844
P. Perje´si et al. / European Journal of Medicinal Chemistry 43 (2008) 839e845
(t, 1H, Ar-H), 7.19 (d, 2H, Ar-H, J ¼ 8.35 Hz), 7.52 (m, 1H,
Ar-H), 7.60 (d, 2H, Ar-H), 7.80 (s, 1H, aCH), 8.04 (dd, 1H,
Ar-H). Found: C, 60.83; H, 3.58%. Anal. (C16H11BrO2) re-
quires C, 60.98; H, 3.52%.
(m, 1H, Ar-H), 7.88 (s, 1H, aCH), 8.04 (dd, 1H, Ar-H).
Found: C, 81.34; H, 5.51%. Anal. (C17H14O2) requires C,
81.58; H, 5.64%.
6.1.1.12. 3-(4-Dimethylaminobenzylidene)-2,3-dihydro-1-ben-
6.1.1.6. 3-(2-Methoxybenzylidene)-2,3-dihydro-1-benzopyran-
zopyran-4-one (1l). M.p. 150e153 ꢁC (lit [16] m.p.ꢂ1148e
4-one (1f). M.p. 105e107 ꢁC (lit [17] m.p. 106e107 ꢁC).
149 ꢁC). Yield: 67%. Rf: 0.67. IR: 1659 (CaO) cm 1H
.
Yield: 56%. Rf: 0.77. IR: 1677 (CaO) cmꢂ1
.
1H NMR
NMR (500 MHz): d: 3.08 (s, 6H, 2 ꢃ NeCH3), 5.47 (s, 2H,
OCH2), 6.75 (d, 2H, Ar-H, J ¼ 8.60 Hz), 6.98 (d, 1H, Ar-H,
J ¼ 8.26 Hz), 7.08 (t, 1H, Ar-H), 7.29 (d, 2H, Ar-H,
J ¼ 7.55 Hz), 7.48 (t, 1H, Ar-H), 7.86 (s, 1H, aCH), 8.04
(d, 1H, Ar-H, J ¼ 7.83 Hz). Found: C, 77.27; H, 6.04%.
Anal. (C18H17NO2) requires C, 77.40; H, 6.13%.
(500 MHz): 3.88 (s, 3H, CH3), 5.38 (s, 2H, OCH2), 6.97(d,
2H, Ar-H, J ¼ 8.32 Hz), 7.02 (t, 1H, Ar-H), 7.08 (t, 2H, Ar-
H), 7.41 (t, 1H, Ar-H), 7.49 (t, 1H, Ar-H), 8.03 (s, 1H,
aCH), 8.05 (dd, 1H, Ar-H). Found: C, 76.54; H, 5.35%.
Anal. (C17H14O3) requires C, 76.68; H, 5.30%.
6.1.1.7. 3-(3-Methoxybenzylidine)-2,3-dihydro-1-benzopyran-
6.1.2. Molecular modelling
4-one (1g). M.p. 91e92 ꢁC. Yield: 63%. Rf: 0.76. IR: 1673
The models of 1ael and 2ael were built using BioMedC-
ache 6.1 for Windows [18]. The lowest energy conformations
were obtained from optimized geometry calculations in MO-
PAC using AM1 parameters. The TPSA data were also derived
from this modelling programme.
1
(CaO) cmꢂ1. H NMR (500 MHz); d: 3.86 (s, 3H, OCH3),
5.37 (s, 2H, OCH2), 6.86 (s, 1H, Ar-H), 6.91(d, 1H, Ar-H,
J ¼ 7.55 Hz), 6.99 (m, 2H, Ar-H), 7.08 (t, 1H, Ar-H), 7.38
(t, 1H, Ar-H), 7.51 (m, 1H, Ar-H), 7.08 (t, 1H, Ar-H),
7.86(s, 1H, aCH), 8.04 (dd, 1H, Ar-H). Found: C, 76.72; H,
5.51%. Anal. (C17C14O3) requires C, 76.68; H, 5.30%.
6.1.3. clog P determinations
The clog P calculations were made using a software pack-
age [19].
6.1.1.8. 3-(4-Methoxybenzylidene)-2,3-dihydro-1-benzopyran-
4-one (1h). M.p. 133e135 ꢁC (lit [16] m.p. 131e132 ꢁC).
Yield: 72%. Rf: 0.75. IR: 1665 (CaO) cmꢂ1
.
