Synthesis, spectral characterization, self-assembly and biological studies of N-acyl-2-pyrazolines bearing long alkoxy side chains

Article abstract of DOI:10.1016/j.saa.2013.10.023

A series of new pyrazoline derivatives (1b-4c) bearing N-acyl arms and nine to twelve carbon long alkoxy side chains was synthesized and characterized on the basis of spectroscopic data and microanalysis. The nature of self-assembly to understand the inte

Full text of DOI:10.1016/j.saa.2013.10.023

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 120 (2014) 176–184
Contents lists available at ScienceDirect
Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy
journal homepage: www.elsevier.com/locate/saa
Synthesis, spectral characterization, self-assembly and biological studies
of N-acyl-2-pyrazolines bearing long alkoxy side chains
b
a,
c
d
Asghar Abbas a, , Habiba Nazir , Muhammad Moazzam Naseer , Michael Bolte , Safdar Hussain ,
⇑
⇑
Noureen Hafeez e, Aurangzeb Hasan a,f
a Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan
b Department of Biochemistry, Pir Mehr Ali Shah Arid Agriculture University, Rawalpindi, Pakistan
c Institut fur Anorganische Chemie, J.W. Goethe-Universitat Frankfurt, Max-von-Laue-Str. 7, 60438 Frankfurt/Main, Germany
d Department of Forensic Medicine & Toxicology, National University of Science and Technology, Islamabad 44000, Pakistan
e Department of Forensic Medicine & Toxicology, IIMC, Riphah International University Islamabad, Pakistan
f Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
A series of new pyrazoline derivatives equipped with N-acyl arms and long alkoxy groups as side chains
was synthesized to investigate the effect of alkoxy chain length on molecular packing and bioactivity.
ꢀ
Pyrazolines are attractive drug
scaffold with many biological
applications.
ꢀ
Synthesis of new pyrazoline
derivatives equipped with N-acyl
arms and long alkoxy side chains.
Spectral, self-assembly, antifungal
and anti-inflammatory studies.
Effect of alkoxy chain length on
molecular packing and bioactivity.
O
R2
N
N
ꢀ
ꢀ
R1
O
1b-4b: R1 = Cn H2n+1; R2 =CH3
1b
4c
: R = Cn H2n+1; R2 =C2
n = 9-12
1
1c-4c
H5
Antifungal
Anti-inflammatory
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new pyrazoline derivatives (1b–4c) bearing N-acyl arms and nine to twelve carbon long alkoxy
side chains was synthesized and characterized on the basis of spectroscopic data and microanalysis. The
nature of self-assembly to understand the interplay of alkoxy chain crystallization and various supramo-
lecular interactions was investigated using single crystal X-ray diffraction studies. Interesting self-assem-
bled supramolecular structures of 1b and 4c were observed in the crystal lattice owing to various CHꢁ ꢁ ꢁO,
Received 2 September 2013
Received in revised form 30 September 2013
Accepted 2 October 2013
Available online 14 October 2013
Hꢁ ꢁ ꢁH, CHꢁ ꢁ ꢁ
p
, lonepairꢁ ꢁ ꢁ
p
and
p p interactions. Further, all the synthesized compounds (1b–4c) were
ꢁ ꢁ ꢁ
Keywords:
Pyrazolines
Spectral characterization
Self assembly
Antifungal
screened for their in vitro antifungal and anti-inflammatory activities. Compounds 2b, 3b, 2c and 3c
showed significant to moderate antifungal activity against Microsporum canis whereas most of the other
compounds were found inactive against all the five tested fungal strains. Good anti-inflammatory activity
was observed for compounds 1b with IC50 value 331 lM compared to 273 lM for Indomethacine, a stan-
dard reference drug. The bio-activity data demonstrates the relationship between lipophilicity, solubility
Anti-inflammatory
and bioavailability.
Ó 2013 Elsevier B.V. All rights reserved.
Introduction
⇑
Corresponding authors. Tel.: +92 333 5009600; fax: +92 51 90642241.
E-mail addresses: profazmi@hotmail.com (A. Abbas), moazzam@qau.edu.pk
Diversely substituted pyrazolines embedded with variety of
functional groups represent a class of compounds of immense
(M.M. Naseer).
1386-1425/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.saa.2013.10.023

A. Abbas et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 120 (2014) 176–184
177
importance in heterocyclic chemistry [1–6]. Pyrazoline ring is a
General procedure for the synthesis of compounds (1a–4c)
dihydropyrazole having two adjacent nitrogen atoms and one
endocyclic double bond. Considerable amount of research activity
has been directed towards this class by the medicinal chemists.
Among all its isomers, 2-pyrazoline has gained more attention
due to its broad spectrum biological properties [7–9] and its pres-
ence in a number of pharmacologically important molecules such
as azolid/tandearil (anti-inflammatory), phenazone/amidopyrene/
methampyrone (analgesic and antipyretic), anturane (uricosuric)
and indoxacarb (insecticidal). Therefore, a number of pharmaco-
logical activities [7–9] are documented in recent years for this class
of compounds and still it is an active area of research [10–15].
The properties of solids are often governed by the way in which
their constituent molecules are packed [16–23]. Therefore, under-
standing of the molecular packing is crucial in crystal engineering
and structural chemistry to deliberately engineer the solid state
materials of desired properties and functions. Both intra- and
intermolecular interactions, such as hydrogen bonding, Van der
The compounds (1aꢂ4c) were synthesized following the previ-
ously reported procedure [39]. The carboxylic acid solution
(25 ml) of the respective 4-alkoxychalcone (0.01 mol) containing
a few drops of hydrochloric acid was heated at 60–65 °C for
30 min with constant stirring. Hydrazaine hydrate (80%) (1.0 g,
0.02 mol) was then added dropwise to the reaction flask. After
complete addition, the reaction mixture was heated to reflux for
another 4–5 h. The reaction mixture was then cooled to room
temperature and poured onto the crushed ice. The precipitates
thus formed, were filtered, washed with distilled water and dried.
The crude products were further purified by silica gel column
chromatography using petroleum ether/ethyl acetate (4:1) as
the mobile phase.
1-Acetyl-3-phenyl-5-(4-nonyloxyphenyl)-2-pyrazoline (1b)
Yield 85%; yellowish white crystals; m.p. 78–81 °C; Rf = 0.69
(petroleum ether:ethyl acetate, 4:1), FT-IR (KBr, cmꢂ1) 1677 (s),
1648 (s), 1499 (s), 1295 (m), 1254 (s), 1050 (m), 1H NMR
(300 MHz, CDCl3) d 0.90 (t, 3H, J = 7.2 Hz, AOA(CH2)8ACH3), 1.29–
1.50 (m 12H, AOACH2ACH2A(CH2)6ACH3), 1.77 (qn 2H, J = 7.8 Hz,
AOACH2ACH2AC7H15), 2.43 (s, 3H, O@CACH3), 3.18 (dd, 1H,
J = 4.8, 17.7 Hz, Ha), 3.74 (dd, 1H, J = 12.0, 17.7 Hz, Hb), 3.92 (t, 2H,
J = 6.6 Hz, AOACH2A), 5.57 (dd, 1H, J = 4.5, 11.7 Hz, Hx), 6.85 (d,
Waals interaction, CHꢁ ꢁ ꢁ
p
and
pꢁ ꢁ ꢁp stacking play an important
role in controlling the self-assembly of molecules in the crystal lat-
tice [24–32]. However, the knowledge of intermolecular forces that
hold the molecules in the solid state is still inadequate, offering a
big challenge to the crystal engineers and supramolecular chem-
ist’s community to fully understand molecular packing and to pre-
determine the self-assembly processes and properties of solids
[33–36].
