H.N. Nagesh et al. / European Journal of Medicinal Chemistry 74 (2014) 333e339
337
Table 3
IC50 g/mL) and selectivity index (SI) value of active compounds (5e, 5j and 5k) against mouse macrophage cell lines (RAW264.7).
(
m
Entry
Compound
MIC (
mg/mL) in MTB H37Rv
% Cell inhibition at 50
m
g/mL
IC50 approximation
SI value IC50/MIC
1
2
3
5e
5j
5k
1.56
1.56
1.56
21.4
18.2
16.4
>40
>40
>40
>25
>25
>25
5.2.6. 6-[4-(3-Methoxyphenyl)piperazin-1-yl]phenanthridine (5f)
5.2.11. 6-[4-(Pyridin-2-yl)piperazin-1-yl]phenanthridine (5k)
Yield ¼ 75%; mp ¼ 147e149 ꢀC; 1H NMR (400 MHz, CDCl3)
Yield ¼ 79%; mp ¼ 113e115 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.47
d 8.59
(d, J ¼ 8.2 Hz, 1H), 8.39 (dd, J ¼ 8.1, 1.1 Hz, 1H), 8.22 (dd, J ¼ 8.2,
0.8 Hz, 1H), 7.93 (dd, J ¼ 8.2, 1.0 Hz, 1H), 7.79e7.72 (m, 1H), 7.61 (tt,
J ¼ 8.3, 1.4 Hz, 2H), 7.45 (ddd, J ¼ 8.3, 7.1, 1.3 Hz, 1H), 7.19 (t,
J ¼ 8.0 Hz,1H), 6.84 (d, J ¼ 7.6 Hz, 2H), 6.71 (d, J ¼ 7.5 Hz,1H), 3.96 (s,
3H), 3.69e3.64 (m, 4H), 3.52e3.46 (m, 4H). 13C NMR (100.61 MHz,
(d, J ¼ 8.1 Hz,1H), 8.46 (d, J ¼ 8.2 Hz, 1H), 8.32e8.27 (m, 1H), 8.25 (s,
1H), 7.96 (d, J ¼ 8.2 Hz, 1H), 7.80 (t, J ¼ 7.6 Hz, 1H), 7.69e7.60 (m,
2H), 7.55 (dd, J ¼ 10.7, 3.8 Hz, 1H), 7.51 (t, J ¼ 5.4 Hz, 1H), 6.78 (d,
J ¼ 8.6 Hz, 1H), 6.68 (dd, J ¼ 6.7, 5.3 Hz, 1H), 3.90e3.79 (m, 4H),
3.68e3.59 (m, 4H). 13C NMR (100.61 MHz, CDCl3)
d 160.01, 150.78,
CDCl3)
d
159.87, 150.28, 148.24, 144.45, 137.23, 135.72, 130.35,
148.03,143.75,137.53,134.99,130.20,128.75,128.58,126.81,126.42,
124.86, 122.75, 122.66, 121.89, 121.45, 113.57, 107.33, 50.96, 45.48.
HRMS: (ESI m/z) for C22H21N4 calcd: 341.1761, found: 341.1776
(M þ H)þ.
129.32, 128.46, 126.17, 125.34, 124.13, 123.56, 122.64, 121.85, 120.56,
115.34, 114.88, 106.42, 58.67, 52.63, 46.61. HRMS: (ESI m/z) for
C
24H24N3O calcd: 370.1914, found: 370.1923 (M þ H)þ.
