6
Firoz A. Kalam Khan et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
Table 3
In silico physicochemical pharmacokinetic parameters important for good oral bioavailability of synthesized compounds 5(a–m)
Entry
Rule
% ABS
TPSA (A2)
n-ROTB
MV
MW
miLogP
n-ON acceptors
n-OHNH donors
Lipinski’s violations
—
—
—
4
4
4
4
4
4
4
5
5
4
4
5
5
—
<500
65
<10
2
3
3
2
2
2
3
2
2
4
5
4
<5
1
2
2
1
1
1
1
1
1
1
1
1
1
61
0
0
0
0
0
0
0
1
1
0
0
1
0
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
g
h
i
97.16
90.19
90.19
97.16
97.16
97.16
91.28
97.16
97.16
88.27
86.56
89.53
92.86
34.30
54.52
54.52
34.30
34.30
34.30
51.36
34.30
34.30
60.08
65.02
56.42
46.77
261.85
269.87
269.87
271.54
271.54
285.08
267.13
293.15
293.15
253.54
238.91
317.94
344.92
272.35
288.35
288.35
271.34
271.34
305.79
287.34
340.35
340.35
274.33
263.30
359.45
375.45
4.88
4.61
4.40
3.96
3.98
4.61
4.59
5.77
5.75
3.30
2.30
5.47
4.92
j
k
l
m
4
%
ABS: percentage absorption, TPSA: topological polar surface area, n-ROTB: number of rotatable bonds, MV: molecular volume, MW: molecular weight, miLogP: logarithm of
partition coefficient of compound between n-octanol and water, n-ON acceptors: number of hydrogen bond acceptors, n-OHNH donors: number of hydrogen bonds donors.
1
(
2
C–H of CH
H, CH
2
), 2215 (CN); H NMR (400 MHz, CDCl
3
) d ppm: 4.49 (s,
118.69, 127.22, 128.94, 130.01, 132.81, 133.73, 133.92, 137.42,
141.48, 145.19, 154.41; ES-MS m/z: 364.08 [M+H ]; Elemental
Analysis for C20H14ClN O . Calcd C, 66.03; H, 3.88; Cl, 9.75; N,
3 2
+
2
), 5.20 (s, 1H, NH), 5.76 (s, 1H, OH), 7.46–8.41 (m, 12H, aro-
matic); C NMR (100 MHz, CDCl
1
3
3
) d ppm: 48.37, 110.69, 113.21,
1
1
18.68, 119.13, 127.63, 127.87, 129.10, 129.98, 133.92, 138.49,
11.55; O, 8.80; Found: C, 65.86; H, 3.88; Cl, 9.72; N, 11.52; O, 8.82.
+
41.49, 144.96, 146.47, 156.49; ES-MS m/z: 301.16 [M+H ]; Ele-
O. Calcd C, 79.98; H, 5.37; N, 9.33;
0
mental Analysis for C20
H
16
N
2
4.1.1.7.
4 -((4-Carboxyphenylamino)methyl)biphenyl-2-car-
O, 5.33; Found: C, 79.30; H, 5.35; N, 9.32; O, 5.30.
bonitrile (5g).
Yield: 82%; mp: 172–174 °C; IR (KBr,
cm ): 3348 (N–H), 3260 (O–H of COOH), 3013 (C–H of aromatic),
2815 (C–H of CH
), 2232 (CN), 1760 (C@O of COOH); 1H NMR
(400 MHz, CDCl ) d ppm: 5.09 (s, 2H, CH ), 5.64 (s, 1H, NH),
7.24–7.67 (m, 12H, aromatic), 10.01 (s, 1H, COOH); C NMR
(100 MHz, CDCl ) d ppm: 47.24, 111.19, 113.78, 118.65, 119.36,
mmax in
ꢀ1
0
4
.1.1.3.
4 -((4-Hydroxyphenylamino)methyl)biphenyl-2-car-
2
bonitrile (5c).
Yield: 90%; mp: 136–138 °C; IR (KBr,
m
max in
3
2
ꢀ
1
13
cm ): 3536 (O–H), 3319 (N–H), 3018 (C–H of aromatic), 2823
1
(
(
C–H of CH
s, 2H, CH
2
), 2210 (CN); H NMR (400 MHz, CDCl
), 4.57 (s, 1H, NH), 5.63 (s, 1H, OH), 7.84–8.74 (m,
3
) d ppm: 4.26
3
2
127.17, 127.62, 128.21, 128.90, 131.79, 133.73, 137.20, 137.29,
1
3
1
1
1
2H, aromatic); C NMR (100 MHz, CDCl
10.23, 115.52, 117.69, 125.47, 126.10, 127.35, 128.59, 135.49,
3
) d ppm: 46.33, 108.58,
139.03, 145.01, 151.04, 151.81, 166.49; ES-MS m/z: 329.35 [M
+
+H ]; Elemental Analysis for C21
H
16
N
2
O
2
. Calcd C, 76.81; H, 4.91;
37.78, 140.53, 142.25, 149.35, 158.65; ES-MS m/z: 301.25 [M
N, 8.53; O, 9.74; Found: C, 75.86; H, 4.88; N, 8.50; O, 9.72.
+
+H ]; Elemental Analysis for C20
H
16
N
2
O. Calcd C, 79.98; H, 5.37;
0
N, 9.33; O, 5.33; Found: C, 79.95; H, 5.36; N, 9.31; O, 5.34.
4.1.1.8. 4 -((4-(Trifluoromethyl)phenylamino)methyl)biphenyl-
2
-carbonitrile (5h).
Yield: 90%; mp: 160–162 °C; IR (KBr,
0
ꢀ1
4
.1.1.4. 4 -((2-Nitrophenylamino)methyl)biphenyl-2-carboni-
mmax in cm ): 3346 (N–H), 3013 (C–H of aromatic), 2815 (C–H of
1
trile (5d).