0
0
2H, J = 8.7 Hz, ArHc@c ), 7.17 (d, 2H, J = 8.7 Hz, ArHd@d ), 7.44–7.47
(m, 3H, ArHf@f , g), 7.75–7.79 (m, 2H, ArHe@e ), 13C NMR (75 MHz,
CDCl3) d 14.1, 22.0, 22.6, 26.0, 29.1, 29.2, 29.3, 29.5, 31.8, 42.3,
59.4, 68.0, 114.7 (2C), 126.5 (2C), 126.9 (2C), 128.7 (2C), 130.2,
131.5, 133.8, 153.8, 158.6, 168.8, (EI) m/z (M+Å 406, Base Peak
363). Anal. calcd. for C26H34N2O2: C, 76.81; H, 8.43; N, 6.89; Found:
C, 76.77; H, 8.39; N, 6.96%.
The interaction of drugs with biological systems depends on the
ability of a particular drug to penetrate various biological mem-
branes, tissues and barriers. Both lipophilicity of drug as physico-
chemical parameter and composition of microbial membranes
play an important role in the permeation of a drug through the
microbial membranes for further drug action [37,38]. Owing to
their structural diversity, easy access and tremendous importance,
a series of new pyrazoline derivatives equipped with N-acyl arms
and long alkoxy groups as side chains were chosen to investigate
the effect of alkoxy chain length on molecular packing and bioac-
tivity. The molecules were designed to understand the significance
of the interplay of weak interactions and the role of alkoxy side
chain toward the self-assembly in the solid state. Effect of alkoxy
chains on antifungal and anti-inflammatory activities of the syn-
thesized compounds was also investigated. The compounds of
the present series as potential chelating agents may be good future
candidates for the design of metal-based therapeutic agents with
improved bioactivities.
0
0
1-Acetyl-3-phenyl-5-(4-decyloxyphenyl)-2-pyrazoline (2b)
Yield 87%; yellowish white crystals; m.p. 81–83 °C; Rf = 0.71
(petroleum ether:ethyl acetate, 4:1), FT-IR (KBr, cmꢂ1) 1685
(s), 1637 (s), 1497 (s), 1293 (m), 1252 (s), 1049 (m), 1H NMR
(300 MHz, CDCl3) d 0.90 (t, 3H, J = 7.0 Hz, AOA(CH2)9ACH3),
1.29–1.50 (m 14H, AOACH2ACH2A(CH2)7ACH3), 1.77 (qn 2H,
J = 7.0 Hz, AOACH2ACH2AC8H17), 2.43 (s, 3H, O@CACH3), 3.18
(dd, 1H, J = 4.5, 17.4 Hz, Ha), 3.74 (dd, 1H, J = 12.0, 17.7 Hz,
Hb), 3.93 (t, 2H, J = 6.6 Hz, AOACH2A), 5.57 (dd, 1H, J = 4.5,
0
11.7 Hz, Hx), 6.84 (d, 2H, J = 8.7 Hz, ArHc@c ), 7.17 (d, 2H,
0
0
J = 8.7 Hz, ArHd@d ), 7.44–7.47 (m, 3H, ArHf@f , g), 7.75–7.79 (m,
2H, ArHe@e ), 13C NMR (75 MHz, CDCl3) d 14.1, 22.0, 22.6, 26.0,
0
29.2, 29.3, 29.3, 29.5, 29.5, 31.9, 42.2, 59.4, 68.0, 114.7 (2C),
126.5 (2C), 126.9 (2C), 128.7 (2C), 130.2, 131.5, 133.8, 153.8,
158.6, 168.8, (EI) m/z (M+Å 420, Base Peak 377). Anal. calcd. for
Experimental
C
27H36N2O2: C, 77.10; H, 8.63; N, 6.66; Found: C, 77.03; H,
Materials and methods
8.57; N, 6.73%.
All reagents and solvents were used as obtained from the sup-
plier or recrystallized/redistilled as required. Thin layer chroma-
tography (TLC) was performed using aluminum sheets (Merck)
coated with silica gel 60 F254. Elemental analyses were carried
out with a CHNS Analyzer, Model LECO-183. 1H and 13C NMR spec-
tra of compounds were recorded with a Bruker 300 MHz spectrom-
eter using deuterated solvents and TMS as internal standard. IR
spectra of compounds were recorded on a Bio-Rad FTS 3000 MX
spectrophotometer (400–4000 cmꢂ1). The melting points of com-
pounds were determined using capillary tubes and an electrother-
mal melting point apparatus, model MP-D Mitamura Riken Kogyo,
Japan. In vitro anti-inflammatory and antifungal properties were
studied at Panjwani Center for Molecular Medicine and Drug Re-
search, International Center for Chemical Sciences, University of
Karachi, Pakistan.
1-Acetyl-3-phenyl-5-(4-undecyloxyphenyl)-2-pyrazoline (3b)
Yield 88%; yellowish white crystals; m.p. 80–82 °C; Rf = 0.68
(petroleum ether:ethyl acetate, 4:1), FT-IR (KBr, cmꢂ1) 1683 (s),
1639 (s), 1495 (s), 1298 (m), 1251 (s), 1047 (m), 1H NMR
(300 MHz, CDCl3) d 0.90 (t, 3H, J = 7.0 Hz, AOA(CH2)10ACH3), 1.28–
1.50 (m 16H, AOACH2ACH2A(CH2)8ACH3), 1.76 (qn 2H, J = 7.8 Hz,
AOACH2ACH2AC9H19), 2.43 (s, 3H, O@CACH3), 3.18 (dd, 1H,
J = 4.5, 17.7 Hz, Ha), 3.74 (dd, 1H, J = 11.7, 17.7 Hz, Hb), 3.92 (t, 2H,
J = 6.6 Hz, AOACH2A), 5.57 (dd, 1H, J = 4.5, 11.7 Hz, Hx), 6.85 (d,
0
0
2H, J = 8.7 Hz, ArHc@c ), 7.17 (d, 2H, J = 8.7 Hz, ArHd@d ), 7.44–7.48
(m, 3H, ArHf@f , g), 7.75–7.79 (m, 2H, ArHe@e ), 13C NMR (75 MHz,
CDCl3) d 14.1, 22.0, 22.7, 26.0, 29.1, 29.2, 29.3, 29.3, 29.5, 29.6,
31.9, 42.2, 59.4, 68.0, 114.7 (2C), 126.5 (2C), 126.9 (2C), 128.7 (2C),
130.2, 131.5, 133.8, 153.8, 158.6, 168.8, (EI) m/z (M+Å 434, Base Peak
0
0

178
A. Abbas et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 120 (2014) 176–184
0
0
391). Anal. calcd. for C28H38N2O2: C, 77.38; H, 8.81; N, 6.45; Found: C,
77.33; H, 8.75; N, 6.54%.
J = 8.7 Hz, ArHc@c ), 7.17 (d, 2H, J = 8.7 Hz, ArHd@d ), 7.44–7.47 (m,
3H, ArHf@f , g), 7.76–7.80 (m, 2H, ArHe@e ), 13C NMR (75 MHz, CDCl3)
d 9.0, 14.1, 22.7, 26.0, 27.6, 29.2, 29.3, 29.3, 29.4, 29.5, 29.6, 31.9,
42.0, 59.6, 67.9, 114.7 (2C), 126.5 (2C), 126.9 (2C), 128.7 (2C),
130.2, 131.6, 134.0, 153.5, 158.5, 172.2, (EI) m/z (M+Å 448, Base Peak
392). Anal. calcd. for C29H40N2O2: C, 77.64; H, 8.99; N, 6.24; Found: C,
77.58; H, 8.92; N, 6.32%.
