Arch. Pharm. Chem. Life Sci. 2011, 11, 333–339
Cytotoxic 1-aryl-3-isopropylamino-1-propanone hydrochlorides
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structures. The melting points and yields of these compounds
are as follows, namely 1a: 172–1748C (lit. [26] m.p. 174–1768C),
55%; 1b: 170–1718C (lit. [27] m.p. 171–1728C), 58%; 1c: 176–1788C
(lit. [28] 1838C), 64%; 1d: 168–1708C (lit. [27] m.p. 167–1688C, 52%;
1h: 206–2078C (lit. [28] m.p. 207–2088C), 20%.
electron-releasing aryl groups, priority should be given to
incorporating multiple methyl, methoxy and hydroxy
groups into the aryl rings such as the formation of the
3,4,5-trimethyl analog. Second, the influence of ortho sub-
stituents on IC50 figures needs to be developed in consider-
able detail. Third, changes in the conformation of the
molecule by inserting groups on the C8 and C9 atoms in
series 1 and C7 and C8 atoms in series 2 should be
undertaken.
1-(4-Fluorophenyl)-3-isopropylamino-1-propanone
hydrochloride 1e
M.p. 189–1908C. Yield: 44%. 1H-NMR (CDCl3) d 1.51 (d, J ¼ 6.8 Hz,
6H, CH(CH3)2), 3.36–3.40 (m, 3H, CH(CH3)2 and 2 ꢂ H-2), 3.75 (t,
J ¼ 7.1 Hz, 2H, 2 ꢂ H-3), 7.04–7.08 (m, 2H, H-3’/5’), 7.94–7.96 (m,
2H, H-2’/6’), 9.55 (brs, 2H, NH2þ); 13C-NMR (CDCl3) d 19.4
(CH(CH3)2), 35.1, 40.3, 51.3, 116.2, 131.1, 132.5, 166.4, 195.5
(CO); MS (EI) m/z: 194.1 (M – CH3)þ, 209.1 (M)þ; IR (KBr, cmꢁ1):
2446 (NH2þ), 1681 (CO). Calcd. for C12H17ClFNO (245.72): C, 58.66;
H, 6.97; N, 5.70. Found: C, 58.51; H, 6.94; N, 5.74.
Conclusions
A number of reasons for preparing series 1 and 2 as candidate
antineoplastics have been given and in particular the aspira-
tion of their ability to inhibit the growth of human hepatoma
cells. A series of prototypic molecules were prepared and
their structures thoroughly established. Not less than 60%
of the compounds evaluated have greater potency than 5-
fluorouracil against human Huh-7 hepatoma cells. By assess-
ing various physicochemical properties of these molecules,
guidelines for the design of further analogs were achieved.
Future investigations that should be undertaken include
mode of action studies, especially to evaluate whether the
compounds interfere with mitochondrial function, stability
studies of solutions of the compounds and whether greater
toxicity to neoplasms than normal cells is demonstrated.
1-(4-Bromophenyl)-3-isopropylamino-1-propanone
hydrochloride 1f
M.p. 174–1768C. Yield: 38%. 1H-NMR (CDCl3) d 1.49 (d, J ¼ 6.8 Hz,
6H, CH(CH3)2), 3.34–3.38 (m, 3H, CH(CH3)2 and 2 ꢂ H-2), 3.73 (t,
J ¼ 7.3 Hz, 2H, 2 ꢂ H-3), 7.50 (d, J ¼ 8.4 Hz, 2H, H-3’/5’), 7.76 (d,
2H, J ¼ 8.4 Hz, H-2’/6’), 9.55 (brs, 2H, NH2þ); 13C-NMR (CDCl3) d
19.4 (CH(CH3)2), 35.3, 40.2, 51.3, 129.4, 129.8, 132.3, 134.7, 195.8
(CO); MS (EI) m/z: 254 (M – CH3)þ, 256 (M – CH3 þ 2)þ, 270.2
(M þ H)þ, 272.2 (M þ H þ 2)þ; IR (KBr, cmꢁ1): 2462 (NH2þ), 1684
(CO). Calcd. for C12H17BrClNO (306.63): C, 47.00; H, 5.59; N, 4.57.
Found: C, 46.74; H, 5.52; N, 4.59.