Yield: 89%; mp: 120–122 °C; IR (KBr,
cm ): 3330 (N–H), 3033 (C–H of aromatic), 2840 (C–H of CH
225 (CN), 1550 (N–O); 1H NMR (400 MHz, CDCl
s, 2H, CH ), 5.82 (s, 1H, NH), 7.00–7.82 (m, 12H, aromatic);
NMR (100 MHz, CDCl
m
max in
CH
2
), 2232 (CN), 1115 (C–F); H NMR (400 MHz, CDCl
), 4.80 (s, 1H, NH), 6.64–7.77 (m, 12H, aromatic);
C NMR (100 MHz, CDCl ) d ppm: 47.41, 111.20, 112.00, 118.71,
3
) d ppm:
ꢀ
1
2
),
4.44 (s, 2H, CH
2
13
2
(
3
) d ppm: 5.23
3
1
3
2
C
126.62, 126.67, 127.62, 129.15, 129.97, 132.86, 133.74, 137.36,
139.15, 145.01, 150.34; ES-MS m/z: 353.40 [M+H ]; Elemental
Analysis for C21H F N . Calcd C, 71.58; H, 4.29; F, 16.18; N, 7.95;
15 3 2
Found: C, 70.96; H, 4.29; F, 15.96; N, 7.93.
+
3
) d ppm: 40.70, 111.24, 115.08, 118.63,
20.82, 125.75, 127.22, 129.12, 132.88, 134.11, 136.19, 138.04,
1
1
+
44.93, 151.82; ES-MS m/z: 330.15 [M+H ]; Elemental Analysis
. Calcd C, 72.94; H, 4.59; N, 12.76; O, 9.72; Found:
15 3 2
for C20H N O
0
C, 72.90; H, 4.59; N, 12.74; O, 9.70.
4.1.1.9. 4 -((3-(Trifluoromethyl)phenylamino)methyl)biphenyl-
2
-carbonitrile (5i).
Yield: 85%; mp: 154–156 °C; IR (KBr, m
max
0
ꢀ1
4
.1.1.5. 4 -((3-Nitrophenylamino)methyl)biphenyl-2-carboni-
in cm ): 3350 (N–H), 3075 (C–H of aromatic), 2836 (C–H of CH
2
),
1
trile (5e).
Yield: 89%; mp: 146–148 °C; IR (KBr,
cm ): 3335 (N–H), 3040 (C–H of aromatic), 2832 (C–H of CH
220 (CN), 1542 (N–O); 1H NMR (400 MHz, CDCl
s, 2H, CH ), 5.43 (s, 1H, NH), 6.83–7.71 (m, 12H, aromatic);
NMR (100 MHz, CDCl
m
max in
2218 (CN), 1122 (C–F); H NMR (400 MHz, CDCl
2H, CH ), 4.77 (s, 1H, NH), 6.77–7.77 (m, 12H, aromatic);
NMR (100 MHz, CDCl
114.08, 115.71, 118.71, 126.98, 127.60, 127.78, 129.15, 129.72,
132.84, 133.74, 137.36, 139.27, 145.05, 148.10; ES-MS m/z:
353.32 [M+H ]; Elemental Analysis for C21
71.58; H, 4.29; F, 16.18; N, 7.95; Found: C, 71.32; H, 4.28; F,
16.00; N, 7.96.
3
) d ppm: 4.42 (s,
ꢀ
1
13
2
),
2
C
2
(
3
) d ppm: 4.40
3
) d ppm: 47.74, 109.07, 111.23, 114.05,
1
3
2
C
3
) d ppm: 47.71, 106.59, 111.24, 112.33,
18.74, 127.66, 127.77, 129.84, 130.00, 132.88, 133.76, 138.71,
+
1
1
H
15
F
3
N
2
. Calcd C,
+
44.98, 148.64; ES-MS m/z: 330.34 [M+H ]; Elemental Analysis
. Calcd C, 72.94; H, 4.59; N, 12.76; O, 9.72; Found:
15 3 2
for C20H N O
C, 72.98; H, 4.58; N, 12.78; O, 9.75.
0
4
.1.1.10.
4 -((Pyrazin-2-ylamino)methyl)biphenyl-2-carboni-
0
4
.1.1.6. 4 -((4-Chloro-2-nitrophenylamino)methyl)biphenyl-2-
trile (5j).
Yield: 88%; mp: 110–112 °C; IR (KBr,
mmax in
ꢀ1
carbonitrile (5f).
Yield: 88%; mp: 140–142 °C; IR (KBr,
in cm ): 3335 (N–H), 3040 (C–H of aromatic), 2832 (C–H of
CH
), 2220 (CN), 1542 (N–O), 850 (C–Cl); 1H NMR (400 MHz,
CDCl ) d ppm: 4.78 (s, 2H, CH ), 5.22 (s, 1H, NH), 7.45–7.78 (m,
1H, aromatic); C NMR (100 MHz, CDCl ) d ppm: 48.27, 111.25,
m
max
cm ): 3362 (N–H), 3063 (C–H of aromatic), 2820 (C–H of CH
2
),
) d
), 5.02 (s, 1H, NH), 7.24–7.74 (m, 11H, aro-
matic); C NMR (100 MHz, CDCl ) d ppm: 44.44, 105.37, 111.14,
127.18, 127.52, 128.23, 128.89, 133.68, 141.86, 144.96, 162.51;
ꢀ1
1
2228 (CN), 1335 (C–N of pyrazin); H NMR (400 MHz, CDCl
ppm: 4.74 (s, 2H, CH
3
2
2
1
3
3
2
3
1
3
1
3