5.2.12. 6-(4-Ethylpiperazin-1-yl)phenanthridine (5l)
5.2.7. 2-[4-(Phenanthridin-6-yl)piperazin-1-yl]benzonitrile (5g)
Yield ¼ 80%; mp ¼ 78e80 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.54
Yield ¼ 81%; mp ¼ 171e172 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.57
(d, J ¼ 8.2 Hz, 1H), 8.41 (d, J ¼ 7.9 Hz, 1H), 8.31 (d, J ¼ 8.3 Hz, 1H),
7.83 (d, J ¼ 7.5 Hz, 1H), 7.72 (t, J ¼ 7.6 Hz, 1H), 7.59 (t, J ¼ 7.6 Hz, 2H),
7.45 (t, J ¼ 7.6 Hz, 1H), 3.78e3.72 (m, 4H), 3.62e3.57 (m, 4H), 3.42
(d, J ¼ 8.1 Hz, 1H), 8.47 (d, J ¼ 8.2 Hz, 1H), 8.35e8.29 (m, 1H), 8.28 (s,
1H), 7.98 (d, J ¼ 8.2 Hz, 1H), 7.81 (t, J ¼ 7.6 Hz, 1H), 7.68e7.63 (m,
2H), 7.58 (dd, J ¼ 10.7, 3.8 Hz, 1H), 7.52 (t, J ¼ 5.4 Hz, 1H), 6.63 (d,
J ¼ 8.6 Hz, 1H), 6.57 (dd, J ¼ 6.7, 5.3 Hz, 1H), 3.78e3.65 (m, 4H),
(q, 2H), 1.36 (t, 3H). 13C NMR (100.61 MHz, CDCl3)
d 160.85, 151.53,
3.61e3.58 (m, 4H). 13C NMR (100.61 MHz, CDCl3)
d 161.17, 152.26,
147.47, 142.80, 137.32, 135.27, 129.13, 128.46, 127.37, 123.33, 121.96,
119.25, 114.39, 51.14, 48.63, 42.49, 16.40. HRMS: (ESI m/z) for
149.87, 141.31, 138.39, 135.51, 131.22, 129.68, 127.78, 126.69, 126.13,
125.78, 124.56, 122.64, 121.64, 120.53, 118.45, 115.49, 116.23, 108.78,
51.70, 45.33. HRMS: (ESI m/z) for C24H21N4 calcd: 365.1761, found:
365.1779 (M þ H)þ.
C
19H22N3 calcd: 292.1808, found: 292.1821 (M þ H)þ.
5.2.13. 3-[4-(Phenanthridin-6-yl)piperazin-1-yl]phenol (5m)
Yield ¼ 67%; mp ¼ 195e197 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.51
(d, J ¼ 8.2 Hz, 1H), 8.46 (dd, J ¼ 8.1, 1.1 Hz, 1H), 8.29 (dd, J ¼ 8.2,
0.8 Hz,1H), 7.93 (dd, J ¼ 8.2, 1.0 Hz,1H), 7.79 (m, 1H), 7.68 (tt, J ¼ 8.3,
1.4 Hz, 2H), 7.58 (ddd, J ¼ 8.3, 7.1, 1.3 Hz, 1H), 7.25 (t, J ¼ 8.0 Hz, 1H),
6.81 (d, J ¼ 7.6 Hz, 2H), 6.73 (d, J ¼ 7.5 Hz, 1H), 4.88 (s, 1H), 3.65e
3.58 (m, 4H), 3.51e3.45 (m, 4H). 13C NMR (100.61 MHz, CDCl3)
5.2.8. 6-(4-Phenethylpiperazin-1-yl)phenanthridine (5h)
Yield ¼ 86%; mp ¼ 123e125 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.54
(d, J ¼ 8.2 Hz,1H), 8.41 (d, J ¼ 7.9 Hz,1H), 8.15 (d, J ¼ 8.3 Hz,1H), 8.11
(d, J ¼ 9.3 Hz, 2H), 7.82 (d, J ¼ 7.5 Hz, 1H), 7.77 (t, J ¼ 7.6 Hz,1H), 7.58
(m, 5H), 7.52 (t, J ¼ 7.6 Hz, 1H), 3.72e3.65 (m, 8H), 3.46 (t,
J ¼ 7.12 Hz, 2H), 2.73 (t, J ¼ 6.9 Hz, 2H). 13C NMR (100.61 MHz,
d
160.45, 151.67, 149.35, 144.68, 138.25, 135.15, 131.06, 128.75,
127.13, 126.29, 125.47, 124.28, 122.41, 121.23, 120.55, 119.34, 114.56,
109.23, 108.74, 51.33, 44.26. HRMS: (ESI m/z) for C23H22N3O calcd:
356.1757, found: 356.1769 (M þ H)þ.
CDCl3) d 159.21, 151.06, 148.19, 143.66, 140.61, 138.84, 136.11, 131.75,
129.44, 128.92, 127.14, 126.51, 125.60, 123.17, 121.88, 120.47, 119.27,
115.85, 108.31, 50.74, 49.28, 45.78, 32.55. HRMS: (ESI m/z) for
C
25H26N3 calcd: 368.2121, found: 368.2137 (M þ H)þ.
