Molecular Diversity
Table 2 Types of interactions and energy scores for the complexes
formed from compounds 6a–h (R isomer) at the active sites of
NPC1L1 (pdb: 3QNT) studied using MOE 2014
3H, J=8 Hz, Ar–H), 7.32–7.29 (m, 3H, Ar–H), 3.72 (d, 1H,
J=20 Hz, pyrazoline-CH2), 3.59 (d, 1H, J=20 Hz, pyrazo-
line-CH2); 13C NMR (DMSO-d6) δ: 162.96, 153.47, 151.21,
150.87, 142.76, 137.25, 136.50, 132.56, 130.97, 130.07,
128.81, 128.25, 127.80, 125.18, 122.98, 85.18, 50.89; Anal.
calcd for C21H17N3O2 (343.13): C, 73.45; H, 4.99; N, 12.24,
found: C, 73.35; H, 4.97; N, 12.32.
Comp. #
Energy score
Interaction
Receptor
Type
Length (Å)
6a
6b
6c
−10.6907
−10.3158
−11.3639
GLN 95
HIS 124
THR 128
HIS 124
HIS 124
GLN 206
HIS 124
GLN 95
THR 128
HIS 124
SER 56
THR 128
HIS 124
GLU 38
HIS 124
GLU 38
HIS 124
HIS 124
HIS 124
GLN 95
H-bond
pi–pi
H-bond
pi–pi
pi–pi
H-bond
pi–pi
H-bond
H-bond
pi–pi
H-bond
H-bond
pi–pi
H-bond
pi–pi
H-bond
pi–pi
4.44
3.86
2.69
3.67
3.48
3.83
3.78
3.39
2.62
3.84
2.92
2.71
3.89
3.43
3.99
3.09
3.94
3.09
3.96
2.9
3‑(4‑Chlorophenyl)‑5‑hydroxy‑5‑phenyl‑4,5‑dihy‑
dro‑1H‑pyrazol‑1‑yl (pyridin‑3‑yl)methanone 6b White
crystals; yield (2.25 g, 60%), mp 178–180 °C; IR (KBr) ὺ
(cm−1): 3365.13 (OH), 3159.45 (Ar–H), 1693.54 (C=O),
1
6d
6e
−11.920
−10.71
1597.84 (C=N), 1535.58 (C=C); H NMR (DMSO-d6)
δ: 9.19 (s, 1H, OH; exchangeable with D2O), 8.79 (s, 1H,
pyridyl-H-2), 8.20 (d, 1H, J=8 Hz, pyridyl-H-6), 7.89 (d,
1H, J=8 Hz, pyridyl-H-5), 7.86 (d, 1H, J=8 Hz, pyridyl-
H-4), 7.73 (d, J=8 Hz, 2H, Ar–H), 7.58 (d, 2H, J=8 Hz,
Ar–H), 7.39 (t, 3H, J=8 Hz, Ar–H), 7.31(d, J=8 Hz, 2H,
Ar–H), 3.70 (d, 1H, J=20 Hz, pyrazoline-CH2), 3.57 (d,
1H, J=20 Hz, pyrazoline-CH2); 13C NMR (DMSO-d6) δ:
164.36, 152.72, 151.71, 150.27, 143.76, 138.25, 135.50,
131.56, 131.07, 129.37, 128.81, 128.03, 126.80, 125.18,
121.56, 84.32, 50.19; Anal. calcd for C21H16ClN3O2
(377.09): C, 66.76; H, 4.27; N, 11.12, found: C, 66.61; H,
4.39; N, 11.20.