0
0
1-Acetyl-3-phenyl-5-(4-dodecyloxyphenyl)-2-pyrazoline (4b)
Yield 83%; yellowish white crystals; m.p. 82–84 °C; Rf = 0.72
(petroleum ether:ethyl acetate, 4:1), FT-IR (KBr, cmꢂ1) 1684 (s),
1642 (s), 1491 (s), 1294 (m), 1258 (s), 1046 (m), 1H NMR
(300 MHz, CDCl3) d 0.90 (t, 3H, J = 7.0 Hz, AOA(CH2)11ACH3), 1.28–
1.50 (m 18H, AOACH2ACH2A(CH2)9ACH3), 1.76 (qn 2H, J = 7.5 Hz,
AOACH2ACH2AC10H21), 2.43 (s, 3H, O@CACH3), 3.18 (dd, 1H,
J = 4.5, 17.7 Hz, Ha), 3.74 (dd, 1H, J = 11.7, 17.7 Hz, Hb), 3.93 (t, 2H,
J = 6.6 Hz, AOACH2A), 5.57 (dd, 1H, J = 4.5, 11.7 Hz, Hx), 6.84 (d,
1-Propionyl-3-phenyl-5-(4-dodecyloxyphenyl)-2-pyrazoline (4c)
Yield 82%; yellowish white crystals; m.p. 70–73 °C; Rf = 0.70
(petroleum ether:ethyl acetate, 4:1), FT-IR (KBr, cmꢂ1) 1687 (s),
1647 (s), 1497 (s), 1296 (m), 1254 (s), 1051 (m), 1H NMR (300 MHz,
CDCl3) d 0.91 (t, 3H, J = 7.0 Hz, AOA(CH2)11ACH3), 1.21 (t, 3H,
J = 7.5 Hz, O@CACH2ACH3), 1.29–1.47 (m 18H, AOACH2ACH2-
A(CH2)9ACH3), 1.77 (qn 2H, J = 7.5 Hz, AOACH2ACH2AC10H21),
2.83 (q, 2H, J = 7.5 Hz, O@CACH2ACH3), 3.17 (dd, 1H, J = 4.5,
17.7 Hz, Ha), 3.73 (dd, 1H, J = 11.7, 17.7 Hz, Hb), 3.93 (t, 2H,
J = 6.6 Hz, AOACH2A), 5.55 (dd, 1H, J = 4.5, 11.7 Hz, Hx), 6.83 (d, 2H,
0
0
2H, J = 8.7 Hz, ArHc@c ), 7.17 (d, 2H, J = 8.7 Hz, ArHd@d ), 7.44–7.49
(m, 3H, ArHf@f , g), 7.76–7.79 (m, 2H, ArHe@e ), 13C NMR (75 MHz,
CDCl3) d 14.1, 22.0, 22.7, 26.0, 29.1, 29.2, 29.3, 29.3, 29.5, 29.5,
29.6, 31.9, 42.2, 59.4, 68.0, 114.7 (2C), 126.5 (2C), 126.9 (2C), 128.7
(2C), 130.2, 131.5, 133.8, 153.8, 158.6, 168.8 (EI) m/z (M+Å 448, Base
Peak 405). Anal. calcd. for C29H40N2O2: C, 77.64; H, 8.99; N, 6.24;
Found: C, 77.59; H, 8.91; N, 6.33%.
0
0
0
0
J = 8.7 Hz, ArHc@c ), 7.17 (d, 2H, J = 8.7 Hz, ArHd@d ), 7.44–7.47 (m,
3H, ArHf@f , g), 7.75–7.80 (m, 2H, ArHe@e ), 13C NMR (75 MHz, CDCl3)
d 14.1, 22.7, 26.0, 27.6, 29.2, 29.3, 29.3, 29.5, 29.6, 29.6, 29.6, 31.9,
42.0, 59.6, 68.0, 68.1, 114.7 (2C), 126.5 (2C), 126.9 (2C), 128.7 (2C),
130.1, 131.6, 134.0, 153.5, 158.5, 172.2, (EI) m/z (M+Å 462, Base Peak
406). Anal. calcd. for C30H42N2O2: C, 77.88; H, 9.15; N, 6.05; Found:
C, 77.82; H, 9.09; N, 6.13%.
0
0
1-Propionyl-3-phenyl-5-(4-nonyloxyphenyl)-2-pyrazoline (1c)
Yield 86%; yellowish white crystals; m.p. 71–74 °C; Rf = 0.71
(petroleum ether:ethyl acetate, 4:1), FT-IR (KBr, cmꢂ1) 1679 (s),
1645 (s), 1497 (s), 1291 (m), 1258 (s), 1053 (m), 1H NMR
(300 MHz, CDCl3) d 0.91 (t, 3H, J = 7.0 Hz, AOA(CH2)8ACH3), 1.21
(t, 3H, J = 7.5 Hz, O@CACH2ACH3), 1.30–1.45 (m 12H, AOACH2-
ACH2A(CH2)6ACH3), 1.77 (qn 2H, J = 7.8 Hz, AOACH2ACH2AC7-
H15), 2.83 (q, 2H, J = 7.5 Hz, O@CACH2ACH3), 3.17 (dd, 1H, J = 4.8,
17.7 Hz, Ha), 3.73 (dd, 1H, J = 11.7, 17.7 Hz, Hb), 3.93 (t, 2H,
J = 6.6 Hz, AOACH2A), 5.55 (dd, 1H, J = 4.5, 11.7 Hz, Hx), 6.85 (d,
Single crystal X-ray crystallography
Data collection and structural refinement of 1b and 4c
In order to investigate the effect of alkoxy chain on solid state
self assembly, the single crystals of compound 1b and 4c were
grown in ethanolic solution. The pale yellow crystals were
mounted in random orientation on a glass fiber on a Stoe IPDS-II
two circle diffractometer [40] equipped with graphite monochro-
0
0
2H, J = 8.7 Hz, ArHc@c ), 7.17 (d, 2H, J = 8.7 Hz, ArHd@d ), 7.44–7.46
(m, 3H, ArHf@f , g), 7.76–7.79 (m, 2H, ArHe@e ), 13C NMR (75 MHz,
CDCl3) d 9.0, 14.1, 22.6, 26.0, 27.6, 29.2, 29.3, 29.4, 29.5, 31.8,
42.0, 59.6, 67.9, 114.7 (2C), 126.5 (2C), 126.9 (2C), 128.7 (2C),
130.2, 131.6, 134.0, 153.5, 158.5, 172.2, (EI) m/z (M+Å 420, Base Peak
364). Anal. calcd. for C27H36N2O2: C, 77.10; H, 8.63; N, 6.66; Found:
C, 77.03; H, 8.58; N, 6.74%.
0
0
mated Mo K
a radiation (k = 0.71073 Å). The structure was solved
by direct methods using SHELXS97 and refined with full-matrix
least-squares on F2 with SHELXL-97 [41]. All non-hydrogen atoms
were refined anisotropically. Hydrogen atoms were located in a
difference map but refined using a riding model. The crystal data
and refinement details are summarized in Table 1.
