75 (methanol); 1H NMR
), 1.18–1.39
), 2.46 (t, J = 6.8 Hz, 2H,
Ph), 3.11 (q, J = 6.2 Hz, 2H, CH NH CO), 3.43 (s,
CH Ar), 5.38 (t,
Ph), 3.98 (t, J = 6.3 Hz, 2H, CH
J = 6.0 Hz, 1H, NH), 6. 47 (d, J = 9.5 Hz, 1H, Ar), 6.63–7.34 (m, 7H, Ar),
m, 10H), 1.90–1.97 (m, 2H,
6.8 Hz, 2H, CH
NH
–
2
–
–
3
(300 MHz, DMSO‑d
(m, 13H, CH CH
CH NH CH
2H, NH(Me)
6
) δ (ppm) 0.77–0.86 (m, 6H, 2 × CH
3
=
2
NH
–
2
–
J
=
–
3
,
–
3
), 2.18 (s, 3H, N CH
–
3
CH
2
–
–
–
–
2
2
–
–
2
2
– –
2
6
1
H, CH
2
–
O
–
Ar), 5.08 (t, J = 6, 1H, NH), 6.31 (d, J = 9.5 Hz, 1H, Ar),
–
–
2
2
O
– –
.72–6.82 (m, 1H, Ar), 6.79–6.85 (m, 2H, Ar), 6.96 (dd, J = 7.8, 2.4 Hz,
H, Ar), 7.03 (t, J = 2.0 Hz, 1H, Ar), 7.12 (d, J = 7.6 Hz, 1H, Ar), 7.55 (d,
1
3
7.63 (d, J = 9.5 Hz, 1H, Ar), 12.18 (s, 1H, NH-ring); C NMR (75 MHz,
J = 8.7 Hz, 1H, Ar), 7.69 (t, J = 5.7 Hz, 1H, Ar), 7.80 (d, J = 9.5 Hz, 1H,
DMSO‑d ) δ (ppm) 13.5, 14.2, 23.0, 23.8, 24.9, 26.0, 28.5, 29.8, 30.7,
6
Ar), 11.59 (s, 1H, NH-ring); 13C NMR (75 MHz, DMSO‑d
) δ (ppm)14.2,
2.8, 23.4, 24.0, 26.98, 29.0, 31.3, 42.5, 44.0, 56.2, 61.3, 68.1, 104.5,
31.8, 42.2, 44.0, 57.9, 63.6, 69.3, 112.7, 115.8, 125.2, 126.3, 128.3,
129.7, 130.3, 131.2, 133.8, 140.8, 145.6, 153.5, 154.7, 158.0, 161.9,
6
2
1
1
+
09.4, 115.7, 119.2, 119.3, 119.4, 122.3, 122.8, 125.3, 130.2, 133.5,
162.0; (ESI, m/z): 522 [M+1] ; Anal. calcd: C, 70.98; H, 8.14; N, 8.28;
+
40.4, 141.3, 151.5, 154.0, 155.2, 162.3; (ESI, m/z): 480.6 [M+1] ;
found: C, 70.90; H, 8.16; N, 8.24.
Anal. calcd: C, 70.12; H, 7.78; N, 8.76; N, 7.76; found: C, 70.16; H, 7.72;
N, 8.71.
4.4.10. 3-((methyl(5-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)pentyl)
amino)methyl)phenyl (4-phenylbutyl)carbamate (3q)
4
.4.6. 3-((methyl(3-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)propyl)amino)
methyl)phenyl (2-ethylhexyl)carbamate (3m)
0. 53 (methanol); 1H NMR
) δ (ppm) 0.77–0.86 (m, 6H, 2 × CH ), 1.19–1.39
m, 9H), 1.84–191 (m, 2H, CH ), 2.19 (s, 3H, N CH ), 2.46 (t, J =
Ph), 3.11 (q, J = 6 Hz, 2H, CH NH CO),
Ph), 3.97 (t, J = 6.1 Hz, 2H, CH Ar),
.37 (t, J = 5.8, 1H, NH), 6.47 (d, J = 9.4 Hz, 1H, Ar), 6.64–6.73 (m, 2H,
C
33
H
39
N
3
O
4
(541.29); mp: 83–86; Rf = 0. 75 (methanol); 1H NMR
(300 MHz, DMSO‑d
2.2.47–2.59 (m, 4H, CH
6.1, 2H, 2H, CH NH CO), 3.41 (s, 2H, NH(Me)
= 6.4 Hz, 2H,), 5.13 (t, J = 6 Hz, 1H, NH), 6.46 (d, J = 9.5 Hz, 1H, Ar),
6
) δ (ppm) 1.35–1.75 (m, 10H), 2.13 (s, 3H, N
NH CH Ph, CH NH
CO), 3.06 (q, J =
CH Ph), 3.91 (t, J
–
CH ),
3
C
29
H
39
N
3
O
4
(493.29); 63–65 ◦C; R
300 MHz, DMSO‑d
f
=
2
–
–
2
2
– –
(
(
6
–
–
3
2
–
–
– –
2
–
–
2
3
1
3
6
3
5
.8 Hz, 2H, CH
2
NH
–
CH
CH
2
–
2
2
–
2
–
6.88–7.28 (m, 10, Ar), 7.61 (d, J = 9.5, Ar), 12.25 (s, 1H, NH-ring);
C
.43 (s, 2H, NH(Me)
–
–
–
O
–
NMR (75 MHz, DMSO‑d ) δ (ppm) 26.4, 27.9, 30.02, 31.3, 37.5, 44.7,
6
45.3, 55.1, 63.3, 71.5, 114.7, 119.3, 121.5, 123.7, 125.1, 128.3, 130.7,
133.3, 136.4, 140.3, 142.5, 145.8, 146.4, 148.8, 149.2, 151.3, 156.5,
Ar), 6.86–7.08 (m, 3H, Ar), 7.11–7.22 (m, 1H, Ar), 7.33 (d, J = 8.5 Hz,
1
3
+
1
H, Ar), 7.63 (d, J = 9.6 Hz, 1H, Ar), 12.25 (s, 1H, NH-ring); C NMR
158.1, 162.0; (ESI, m/z): 542 [M+1] ; Anal. calcd: C, 73.17; H, 7.26; N,
(
75 MHz, DMSO‑d ) δ (ppm)10.8, 14.2, 22.7, 24.3, 21.7, 25.6, 27.7,
6
7.76; found: C, 73.11; H, 7.24; N, 7.79.
3
1
1
0.7, 42.0, 43.5, 51.7, 65.5, 68.3, 99.4, 113.2, 114.3, 119.2, 119.8,
20.5, 122.8, 124.6, 130.5, 132.3, 141.7, 142.3, 151.6, 155.3, 162,
4.5. FAAH inhibition assay
+
63.7; (ESI, m/z): 494 [M+1] ; Anal. calcd: C, 70.56; H, 7.96; N, 8.51;
N, 7.76; found: C, 70.49; H, 7.95; N, 8.47.
In vitro Activity evaluation of all final compounds was performed by
fluorescence-based Cayman FAAH inhibitor screening assay Kit (item
number: 10005196) [39]. 7-amino-4-methylcoumarin-arachidonamide
(
AMC-AA) is hydrolyzed by the FAAH and release the fluorophore
1
2