1H NMR
6.1.4. Statistical evaluations
(500 MHz): d: 3.88 (s, 3H, OCH3), 5.40 (s, 2H, OCH2), 6.99
(q, 3H, Ar-H), 7.08 (t, 1H, Ar-H), 7.30(d, 2H, Ar-H), 7.50
(t, 1H, Ar-H), 7.86 (s, 1H, aCH), 8.02 (dd, 1H, Ar-H). Found:
C, 76.47; H, 5.33%. Anal. (C17H14O3) requires C, 76.68; H,
5.30%.
Linear, semilogarithmic and logarithmic plots were made
between the q1, clog P and TPSAvalues of 1ael and the IC50 fig-
ures of these compounds in the L1210 assay using a commercial
software package [20]. The Pearson coefficients and signifi-
cance when the q1 values of 1ael were plotted against IC50
figures were as follows, namely ꢂ0.527, 0.079 (linear), ꢂ0.637,
0.026 (semilogarithmic) and ꢂ0.646, 0.023 (logarithmic).
6.1.1.9. 3-(2,4-Dimethoxybenzylidene)-2,3-dihydro-1-benzo-
pyran-4-one (1i). M.p. 133e135 ꢁC. Yield: 72%. Rf: 0.67.
1
IR: 1663 (CaO) cmꢂ1. H NMR (500 MHz): d: 3.87 (s, 3H,
6.1.5. Cytotoxicity screens
OCH3), 3.89 (s, 3H, OCH3), 5.28 (s, 2H, OCH2), 6.53 (s,
1H, Ar-H), 6.55 (d, 1H, Ar-H, J ¼ 8.41 Hz), 6.97 (d, 1H,
Ar-H, J ¼ 8.27 Hz), 7.02 (d, 1H, Ar-H, J ¼ 8.38 Hz), 7.08 (t,
1H, Ar-H, J ¼ 8.38 Hz), 7.49 (t, 1H, Ar-H), 8.02 (s, 1H,
aCH), 8.05 (d, 1H, Ar-H, J ¼ 7.77 Hz). Found: C, 72.79; H,
5.57%. Anal. (C18H16O4) requires C, 72.96; H, 5.44%.
The methodology for evaluating 1ael in the Molt 4/C8,
CEM and L1210 assays has been described previously [21].
In brief, cells were incubated at 37 ꢁC in RPMI 1640 medium
for 72 h using Molt 4/C8 and CEM cells and for 48 h in the
L1210 assay.
The methodology for evaluating 1ael and melphalan
against HSC-2, HSC-3, HSC-4, HGF, HPC and HPLF cells
has been described previously [22]. In brief, the cells were
incubated in DMEM medium supplemented with 10% heat-in-
activated fetal bovine serum and cell viability was assessed by
the MTT method. A similar process was followed using HL-60
cells except they were cultured in RPMI 1640 medium
containing 10% fetal bovine serum and the cytotoxicity was
evaluated using the trypan blue exclusion procedure. The
time of incubation was 24 h.
6.1.1.10. 3-(3-Methylbenzylidene)-2,3-dihydro-1-benzopyran-
4-one (1j). M.p. 68e71 ꢁC. Yield: 74%. Rf: 0.80. IR: 1670
(CaO) cmꢂ1 1H NMR (500 MHz): d: 2.42 (s, 3H, CH3),
.
5.37 (s, 2H, OCH2), 6.98 (d, 1H, Ar-H, J ¼ 8.31 Hz), 7.10
(q, 3H, Ar-H), 7.24(d, 1H, Ar-H, J ¼ 7.55 Hz), 7.36 (t, 1H,
Ar-H), 7.51 (m, 1H, Ar-H), 7.87(s, 1H, aCH), 8.04 (dd, 1H,
Ar-H). Found: C, 81.45; H, 5.78%. Anal. (C17H14O2) requires
C, 81.58; H, 5.64%.
6.1.1.11. 3-(4-Methylbenzylidene)-2,3-dihydro-1-benzopyran-
6.1.6. Evaluation of 1ael for murine toxicity
and neurotoxicity
These experiments were conducted by the National Insti-
tute of Neurological Disorders and Stroke according to their
protocols [23]. In brief, doses of 30, 100 and 300 mg of
1ael were injected intraperitoneally into mice and death of
4-one (1k). M.p. 114e117 ꢁC (lit [16] m.p. 115e116 ꢁC).
Yield: 67%. Rf: 0.83. IR: 1668 (CaO) cmꢂ1
.
1H NMR
(500 MHz): d: 2.42 (s, 3H, CH3), 5.38 (s, 2H, OCH2), 6.98
(d, 1H, Ar-H, J ¼ 8.29 Hz), 7.09 (t, 1H, Ar-H), 7.23 (d, 2H,
Ar-H, J ¼ 8.08 Hz), 7.28 (d, 2H, Ar-H, J ¼ 7.97 Hz), 7.50