1-Propionyl-3-phenyl-5-(4-decyloxyphenyl)-2-pyrazoline (2c)
Yield 83%; yellowish white crystals; m.p. 67–69 °C; Rf = 0.69
(petroleum ether:ethyl acetate, 4:1), FT-IR (KBr, cmꢂ1) 1684 (s),
1639 (s), 1495 (s), 1295 (m), 1257 (s), 1048 (m), 1H NMR
(300 MHz, CDCl3) d 0.91 (t, 3H, J = 7.0 Hz, AOA(CH2)9ACH3), 1.21
(t, 3H, J = 7.8 Hz, O@CACH2ACH3), 1.29–1.47 (m 14H, AOACH2-
ACH2A(CH2)7ACH3), 1.77 (qn 2H, J = 7.8 Hz, AOACH2ACH2AC8H17),
2.83 (q, 2H, J = 7.5 Hz, O@CACH2ACH3), 3.17 (dd, 1H, J = 4.8, 17.7 Hz,
Ha), 3.73 (dd, 1H, J = 12.0, 17.7 Hz, Hb), 3.93 (t, 2H, J = 6.6 Hz,
AOACH2A), 5.55 (dd, 1H, J = 4.5, 11.7 Hz, Hx), 6.84 (d, 2H,
Biological activity
Antifungal studies (in vitro)
All compounds were studied against six fungal cultures for anti-
fungal activities. Sabouraud dextrose agar (SDA) (Oxoid, Hamp-
shire, England) was seeded with 105 (cfu) mLꢂ1 fungal spore
suspensions and transferred to Petri plates. Discs soaked in
0
0
J = 8.7 Hz, ArHc@c ), 7.17 (d, 2H, J = 8.7 Hz, ArHd@d ), 7.44–7.47 (m,
20 mL (200 lg/mL in DMSO) of each compound were placed at dif-
3H, ArHf@f , g), 7.76–7.80 (m, 2H, ArHe@e ), 13C NMR (75 MHz, CDCl3)
d 9.0, 14.1, 22.6, 26.0, 27.6, 29.2, 29.3, 29.3, 29.5, 29.5, 31.9, 42.0,
59.6, 68.0, 114.7 (2C), 126.5 (2C), 126.9 (2C), 128.7 (2C), 130.2,
131.6, 134.0, 153.5, 158.5, 172.2, (EI) m/z (M+Å 434, Base Peak 378).
Anal. calcd. for C28H38N2O2: C, 77.38; H, 8.81; N, 6.45; Found: C,
77.32; H, 8.77; N, 6.53%.
ferent positions on the agar surface. The plates were incubated at
32 °C for 7 days. The results were recorded as % of inhibition and
compared with standard reference drugs miconazole and ampho-
tericin B.
0
0
Assay procedure (agar tube dilution). Test tubes were marked up to
10 cm from the base. Then 4 mL volume of SDA was poured into
screw-capped tubes or cotton plugged test tubes and was auto-
claved at 121 °C. Test tubes were allowed to cool down to 50 °C
1-Propionyl-3-phenyl-5-(4-undecyloxyphenyl)-2-pyrazoline (3c)
Yield 87%; yellowish white crystals; m.p. 72–75 °C; Rf = 0.73
(petroleum ether:ethyl acetate, 4:1), FT-IR (KBr, cmꢂ1) 1683 (s),
1632 (s), 1498 (s), 1297 (m), 1259 (s), 1053 (m), 1H NMR
(300 MHz, CDCl3) d 0.90 (t, 3H, J = 7.0 Hz, AOA(CH2)10ACH3), 1.20
(t, 3H, J = 7.8 Hz, O@CACH2ACH3), 1.28–1.47 (m 16H, AOACH2-
ACH2A(CH2)8ACH3), 1.76 (qn 2H, J = 7.5 Hz, AOACH2ACH2AC9H19),
2.83 (q, 2H, J = 7.5 Hz, O@CACH2ACH3), 3.17 (dd, 1H, J = 4.8, 17.7 Hz,
Ha), 3.73 (dd, 1H, J = 12.0, 17.7 Hz, Hb), 3.92 (t, 2H, J = 6.6 Hz,
AOACH2A), 5.55 (dd, 1H, J = 4.5, 11.7 Hz, Hx), 6.84 (d, 2H,
and non-solidified SDA was loaded with 67
lL of test compound
to obtain a concentration of 200 g/mL. Test tubes were then al-
l
lowed to solidify in slanting position at room temperature. Test
tubes were prepared in triplicates for each fungal species. Test
tubes containing solidified media and test compound were inocu-
lated with 4 mm diameter piece of inoculums taken from a 7 days
old culture of fungus. Positive and negative control test tubes were
also inoculated with Miconazole/Amphotericin
B and DMSO

A. Abbas et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 120 (2014) 176–184
179
Table 1
Crystallographic data for 1b and 4c.
Crystal data
1b
4c
Chemical formula
Mr
C
26H34N2O2
C30H42N2O2
462.66
406.55
Crystal system, space group
Temperature (K)
a, b, c (Å)
Triclinic, Pꢀ1
173
6.2697 (6), 7.3333 (7), 27.826 (3)
Monoclinic, P21/c
173
5.3072 (4), 28.2115 (15), 18.4326 (13)
a
, b,
c
(°)
86.588 (8), 86.561 (8), 64.862 (7)
1155.3 (2)
2
95.479 (6)
2747.2 (3)
4
V (Å3)
Z
Radiation type
Mo K
0.07
a
Mo K
0.07
a
l
(mmꢂ1
)
Crystal size (mm)
0.22 ꢃ 0.13 ꢃ 0.12
0.32 ꢃ 0.14 ꢃ 0.13
Data collection
Diffractometer
STOE IPDS II two-circle-diffractometer
STOE IPDS II two-circle-diffractometer
Absorption correction
No. of measured, independent and
–
–
Observed [I > 2
r
(I)] reflections
11042, 4148, 3141
0.058
0.599
26062, 4980, 3143
0.083
0.601
Rint
(sin h/k)max (Åꢂ1
)
Refinement
R[F2 > 2
r
(F2)], wR(F2), S
0.041, 0.108, 0.96
0.043, 0.105, 0.88
No. of reflections
No. of parameters
No. of restraints
H-atom treatment
4148
274
0
4980
308
0
H-atom parameters constrained
0.14, ꢂ0.19
H-atom parameters constrained
0.21, ꢂ0.21
D
imax
,
D
imin (e Åꢂ3
)
respectively. The whole procedure was carried out in laminar flow
hood (LFH) under strict sterile conditions. Test tubes were incu-
bated at 28 °C during 7 days. Cultures were examined twice a week
during the incubation period. Reading was taken by measuring the
linear length of fungus in slant by measuring growth (mm) and
growth inhibition was calculated with reference to negative con-
trol. Percentage inhibition of fungal growth for each concentration
of compound was determined by using the following formula:
serum, followed by centrifugation at 3000 rpm whereby the pellet
was resuspended in PBS buffer. Absorbance was measured at
450 nm. Aspirin and indomethacin were used as positive controls
which are widely used as non-steroidal anti-inflammatory drugs
(NSAIDs) for the treatment of several inflammatory diseases.
The IC50 values were calculated by comparison with the DMSO ta-
ken as blank and expressed as the percent inhibition of superox-
ide anions produced. The percent inhibitory activity by the
samples was determined against a DMSO blank and calculated
using the following formula:
Percentage inhibition of fungal growth
Linear growth in test ðmmÞ
ꢀ
ꢁ
¼ 100 ꢂ
ꢃ 100
0D Test Compound
0D Control
Linear growth in control ðmmÞ
% Inhibition ¼ 100 ꢂ
ꢃ 100
IC50 of samples was determined by using EZ-FIT Windows-
based software.