6f
−11.33
6g
−10.7410
−10.7699
−8.79
6h
Ezetimibe
H-bond
pi–pi
H-bond
3‑(4‑Bromophenyl)‑5‑hydroxy‑5‑phenyl‑4,5‑dihy‑
dro‑1H‑pyrazol‑1‑yl (pyridin‑3‑yl)methanone 6c Color-
less solid; yield (2.73 g, 64%); mp 152–154 °C; IR (KBr)
ὺ (cm−1): 3272.13 (OH), 3163.50 (Ar–H), 1699.79 (C=O),
General procedure for synthesis
of (4,5‑dihydro‑5‑hydroxy‑3,5‑diphenylpyrazol‑1‑yl)
(pyridin‑3‑yl)methanone derivatives (6a–h)
1
1597.84 (C=N), 1535.58 (C=C); H NMR (DMSO-d6) δ:
8.98 (s, 1H, OH; exchangeable with D2O), 8.71 (s, 1H, pyri-
dyl-H-2), 8.18 (d, 1H, J=4 Hz, pyridyl-H-6), 7.91 (d, 1H,
J=8 Hz, pyridyl-H-5), 7.86 (d, 1H, J=8 Hz, pyridyl-H-4),
7.73 (d, J=8 Hz, 2H, Ar–H), 7.58 (d, 2H, J=8 Hz, Ar–H),
7.40 (d, 2H, J=8 Hz, Ar–H), 7.34–7.29(m, 3H, Ar–H), 3.69
(d, 1H, J=20 Hz, pyrazoline-CH2), 3.59 (d, 1H, J=20 Hz,
pyrazoline-CH2); 13C NMR (DMSO-d6) δ: 160.56, 152.82,
151.76, 150.27, 142.71, 137.27, 135.53, 132.49, 131.44,
130.39, 129.38, 128.83, 128.44, 127.34, 123.48, 82.48,
51.65; Anal. calcd for C21H16BrN3O2 (421.04): C, 59.73; H,
3.82; N, 9.95, found: C, 59.60; H, 3.66; N, 9.79.
Nicotinic acid hydrazide 5 (1.37 g, 0.01 mol) was added
to a solution of the appropriate dibromochalcone deriva-
tives 4a–h (0.01 mol) in absolute ethanol (30 mL). Tri-
ethylamine (2 mL) was added to the mixture. The reaction
mixture was heated at reflux for 12–24 h. The progress
of the reaction was monitored by TLC using hexane/ethyl
acetate (7:3) as an eluent. The volume of the solution was
reduced, cooled, poured on crushed ice and kept over-
night. The precipitated was washed successively with
water, filtered off, dried and recrystallized from ethanol
to get 5-hydroxypyrazoles 6a–h.
3‑(4‑Fluorophenyl)‑5‑hydroxy‑5‑phenyl‑4,5‑dihy‑
dro‑1H‑pyrazol‑1‑yl (pyridin‑3‑yl)methanone 6d White
crystals; yield (2 g, 55%); m.p. 217–218 °C; IR (KBr) ὺ
(cm−1): 3312.13 (OH), 3031.79 (Ar–H), 1696.95 (C=O),
5 ‑ H y d r ox y ‑ 3 , 5 ‑ d i p h e n y l ‑ 4 , 5 ‑ d i h y d r o ‑ 1 H‑ p y r a ‑
zol‑1‑yl(pyridin‑3‑yl) methanone 6a White crystals; yield
(2.25 g, 66%), mp 188–190 °C; IR (KBr) ὺ (cm−1): 3361.35
(OH), 3161.66 (Ar–H), 1694.05 (C=O), 1595.68 (C=N),
1
1597.84 (C=N), 1529.58 (C=C); H NMR (DMSO-d6) δ:
1
1532.58 (C=C); H NMR (DMSO-d6) δ: 9.21 (s, 1H,
9.11 (s, 1H, OH; exchangeable with D2O), 8.84 (s, 1H, pyri-
dyl-H-2), 8.30 (d, 1H, J=4 Hz, pyridyl-H-6), 7.78 (d, 1H,
J=4 Hz, pyridyl-H-5), 7.65 (d, 1H, J=4 Hz, pyridyl-H-4),
7.56 (d, J=8 Hz, 2H, Ar–H), 7.46 (d, 2H, J=8 Hz, Ar–H),
7.38 (d, 2H, J=8 Hz, Ar–H), 7.32–7.29(m, 3H, Ar–H), 3.72
OH; exchangeable with D2O), 8.81 (s, 1H, pyridyl-H-2),
8.27 (d, 1H, J=8 Hz, pyridyl-H-6), 7.97 (d, 1H, J=8 Hz,
pyridyl-H-5), 7.85 (d, 1H, J=8 Hz, pyridyl-H-4), 7.74 (d,
J=8 Hz, 2H, Ar–H), 7.58 (d, 2H, J=8 Hz, Ar–H), 7.39 (t,
1 3