1-(4-Hydroxyphenyl)-1-isopropylamino-1-propanone
hydrochloride 1g
M.p 195–1968C. Yield: 10%. 1H-NMR (CD3OD) d 1.39 (d, J ¼ 6.4 Hz,
6H, CH(CH3)2), 3.37–3.46 (m, 5H, CH(CH3)2, 2 ꢂ H-2 and 2 ꢂ H-3),
4.87 (brs, 1H, OH), 6.87 (d, J ¼ 8.8 Hz, 2H, H-3’/5’), 7.92 (d,
J ¼ 8.8 Hz, 2H, H-2’/6’); 13C-NMR (CD3OD) d 18.0 (CH(CH3)2),
34.0, 40.2, 51.2, 115.3, 128.0, 130.7, 163.2, 195.6 (CO); MS (EI)
m/z: 192.4 (M – CH3)þ, 206.3 (M – H)þ; IR (KBr, cmꢁ1): 2449 (NH2þ),
1658 (CO). Calcd. for C12H18ClNO2 (243.73): C, 59.13; H, 7.44, N,
5.75. Found: C, 58.97; H, 7.62; N, 5.76.
Experimental
General
Melting points were determined using a Buchi 530 instrument
and are uncorrected. 1H-NMR (400 MHz) and 13C-NMR (100 MHz)
of 1a–i and 2 were determined on a Varian Mercury Plus
spectrometer. The electron-impact mass spectra were obtained
using a Thermo-Finnegan mass analyzer while the infrared
spectra were determined as potassium bromide discs on a
Mattson1000 FT-IR spectrophotometer. The elemental analyses
were generated using a Leco CHNS-932 instrument.
3-(2,4-Dichlorophenyl)-1-isopropylamino-1-propanone
hydrochloride 1i
M.p. 158–1598C. Yield: 37%. 1H-NMR (CDCl3) d 1.47 (d, J ¼ 6.8 Hz,
6H, CH(CH3)2), 3.34–3.39 (m, 3H, CH(CH3)2 and 2 ꢂ H-2), 3.73 (t,
J ¼ 7.1 Hz, 2H, 2 ꢂ H-3), 7.24–7.26 (m, 1H, H-5’), 7.37 (s, 1H, H-3’),
7.64 (d, J ¼ 8.4 Hz, 1H, H-6’), 9.52 (brs 2H, NH2þ); 13C-NMR (CDCl3)
d 19.4 (CH(CH3)2), 39.1, 39.8, 51.4, 127.7, 130.9, 131.4, 132.7,
135.6, 138.6, 197.6 (CO); MS (EI) m/z: 244.1(M – CH3)þ, 246.1(M
– CH3 þ 2)þ, 248(M – CH3 þ 4)þ, 259.1 (M)þ; IR (KBr, cmꢁ1): 2451
(NH2þ), 1682 (CO). Calcd. for C12H16Cl3NO (296.62): C, 48.59; H,
5.44; N, 4.72. Found: C, 48.50; H, 5.36; N, 4.77.
Synthesis of series 1 and 2
A mixture of the appropriate ketone (50 mmol), paraformalde-
hyde (50 mmol), and isopropylamine hydrochloride (27 mmol)
was heated in an oil bath at 1308C. The reaction vessel was then
removed from the oil bath and when the temperature of the
mixture dropped to 658C, ethyl acetate (40–80 mL) was added.
The mixture was stirred at room temperature for 24 h and the
resultant precipitates were then collected and, with the excep-
tion of 1f, were recrystallized from ether/methanol (1a, b, d, 2) or
methanol (1c, e, g–i). The Mannich base 1f was passed through a
column of silica gel 60 (70–230 mesh) using methanol as the
eluant and after evaporation of the solvent, the product was
recrystallized from methanol.
3-Isopropylamino-1-(2-thienyl)-1-propanone hydrochloride 2
M.p. 165–1668C. Yield: 25%. 1H-NMR (CDCl3) d 1.51 (d, J ¼ 6.4 Hz,
6H, CH(CH3)2), 3.37–3.41 (m, 3H, CH(CH3)2 and 2 ꢂ H-2), 3.73 (t,
J ¼ 7.3 Hz, 2H, 2 ꢂ H-3), 7.05 (t, J ¼ 4.4 Hz, 1H, H-4’), 7.63 (d,
J ¼ 4.8 Hz, 1H, H-3’), 7.78 (d, J ¼ 3.6 Hz, 1H, H-5’), 9.56 (brs, 2H,
NH2þ); 13C-NMR d 19.4 (CH(CH3)2), 35.6, 40.2, 51.2, 128.6, 133.4,
134.9, 142.9, 189.7 (CO); MS (EI) m/z: 182.1 (M – CH3)þ, 197.0 (M)þ;
The 1H-NMR, 13C-NMR and IR spectroscopy as well as the mass
spectra and elemental analyses of 1a–d, h, which have been
described previously, are consistent with the proposed
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