A. Ahmad et al. / European Journal of Medicinal Chemistry 70 (2013) 887e900
897
Table 12
34.89, 31.28, 30.97, 29.98, 29.86, 29.69, 29.40, 29.27, 29.10, 26.67,
25.38, 24.46, 22.73, 18.89, 13.96. MS (ESI): m/z ¼ 404.190 [M þ Na]þ,
calculated ¼ 404.504.
The ligand molecules with number of molecular interactions and the scores for
strength of binding.
S12 protein
4.2.2.3. 5-(Carbomethoxyheptyl)-4-[(20R)-20-hydroxyoctyl]-3-
propyl-4,5-dihydroisoxazole (9). Yellow oily liquid; yield: 80%; IR
(KBr, cmꢀ1): 3328 (OH stretching), 2924 (CH stretching),1738 (C]O
stretching), 1447 (C]N stretching). 1H NMR (CDCl3, dH): 5.32 (2H,
m, HCeCH ring), 4.20 (1H, m, CHeOH), 3.60 (3H, s, OeCH3), 2.65
(2H, t, J ¼ 7.54 Hz, CH2COOCH3), 2.35 (2H, t, J ¼ 7.45 Hz,
CH2CH2CH3), 2.10 (4H, m, H2CHCeCHCH2), 1.80 (1H, m, CHeOH),
1.68 (2H, m, CH2CH2COOCH3), 1.42 (2H, m, CH2CH2CH3), 1.30 (18H,
br.s, CH2 chain), 0.95 (3H, t, J ¼ 7.25 Hz, CH2CH2CH3), 0.87 (3H, dist.t,
CH3). 13C NMR (CDCl3, dC): 176.41, 158.70, 80.01, 72.19, 52.85, 43.41,
39.56, 35.60, 34.84, 29.99, 29.75, 29.51, 29.39, 29.28, 29.01, 27.48,
25.40, 24.91, 21.99, 19.57, 14.00. MS (ESI): m/z ¼ 420.409 [M þ Na]þ,
calculated ¼ 420.503.
Comp.
Hydrogen
bonds
Hydrophobic
interactions
Glide
score
Binding energy
(kcal/Mol)
Log (Kd)
6
7
8
9
3 (2)
3 (3)
4 (3)
5 (4)
4 (3)
3 (2)
29 (7)
19 (7)
34 (6)
31 (8)
28 (10)
10 (3)
ꢀ1.97
0.87
ꢀ2.14
ꢀ1.25
ꢀ0.64
ꢀ1.50
ꢀ5.39
ꢀ5.40
ꢀ6.18
ꢀ5.75
ꢀ6.19
ꢀ5.69
3.95
3.96
4.53
4.22
4.54
4.17
10
Cipro.
The number of residues involved in the hydrogen & hydrophobic interactions are
provided in brackets with the total number of interactions the molecule is experi-
encing. The binding energy and -log (Kd) values are calculated using X-Score. The
more negative is the glide score, the better is the docking. Cipro.: Ciprofloxacin.
4.2.1.2. 5-(Carboxyoctyl)-3-propylisoxazole
(6). White
solid;