Anti-inflammatory studies (in vitro)
Isolation of human neutrophils. Inflammation occurs as a defensive
response, which induces physiological adaptations to limit tissue
damage and removes the pathogenic infection. Reactive oxygen
species (ROS) are formed subsequent to the assembly and activa-
tion of the phagocyte-specific enzyme, NADPH Oxidase. This pro-
cess is initiated by the production of superoxide anion during a
‘respiratory burst’ of non-mitochondrial oxygen uptake by an
NADPH oxidase system. This study used the water–soluble tetrazo-
lium salt (WST-1) to measure superoxide production by neutro-
phils activated by opsonized zymosan, which induces phagocytic
activation of neutrophils. This technique is more sensitive and reli-
able as compared to other available techniques.
Results and discussion
Chemistry
The compounds (1b–4c) were synthesized by reacting equimo-
lar quantities of (E)-3-(4-alkyloxyphenyl)-1-phenylprop-2-en-1-
ones (1aꢂ4a) and hydrazine in glacial acetic acid/propionic acid
solvent containing catalytic amount of hydrochloric acid
(Scheme 1) and purified by silica gel column chromatography
using petroleum ether/ethyl acetate as mobile phase. All the prod-
ucts were obtained as solids in 82–88% yield. The structures of all
the compounds were established on the basis of spectroscopic data
and microanalysis. The three dimensional structure of the new pyr-
azoline derivatives was further proved unambiguously by the sin-
gle crystal X-ray diffraction analysis of 1b and 4c.
Respiratory burst assay. Anti-inflammatory activity of the com-
pounds was determined by using a modified assay of Tan and
Berridge [42]. This in vitro assay was based on the reduction of
highly water–soluble tetrazolium salt (WST-1) in the presence
of activated neutrophils. Anti-inflammatory activity was deter-
mined in a total volume of 200
lL MHS (pH 7.4) containing
Spectroscopic characterization of 1b–4c
1.0–104 neutrophils/mL, 250 M WST-1 and various concentra-
l
tions of test compounds. The control contained buffer, neutrophils
IR spectra
and WST-1. All compounds were equilibrated at 37 °C and the
In the IR spectra of compounds (1b–4c), a sharp band at
reaction was initiated by adding opsonized zymosan
A
1648–1637 cmꢂ1 and 1687–1679 cmꢂ1 was assigned to the
(15 mg/mL), which was prepared by mixing with human pooled
stretching of m(C@N) and m(C@O), respectively. The carbonAnitro-

180
A. Abbas et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 120 (2014) 176–184
R2
gen single bond (CAN) stretching frequencies were observed at
1297–1291 cmꢂ1. The presence of these frequencies suggests the
formation of cyclic pyrazoline ring. Two strong bands at stretching
frequencies in the range of 1259–1251 cmꢂ1 and 1053–1046 cmꢂ1
indicate the presence of ArAOAR group.
1b-4b:R1 =Cn H2n+1;R2 =CH3
O
1
N
2
Hx
N
R1
:R1 =Cn H2n+1;R2 =C2H5
n=9-12
3
1c-4c
4
O
Hb
Ha
Fig. 1. Labelling scheme of protons of compounds 1b–4c.
1H NMR spectra
1H NMR spectral data for all N-acyl pyrazolines recorded in
CDCl3 along with their possible assignments is reported in the
experimental section. All the protons due to pyrazoline and aro-
matic rings were found in their expected chemical shift regions.
The formation of the five membered pyrazoline ring was estab-
lished by the presence of two methylene protons (Ha and Hb) and
one methine proton (Hx) as three doublet of doublets. The singlets
for methyl protons of acetyl group (O@CACH3) in compounds 1b–
4b were observed at 2.43 ppm, whereas a triplet and quartet at
1.20–1.21 and 2.83 ppm was noticed for methyl protons
(O@CACH2ACH3) and the methylene protons (O@CACH2ACH3),
respectively for propionyl group in compounds 1c–4c. In addition,
a triplet was observed at 3.92–3.93 ppm for the methylenic pro-
tons (ArAOACH2A) of the alkoxy chain directly attached to the
oxygen atom. All other protons of alkoxy chain appeared in the
range of 0.9–1.77 ppm. The conclusions drawn from the 1H NMR
data provided further support to the observations of presence of
different functional groups discussed in IR section (Fig. 1).
peak appeared at m/z 406 (Calcd. 406.26) of [C26H34N2O2]+ and
most stable fragment at m/z 363 (Calcd. 363.24) of [C24H31N2O]+
is shown in Fig. 2.
Solid state self-assembly
The self-assembly studies were also carried out to identify the
structural features that govern the molecular alignment in the so-
lid state and to understand the interplay of alkoxy chains crystalli-
zation and various supramolecular interactions, using single
crystal X-ray diffraction studies. For this purpose, good quality sin-
gle crystals of only two compounds 1b and 4c were grown. Se-
lected crystal data and structural refinement parameters of
compound 1b and 4c are given in Table 1. All our attempts to cul-
tivate single crystals for other compounds for these studies were
unsuccessful.
Crystal structure of 1b
13C NMR spectra
Single crystals of 1b were obtained from ethanol solution using
slow evaporation of solvent at ambient conditions and were found
to have a triclinic crystal lattice with the Pꢀ1 space group. The OR-
TEP representation and atom labeling scheme of the compound 1b
is shown in Fig. 3. The central pyrazoline unit is nearly in the same
plane as the phenyl ring at its 3-position, making a dihedral angle
of 1.88° [C(16)AC(11)AC(3)AN(2)]. The alkoxy substituted aryl
ring present on asymmetric carbon of pyrazoline ring is oriented
in such a way that one of its hydrogen is located on top of the pyr-
azoline ring at a distance 2.683 Å from the centre of pyrazoline
ring. The angles around asymmetric carbons are 100.49°
The 13C NMR spectra of compounds (1b–4c) displayed peaks at
67.9–68.0 ppm, 42.0–42.3 ppm and 59.4–59.6 ppm for C3, C4 and
C5 carbons, respectively. All the aromatic carbons were observed
in the range of 114.7–158.6 ppm. The signals for acyl carbons were
noticed in the range of 168.8–172.2 ppm for all the compounds.
Furthermore, the results of 13C NMR data were found to be in good
agreement with the results of IR and 1H NMR spectra of these
compounds.
Mass spectra
[C(4)AC(5)AN(1)],
111.07°
[C(21)AC(5)AN(1)],
114.80°
The electron impact mass spectra (EIMS) of the all the synthe-
sized pyrazoline derivatives 1b–4c are presented in the experi-
mental part. The mass spectral data and fragmentation pattern of
all the synthesized 2-pyrazoline derivatives [39,43], clearly justify
the formation of proposed structures discussed in IR, 1H and 13C
NMR spectroscopy. Further, a molecular ion peak (M+Å) was ob-
served for all the compounds at their respective molecular masses.
The most stable fragments or base peaks were observed by the loss
of N-acyl fragment as radical. The proposed mass fragmentation
pattern of the representative compound 1b where molecular ion
[C(4)AC(5)AC(21)] and 110.00° [C(21)AC(5)AH(5)]. In the pyrazo-
line ring, the CAN, C@N and NAN bond lengths are 1.483 Å, 1.293 Å
and 1.394 Å, respectively.