5.2.14. 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-(2-(4-
(phenanthridin-6-yl)piperazin-1-yl)acetyl)piperazin-1-yl)
quinoline-3-carboxylic acid (5n)
5.2.9. 6-(4-Benzhydrylpiperazin-1-yl)phenanthridine (5i)
Yield ¼ 72%; mp ¼ 175e177 ꢀC; 1H NMR (400 MHz, CDCl3)
Yield ¼ 77%; mp ¼ 270e271 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
8.50
(d, J ¼ 8.2 Hz, 1H), 8.41 (d, J ¼ 7.9 Hz, 1H), 8.23 (d, J ¼ 8.3 Hz, 1H),
7.96 (d, J ¼ 7.5 Hz, 1H), 7.82 (t, J ¼ 7.6 Hz, 1H), 7.72 (m, 5H), 7.67 (t,
J ¼ 7.6 Hz, 2H), 7.5 (m, 5H), 7.41 (t, J ¼ 7.6 Hz,1H), 3.79e3.64 (m, 4H),
3.54e3.48 (m, 4H), 3.39 (s, 1H). 13C NMR (100.61 MHz, CDCl3)
d
15.18 (s, 1H), 8.63 (s, 1H), 8.57 (d, J ¼ 8.2 Hz, 1H), 8.45 (d, J ¼ 7.9 Hz,
1H), 8.16 (d, J ¼ 8.3 Hz, 1H), 7.89 (d, JHeF ¼ 13.2 Hz, 1H), 7.83 (d,
J ¼ 7.5 Hz, 1H), 7.79 (t, J ¼ 7.6 Hz, 1H), 7.63 (t, J ¼ 7.6 Hz, 2H), 7.49 (t,
J ¼ 7.6 Hz, 1H), 7.52 (d, JHeF ¼ 7.5 Hz, 1H), 3.81 (tt, J ¼ 7.2 Hz,
J ¼ 6.9 Hz, 1H), 3.79e3.56 (m, 16H), 3.28 (m, 2H), 1.26 (t, J ¼ 6.9 Hz,
d
160.94, 155.65, 151.27, 149.08, 145.43, 141.35, 138.45, 135.22,
2H), 1.19 (t, J ¼ 7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 176.82,
131.37, 129.11, 128.06, 127.57, 125.18, 124.77, 123.79, 121.31, 120.96,
120.02, 114.17, 70.86, 52.42, 43.26. HRMS: (ESI m/z) for C30H28N3
calcd: 430.2278, found: 430.2288 (M þ H)þ.
167.56, 166.43, 159.87, 150.28, 147.67, 146.23, 143.67, 138.95, 136.79,
134.12, 129.97, 128.32, 127.89, 126.11, 125.56, 124.13, 122.86, 121.64,
121.16, 120.76, 113.21, 111.97, 107.12, 106.33, 61.21, 53.67, 51.87, 51.12,
50.89, 49.16, 46.78, 45.91, 41.39, 35.58, 8.12. HRMS: (ESI m/z) for
5.2.10. 6-(4-(Pyrimidin-2-yl)piperazin-1-yl)phenanthridine (5j)
36H36FN6O4 calcd: 635.2777, found: 635.2796 (M þ H)þ.
Yield ¼ 73%; mp ¼ 154e155 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.61
C
(d, J ¼ 8.2 Hz, 1H), 8.47 (d, J ¼ 7.9 Hz, 1H), 8.25 (d, J ¼ 8.3 Hz, 1H),
8.19 (d, J ¼ 9.3 Hz, 2H), 7.96 (d, J ¼ 7.5 Hz, 1H), 7.83 (t, J ¼ 7.6 Hz, 1H),
5.2.15. 6-[4-Methylpiperazin-1-yl]phenanthridine (5o)
Yield ¼ 76%; mp ¼ 97e98 ꢀC; 1H NMR (400 MHz, CDCl3)
7.67 (t, J ¼ 7.6 Hz, 2H), 6.95 (d, J ¼ 9.4 Hz, 2H), 3.75e3.67 (m, 8H). 13
C
d 8.58
NMR (100.61 MHz, CDCl3)
d
161.83, 159.38, 157.69, 155.39, 150.21,
(d, J ¼ 8.2 Hz, 1H), 8.41 (d, J ¼ 7.9 Hz, 1H), 8.27 (d, J ¼ 8.3 Hz, 1H),
7.92 (d, J ¼ 7.5 Hz, 1H), 7.86 (t, J ¼ 7.6 Hz, 1H), 7.76 (t, J ¼ 7.6 Hz, 2H),
7.55 (t, J ¼ 7.6 Hz, 1H), 3.65e3.59 (m, 8H), 3.43 (s, 3H). 13C NMR
147.62, 144.74, 138.08, 136.73, 130.23, 128.98, 127.12, 126.78, 125.25,
123.43, 120.03, 113.78, 54.11, 44.64. HRMS: (ESI m/z) for C21H20N5
calcd: 342.1713, found: 342.1722 (M þ H)þ.
(100.61 MHz, CDCl3)
d 161.12, 153.87, 151.89, 144.80, 144.16, 138.97,