M.P ¼ 79e80 ꢃC; yield: 80%; IR (KBr, cmꢀ1): 3285 (OH stretching),
2918 (CH stretching), 1702 (C]O stretching), 1465 (C]N stretch-
ing). 1H NMR (CDCl3, dH): 12.61 (1H, s, COOH), 6.98 (1H, s, CH ring),
2.35 (2H, t, J¼7.52 Hz, CH2COOH), 2.18 (4H, two triplets merged
together, (CH2)5eCH2, CH3CH2CH2), 1.63 (2H, m, CH2CH2COOH),
1.54 (2H, m, CH2CH2CH3), 1.28 (10H, br.s, CH2 chain), 0.90 (3H, t,
J ¼ 7.21 Hz, CH3). 13C NMR (CDCl3, dC): 176.18, 167.86, 82.17, 80.80,
44.26, 35.81, 32.68, 29.83, 29.68, 29.39, 29.01, 27.46, 25.61, 22.93,
14.10. MS (ESI): m/z ¼ 290.210 [M þ Na]þ, calculated ¼ 290.308.
4.2.2.4. 5-[(80R)-80-Hydroxy(carbomethoxydecyl)]-4-pentyl-3-
propyl-4,5-dihydroisoxazole (10). Yellow oily liquid; yield: 75%; IR
(KBr, cmꢀ1): 3294 (OH stretching), 2918 (CH stretching), 1734 (C]O
stretching), 1468 (C]N stretching). 1H NMR (CDCl3, dH): 5.34 (2H,
m, HCeCH ring), 4.41 (1H, m, CHeOH), 3.69 (3H, s, OeCH3), 2.55
(2H, t, J ¼ 7.45 Hz, CH2COOCH3), 2.29 (2H, t, J ¼ 7.50 Hz,
CH2CH2CH3), 1.98 (4H, m, H2CHCeCHCH2), 1.78 (1H, m, CHeOH),
1.67 (2H, m, CH2CH2COOCH3), 1.40 (2H, m, CH2CH2CH3), 1.30 (18H,
br.s, CH2 chain), 0.96 (3H, t, J ¼ 7.25 Hz, CH2CH2CH3), 0.87 (3H, dist.t,
CH3). 13C NMR (CDCl3, dC): 175.43, 156.96, 81.00, 73.16, 51.87, 42.05,
39.02, 34.90, 34.29, 29.82, 29.69, 29.47, 29.37, 29.29, 29.00, 26.83,
4.2.2. Synthesis of 3,5-disubstituted and 3,4,5-trisubstituted-4,5-
dihydroisoxazole derivatives of long chain alkenoates (7e10)
1,4-Phenylene diisocyanate (0.03 mol), nitrobutane (0.01 mol)
and long chain alkenoates (2e5) (0.01 mol) were dissolved in dry
benzene (30 ml). Triethylamine (25-50 drops) was added. The re-
action mixture became turbid and a precipitate was observed. After
8 h at reflux the reaction mixture was cooled. The reaction was
quenched with water (z5 ml) and allowed to stir at room tem-
perature for 1 h. The polyurea (polymer) was removed by filtration
and washed with benzene. The solvent was evaporated on a water
bath and then worked up with diethyl ether-water. Further, the
products (7e10) were purified by silica gel column with petroleum
ether/diethyl ether as eluent. All these novel compounds were
characterized from their spectral data.
4.2.2.1. 5-(Carbomethoxyoctyl)-3-propyl-4,5-dihydroisoxazole (7).
Colorless oily liquid; yield: 85%; IR (KBr, cmꢀ1): 2931 (CH stretch-
ing), 1740 (C]O stretching), 1457 (C]N stretching). 1H NMR
(CDCl3, dH): 4.46 (1H, m, CH2eCH ring), 3.60 (3H, s, OCH3), 2.91 (1H,
dd, JH ꢀH ¼ 16.70 Hz, JH ꢀH ¼ 10.00 Hz, CHeCHZ ring), 2.49 (1H, dd,
Z
Z
E
JH ꢀH ¼ 16.80 Hz, JH ꢀH ¼ 8.10 Hz, CHeCHE ring), 2.25 (4H, two
E
E
Z
triplets partially merging, CH2COOCH3, CH2CH2CH3), 1.60 (6H, m,
CH2CH2CH3, (CH2)5eCH2, CH2CH2COOCH3), 1.25 (10H, br.s, CH2
Chain), 0.92 (3H, t, J ¼ 7.30, CH3). 13C NMR (CDCl3, dC): 174.23,
158.75, 79.97, 51.39, 42.01, 35.22, 34.01, 29.72, 29.32, 29.25, 29.17,
29.09, 25.51, 24.86, 19.74, 13.72. MS (ESI): m/z ¼ 305.700 [M þ Na]þ,
calculated ¼ 306.343.
4.2.2.2. 5-(Carbomethoxyheptyl)-4-octyl-3-propyl-4,5-
dihydroisoxazole (8). Colorless oily liquid; yield: 83%; IR (KBr,
cmꢀ1): 2928 (CH stretching), 1743 (C]O stretching), 1462 (C]N
stretching). 1H NMR (CDCl3, dH): 5.26 (2H, m, HC-CH ring), 3.59 (3H,
s, OeCH3), 2.54 (2H, t, J ¼ 7.60 Hz, CH2COOCH3), 2.42 (2H, t,
J ¼ 7.60 Hz, CH2CH2CH3), 1.95 (4H, m, H2CeCHeCHeCH2), 1.70 (2H,
m, CH2CH2COOCH3), 1.56 (2H, m, CH2CH2CH3), 1.20 (20H, br.s, CH2
Chain), 0.91 (3H, t, J ¼ 7.20 Hz, CH2CH2CH3), 0.81 (3H, dist.t, CH3).
13C NMR (CDCl3, dC): 173.82, 159.24, 80.18, 52.85, 43.01, 35.55,
Fig. 7. All the five molecules docked in the binding site of Cytochrome P451 of
C. albicans. The protein is in cartoon representation and the ligand molecules are in
sticks colored as compound (6), blue; compound (7), cyan; compound (8), yellow;
compound (9), green; compound (10), magenta and a control drug Fluconazole in
black. Heme and bound ligand, Ketoconazole, are also shown in sticks colored red. (For
interpretation of the references to color in this figure legend, the reader is referred to
the web version of this article.)