Fig. 4 shows the molecular packing of 1b in which two indepen-
dent molecules present in asymmetric unit form 1D-supramolecu-
lar chains. The long alkoxy group of 1D-supramolecular chain
structure move in face to face parallel fashion but opposite to its
neighboring 1D-supramolecular chain present in the same asym-
metric unit. These 1D-supramolecular chains with alkoxy groups
running in opposite direction are stacked on each other in the crys-
tal lattice to provide highly packed supramolecular structure
(Fig. 4a). This structure is stabilized by CHꢁ ꢁ ꢁO, CHꢁ ꢁ ꢁ
p
and Hꢁ ꢁ ꢁH
O
N
[44] interactions. Each individual molecule of the chain is con-
nected to its neighboring molecule by CHꢁ ꢁ ꢁO [C(13)AH(13)ꢁ ꢁ ꢁO(1)
2.606 Å] and Hꢁ ꢁ ꢁH [C(14)AH(14)ꢁ ꢁ ꢁH(7A) 2.350 Å] interactions
(Fig. 4b). These supramolecular 1D chains are stacked on top of
N
NH2-NH2
O
R
CH3COOH
HCl/Reflux
1b-4b
1:R=C 9H19
each other utilizing CHꢁ ꢁ ꢁO [C(22)AH(22)ꢁ ꢁ ꢁO(1) 2.412 Å], CHꢁ ꢁ ꢁ
p
H3C
O
O
H
R
O
[C(13)AH(13)ꢁ ꢁ ꢁC(22) 2.892 Å] and Hꢁ ꢁ ꢁH [C(25)AH(25)ꢁ ꢁ ꢁH(31B)
2:R=C10H21
3:R=C11H23
2.396 Å] interactions (Fig. 4c).
R
NaOH/H2O/EtOH
RT,6-8h
1a-4a
O
4
:R=C12H25
O
Crystal structure of 4c
O
The good quality single crystals of 4c were grown in similar
conditions to 1b and were found to have a monoclinic crystal lat-
tice with the P21/c space group. The ORTEP representation and
atom labeling scheme of the compound 4c is shown in Fig. 5. The
central pyrazoline unit is slightly out of plane of the phenyl ring
at its 3-position as compared to 1b, making a dihedral angle of
N
N
NH2-NH2
O
R
CH3CH2COOH
HCl/Reflux
1c-4c
Scheme 1. Synthesis of new N-acyl pyrazolines 1b–4c.

A. Abbas et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 120 (2014) 176–184
181
C9H19
N
H
NH
H
OC9H19
m/z = 220
N
N
H
O
m/z = 237
H
H
OC9H19
m/z = 363
PhOC9H19
N
H
NH
H
H
O
N
NH
H
O
m/z = 221
N
N
H
m/z = 145
OC9H19
H
H
OC9H19
[M+]
m/z = 406
O
N
H
N
NH
m/z = 77
N
H
C7H15
O
m/z = 104
Ph
O
O
C9H19
N
O
N
OC9H19
N
H
H
H
H
H
H
O
H
m/z = 176
OC9H19
m/z = 303
m/z = 161
O
O
CH3
N
N
H
H
O
H
N
H
OH
H
H
m/z = 177
m/z = 118
- CH3CNO
OC9H19
m/z = 288
- HCN
CH3CO
H
N
H
H
H
H
m/z = 77
OH
m/z = 91
OH
m/z = 135
m/z = 120
Fig. 2. Mass fragmentation pattern of 1b.
substituted aromatic ring was measured to be 2.870 Å as compared
to 2.683 Å for 1b. The angles around asymmetric carbons are
101.08° [C(4)AC(5)AN(1)], 112.98° [C(21)AC(5)AN(1)], 115.16°
[C(4)AC(5)AC(21)] and 109.10° [C(21)AC(5)AH(5)]. In the pyrazo-
line ring, the CAN, C@N and NAN bond lengths are 1.475 Å, 1.290 Å
and 1.388 Å, respectively.
Fig. 6 shows the molecular packing of 4c which also shows
stacked 1D-supramolecular chains. However, this structure is dif-
ferent from 1b. Unlike 1b, the alkoxy substitution on individual
molecules of each supramolecular chain moves in alternate fashion
in the crystal lattice. Interestingly, two neighboring 1D-supramo-
lecular chains of 4c are packed with interdigitation of alkoxy
chains in a V/inverted V manner (Fig. 6a). These 1D-supramolecu-
lar chains are stacked on each other in a way similar to 1b. The
stacked supramolecular structure of 4c is stabilized by various
Fig. 3. The ORTEP diagram and atom labeling scheme of 1b.
CHꢁ ꢁ ꢁO, lonepairꢁ ꢁ ꢁ
vidual molecule of the supramolecular chain is connected to its
neighboring molecule by two different
CHꢁ ꢁ ꢁO
[C(13)AH(13)ꢁ ꢁ ꢁO(6) 2.563 Å, C(14)AH(14)ꢁ ꢁ ꢁO(6) 2.663 Å] and
lonepairꢁ ꢁ ꢁ [O(6)ꢁ ꢁ ꢁH(13) 3.209 Å] contacts (Fig. 6b), whereas
CHꢁ ꢁ ꢁ [C(5)AH(5)ꢁ ꢁ ꢁC(11) 2.821 Å], ꢁ ꢁ ꢁ [C(3)ꢁ ꢁ ꢁC(15) 3.395 Å]
and CHꢁ ꢁ ꢁ [C(31)AH(31A)ꢁ ꢁ ꢁC(16) 2.854 Å] interactions are uti-
p
[45], CHꢁ ꢁ ꢁ
p
and
pꢁ ꢁ ꢁ
p interactions. Each indi-
4.58° [C(16)AH(11)AC(3)AN(2)]. Similarly, alkoxy substituted aryl
ring on asymmetric carbon of pyrazoline ring is also slightly tilted
as compared to 1b, not located exactly at the top of pyrazoline ring.
The distance from the center of pyrazoline ring and H(22) of alkoxy
p
p
p p
p

182
A. Abbas et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 120 (2014) 176–184
Fig. 4. (a) Stacked 3D-supramolecular structure of 1b view along a-axis. (b) An infinite 1D-supramolecular chain of 1b stabilized by CHꢁ ꢁ ꢁO [C(13)AH(13)ꢁ ꢁ ꢁO(1) 2.606 Å] and
Hꢁ ꢁ ꢁH [C(14)AH(14)ꢁ ꢁ ꢁH(7A) 2.350 Å] interactions viewed along a-axis. (c) Two successive stacked supramolecular chains of 1b viewed along a-axis stabilized by CHꢁ ꢁ ꢁO
[C(22)AH(22)ꢁ ꢁ ꢁO(1) 2.412 Å], CHꢁ ꢁ ꢁp [C(13)AH(13)ꢁ ꢁ ꢁC(22) 2.892 Å] and Hꢁ ꢁ ꢁH [C(25)AH(25)ꢁ ꢁ ꢁH(31B) 2.396 Å] interactions.
cosmetics, surface coatings, inks and textile industries [39]. In
addition, these compounds having long alkoxy chains are potential
candidates for liquid crystalline studies.
Biological activity
Antifungal studies (in vitro)
The antifungal screening of all the synthesized compounds (1b–
4c) was carried out against Candida albicans (A), Aspergillus flavus
(B), Microsporum canis (C), Fusarium solani (D), and Candida glabrata
(E) fungal strains according to the literature protocol [46]. Four out
of eight compounds showed moderate to significant antifungal
activity (50–80% inhibition) against Microsporum canis (C). Com-
pound 2b was found to be the most active with 80% inhibition
against Microsporum canis (C). Compounds 1b, 3b and 3c also
showed P30% inhibition against Fusarium solani. However, most
of the other compounds either showed no activity or weak activity
against one or more of the tested fungal strains. It is generally true
Fig. 5. The ORTEP diagram and atom labeling scheme of 4c.
lized to stabilize stacking of supramolecular chains on one another
(Fig. 6c). It is important to mention here that this kind of structural
units stabilized by a number of supramolecular interactions repre-
sents and exemplify a unique pattern of self-assembly. These com-
pounds are fluorescent and organic fluorescent materials are used
in a wide range of applications, like electronic display devices,

A. Abbas et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 120 (2014) 176–184
183
Fig. 6. (a) Stacked 3D-supramolecular structure of 4c viewed along a-axis (left) and c-axis (right). (b) An infinite 1D-supramolecular chain of 4c viewed along a-axis stabilized
by CHꢁ ꢁ ꢁO [C(13)AH(13)ꢁ ꢁ ꢁO(6) 2.563 Å, C(14)AH(14)ꢁ ꢁ ꢁO(6) 2.663 Å] and a lonepairꢁ ꢁ ꢁ [O(6)ꢁ ꢁ ꢁH(13) 3.209 Å] contacts. (c) Two successive stacked supramolecular chains of
4c viewed along a-axis stabilized by CHꢁ ꢁ ꢁ [C(5)AH(5)ꢁ ꢁ ꢁC(11) 2.821 Å], ꢁ ꢁ ꢁ [C(3)ꢁ ꢁ ꢁC(15) 3.395 Å] and CHꢁ ꢁ ꢁ [C(31)AH(31A)ꢁ ꢁ ꢁC(16) 2.854 Å] interactions.
p
p
p
p
p
that by increasing the lipophilic character, bioactivity of the com-
pounds also increases due to their greater permeation through
the lipid layer of the membrane. However, for the present series,
it is interesting to note that compounds bearing nine and ten car-
bon alkoxy chains were found to be more active as compared to
compounds with shorter or longer alkyl chains. This trend may
be attributed to lesser lipophilicity of compounds bearing shorter
alkoxy chain and poor solubility of compounds bearing longer alk-
oxy chain in the DMSO solvent, which is used for this bioassay or it
may be credited to different conformational arrangements of alk-
oxy chains. The results of antifungal activities (%inhibition) were
compared with standard reference drugs miconazole and ampho-
tericin B and are presented in Table 2. The results of this in vitro
study demonstrate the relationship between lipophilicity, solubil-
ity and bioavailability.
pound 1b showed good anti-inflammatory activity with IC50 va-
lue 331 M as compared to 273 M for Indomethacine. All other
l
l
compounds showed low anti-inflammatory activity. In literature,
different mechanisms are proposed for anti-inflammatory agents
to explain their in vitro/in vivo mode of action [47]. However, no
general mechanism is reported so far. They probably have multi-
ple cellular mechanisms acting on multiple sites of cellular
infrastructure.
Table 2
Antifungal bioassay of compounds 1b–4c.
Compd.
% Inhibition (at conc. 200
l
g/mL)
Activity profile
(A)
(B)
(C)
(D)
(E)
1b
2b
3b
4b
1c
2c
3c
4c
00
00
00
00
00
00
00
00
108
–
10
00
00
00
00
00
00
00
–
10
80
70
10
00
50
50
10
98
–
40
00
30
20
20
00
30
00
73
–
00
00
00
00
00
00
00
00
110
–
Negative
Positive
Positive
Negative
Negative
Positive
Positive
Negative
Positive
Negative
Antiinflammatory studies (in vitro)
The novel series of N-acyl-2-pyrazolines (1b–4c) was also
screened for their anti-inflammatory activity. The results of this
study were compared with standard reference drug-Indometha-
cine and are summarized in Table 3. The anti-inflammatory
activity of all the tested compounds was first evaluated in terms
of percent growth inhibition. The compounds which
showed P70% inhibition were retested and the results were ex-
pressed as IC50 (inhibitory concentration 50%), the concentration
of the compound which inhibits the inflammation by 50% of
three independent experiments. In the present series, only com-
MICONa
AMPHOb
20
Note: Bold values represent significant results.
a
MICON: miconazole.
b
AMPHO: amphotericin B. (A): candida albicans; (B): aspergillus flavus; (C):
microsporum canis; (D): fusarium solani; (E): candida glabrata.

184
A. Abbas et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 120 (2014) 176–184
[3] H.Y. Wang, X.X. Zhang, J.J. Shi, G. Chen, X.P. Xu, S.J. Ji, Spectrochim. Acta A 93
Table 3
(2012) 343–347.
Anti-inflammatory activity of 1b–4c.
[4] S. Ningaiah, U.K. Bhadraiah, S. Keshavamurthy, C. Javarasetty, Bioorg. Med.
Chem. Lett. 23 (2013) 4532–4539.
[5] F.F. Jian, P.S. Zhao, H.M. Guo, Y.F. Li, Spectrochim. Acta A 69 (2008) 647–653.
[6] P.S. Zhao, R.Q. Li, H.Y. Wang, F.F. Jian, H.M. Guo, Spectrochim. Acta A 74 (2009)
87–93.
Compd.
R1
R2
% Inhibition and IC50
% Inhibition (at IC50 SEM
M)
Activity
profile
500
l
M)
(l
[7] A. Marella, M.R. Ali, M.T. Alam, R. Saha, O. Tanwar, M. Akhter, M.
Shaquiquzzaman, M.M. Alam, Mini Rev. Med. Chem. 13 (2013) 921–931.
[8] S. Kumar, S. Bawa, S. Drabu, R. Kumar, H. Gupta, Recent Pat. Anti-infect. Drug
Discov. 4 (2009) 154–163.
[9] M.R. Shaaban, A.S. Mayhoub, A.M. Farag, Expert Opin. Ther. Pat. 22 (2012) 253–
291.
[10] D. Secci, S. Carradori, A. Bolasco, B. Bizzarri, M.D. Ascenzio, E. Maccioni, Curr.
Top. Med. Chem. 12 (2012) 2240–2257.
[11] K.M. Amin, A.A.M. Eissa, S.M. Abou-Seri, F.M. Awadallah, G.S. Hassan, Euro. J.
Med. Chem. 60 (2013) 187–198.
1b
2b
3b
4b
1c
2c
3c
C9H19
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
C2H5
–
71%
34%
03%
10%
07%
10%
14%
34%
92
331.45 1.167
–
–
–
–
–
–
–
Good
C
C
C
10H21
11H23
12H25
Weak
Weak
Weak
Weak
Weak
Weak
Weak
Standard
C9H19
C
C
C
–
10H21
11H23
12H25
4c
INDOMa
273.12 2.33
[12] A. Ciupa, P.A. De Bank, M.F. Mahon, P.J. Wood, Lorenzo Caggiano, Med. Chem.
Commun. 4 (2013) 956–961.
[13] D. Havrylyuk, B. Zimenkovsky, O. Vasylenko, C.W. Day, D.F. Smee, P. Grellier, R.
Lesyk, Euro. J. Med. Chem. 66 (2013) 228–237.
Note: Bold values represent significant results.
a
INDOM: indomethacine (standard drug).
[14] D. Havrylyuk, B. Zimenkovsky, O. Vasylenko, A. Gzella, R. Lesyk, J. Med. Chem.
55 (2012) 8630–8641.
[15] M.Y. Wani, A.R. Bhat, A. Azam, D.H. Lee, I. Choi, F. Athar, Euro. J. Med. Chem. 54
(2012) 845–854.
Conclusions
[16] M. Eddaoudi, J. Kim, N. Rosi, D. Vodak, J. Wachter, M. O’Keeffe, O.M. Yaghi,
Science 295 (2002) 469.
[17] X. Li, X. Guo, X. Xu, G. Ma, S. Lin, Inorg. Chem. Commun. 27 (2013) 105.
[18] F.-K. Wang, S.-Y. Yang, R.-B. Huang, L.-S. Zheng, S.R. Batten, Cryst. Eng.
Commun. 10 (2008) 1211.
A series of new N-acyl-2-pyrazolines bearing nine to twelve car-
bon long alkoxy side chains was synthesized to study their solid
state self-assembly behavior for understanding the interplay of
alkoxy chain crystallization and various supramolecular interac-
tions. Their potential as antifungal and anti-inflammatory agents
was also evaluated. Different types of 1D-stacked supramolecular
chains are observed for 1b and 4c in the crystal lattice, where
the difference is only the length of alkoxy chain. These supramolec-
[19] C. Janiak, Dalton Trans. (2003) 2781.
[20] H. Chun, D.N. Dybtsev, H. Kim, K. Kim, Chem. Euro. J. 11 (2005) 3521.
[21] S. Kitagawa, R. Kitaura, S. Noro, Angew. Chem. Int. Ed. 43 (2004) 2334.
[22] O.R. Evans, W.B. Lin, Acc. Chem. Res. 35 (2002) 511.
[23] S.R. Batten, K.S. Murray, Coord. Chem. Rev. 246 (2003) 103.
[24] M.M. Naseer, S. Hameed, Cryst. Eng. Commun. 14 (2012) 4247.
[25] L.F. Lindoy, I. Atkinson, Self Assembly in Supramolecular Systems, Monographs
in Supramolecular Chemistry, vol. 7, Royal Society of Chemistry, Cambridge,
2000.
[26] M. Fujita (Ed.), Molecular Self Assembly-Organic Versus Inorganic Approaches,
Structure and Bonding, vol. 96, Springer, Berlin, 2000.
[27] X. Xu, X. Zhang, X. Liu, L. Wang, E. Wang, Cryst. Eng. Commun. 14 (2012) 3264.
[28] W.L. Leong, J.J. Vittal, Chem. Rev. 111 (2011) 688.
[29] S.R. Batten, N.R. Champness, X.-M. Chen, J.G. Martinez, S. Kitagawa, L.
Öhrström, M. O’Keeffe, M.P. Suh, J. Reedijk, Cryst. Eng. Commun. 14 (2012)
3001.
ular structures are stabilized by various CHꢁ ꢁ ꢁO, Hꢁ ꢁ ꢁH, CHꢁ ꢁ ꢁ
p,
lonepairꢁ ꢁ ꢁ
p
and interactions. In addition, compounds 2b,
pꢁ ꢁ ꢁp
3b, 2c and 3c show significant to moderate antifungal activity
against Microsporum canis. However, most of the other compounds
are inactive against all the five tested fungal strains. Good anti-
inflammatory activity is observed for compound 1b with IC50 value
331 lM as compared to 273 lM for standard reference drug. The
[30] S.R. Batten, R. Robson, Angew. Chem. Int. Ed. 37 (1998) 1460.
[31] B. Moulton, M.J. Zaworotko, Curr. Opi. Solid State Mater. Sci. 6 (2002) 117.
[32] X.T. Wang, Y.L. Bai, F.F. Xing, M. Shao, S.R. Zhu, Inorg. Chem. Commun. 20
(2012) 117.
[33] R. Dey, B. Bhattacharya, E. Colacio, D. Ghoshal, Dalton Trans. 42 (2013) 2094–
2106.
compounds of the present series as potential chelating agents
and with good antifungal and anti-inflammatory properties may
be promising future candidates for the design of metal-based ther-
apeutics with higher and improved bioactivities.
[34] Y. El Aziz, A.R. Bassindale, P.G. Taylor, R.A. Stephenson, M.B. Hursthouse, R.W.
Harrington, W. Clegg, Macromolecules 46 (2013) 988–1001.
[35] Y.A. Getmanenko, M. Fonari, C. Risko, B. Sandhu, E. Galan, L.Y. Zhu, P. Tongwa,
D.K. Hwang, S. Singh, H. Wang, S.P. Tiwari, Y.L. Loo, J.L. Bredas, B. Kippelen, T.
Timofeeva, S.R. Marder, J. Mater. Chem. C 1 (2013) 1467–1481.
[36] A. Lampel, O. Yaniv, O. Berger, E. Bacharach, E. Gazit, F. Frolow, Acta.
Crystallogr. F 69 (2013) 602–606.
[37] C.D.P. Klein, G.F. Tabeteh, A.V. Laguna, U. Holzgrabe, K. Mohr, Euro. J. Pharma.
Sci. 14 (2001) 167–175.
[38] E. Pop, D.C. Oniciu, M.E. Pape, C.T. Cramer, J.-L.H. Dasseux, Croatica Chemica
Acta 77 (2004) 301–306.
Acknowledgements
The authors A.A. and M.M.N. are grateful to Higher Education
Commission (HEC) of Pakistan for financial support. We are also
thankful to Panjwani Center for Molecular Medicine and Drug Re-
search, HEJ Research Institute of Chemistry, International Center
for Chemical Sciences, University of Karachi, Pakistan for biological
studies.
[39] A. Hasan, A. Abbas, M.N. Akhtar, Molecules 16 (2011) 7789–7802.
[40] Stoe & Cie, X-AREA Stoe & Cie Darmstadt, Germany, 2001.
[41] G.M. Sheldrick, SHELXS97 and SHELXL97, University of Göttingen, Germany,
1997.
Appendix A. Supplementary material
[42] A.S. Tan, M.V. Berridge, J. Immunol. Meth. 238 (2000) 59–68.
[43] E.F. Saad, N.M. Hamada, S.M. Sharaf, S.K. El-Sadany, A.M. Moussa, M. Elba,
Rapid Commun. Mass Spectrom. 12 (1998) 833–836.
[44] C.F. Matta, J. Hernandez-Trujillo, T.H. Tang, R.F. Bader, Chemistry 9 (2003)
1940–1951.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.saa.2013.10.023.
[45] T.J. Mooibroek, P. Gamez, J. Reedijk, Cryst. Eng. Commun. 10 (2008) 1501–
1515.
References
[46] A.U. Rahman, M.I. Choudhary, W.J. Thomsen, Bioassay Techniques for Drug
Development, Harwood Academic Publishers, The Netherlands, 2001. pp. 22.
[47] Y. Bellik, L. Boukraâ, H.A. Alzahrani, B.A. Bakhotmah, F. Abdellah, S.M.
Hammoudi, M. Iguer-Ouada, Molecules 18 (2013) 322–353.
[1] T.M. Acker, A. Khatri, K.M. Vance, C. Slabber, J. Bacsa, J.P. Snyder, S.F. Traynelis,
D.C. Liotta, J. Med. Chem. 56 (2013) 6434–6456.
[2] S.P. Sakthinathan, G. Vanangamudi, G. Thirunarayanan, Spectrochim. Acta A 95
(2012) 693–700.