Med Chem Res (2012) 21:3741–3749 MEDICINAL

DOI 10.1007/s00044-011-9912-x
CHEMISTRY
RESEARCH
ORIGINAL RESEARCH

Anti-HIV-1 and cytotoxicity studies of piperidyl-thienyl chalcones

and their 2-pyrazoline derivatives
Syed Umar Farooq Rizvi • Hamid Latif Siddiqui •
Melissa Johns • Mervi Detorio • Raymond F. Schinazi

Received: 22 May 2011 / Accepted: 16 November 2011 / Published online: 4 December 2011
Ó Springer Science+Business Media, LLC 2011

Abstract A series of 12 new pyrazoline derivatives was et al., 1995), antifungal (Nowakowska, 2007), antioxidant
prepared from piperidyl chalcones, which in turn were (Mukherjee et al., 2001), antimalarial (Wu et al., 2002),
synthesized by condensing 4-piperidin-1-ylbenzaldehyde antituberculosis (Sivakumar et al., 2007), analgesic (Viana
with diverse acetylthiophenes. The target compounds were et al., 2003), anti-HIV (Tiwari et al., 1989), antitumor
characterized by spectroscopic techniques (NMR, IR, MS) (Shibata, 1994), anticancer (Wattenberg et al., 1994), antiviral
and elemental analysis. All the compounds were screened (Trivedi et al., 2007), anti-AIDS (Wu et al., 2003), and an-
for cytotoxic and anti-HIV-1 activities. Compounds 1c, 1g, tileishmanial agents (Boeck et al., 2006).
1j, 2a, 2c, 2e, 2g, and 2k demonstrated potential anti-HIV Pyrazoline derivatives of chalcones have also been
activity but were cytotoxic except for 2e and 2k, which reported to possess a widespread range of biological
displayed no cytotoxicity in primary human cells. Bioassay activities including antibacterial (Nauduri and Reddy,
results show that the type and positions of the substituents 1998), antifungal (Azarifar and Shaebanzadeh, 2002),
seem to be critical for their cytotoxic and anti-HIV-1 antidepressant (Bilgin et al., 1993), antitumor (Taylor and
activities. Patel, 1992), antimicrobial (Ramalingham et al., 1977),
anti-inflammatory, molluscicidal activity (Barsoum et al.,
Keywords Chalcones  Pyrazolines  Cytotoxic activity  2006), antiamoebic (Budakoti et al., 2006), and anticon-
Anti-HIV-1 activity  Acetylthiophenes vulsant (Ozdemir et al., 2007). Considerable attention has
been focused on the pyrazoline family in the last two
decades. Among various pyrazoline derivatives, 2-pyrazo-
Introduction lines seem to be the most frequently studied pyrazoline
type compounds (Lévai, 2005). After the pioneering work
1,3-Diaryl-2-propen-1-ones (commonly known as chalcones) by Fischer and Knövenagel in the late nineteenth century,
are one of the most important classes of natural products, the reaction of a,b-unsaturated aldehydes and ketones
which are abundant in the plant kingdom. Chalcones, either with hydrazines became one of the most popular methods
naturally or synthetically derived, possess a broad spectrum of for the preparation of 2-pyrazolines (Lévai et al., 2004)
biological activities including anti-inflammatory (Ballesteros (Scheme 1).
In the present study, firstly the 4-piperidin-1-ylbenzal-
dehyde nucleus and chalcone functionality have been
incorporated in a single molecule (1a–1l). Then, each of
S. U. F. Rizvi  H. L. Siddiqui (&)
the prepared chalcones was refluxed with hydrazine
Institute of Chemistry, University of the Punjab,
Lahore 54590, Pakistan hydrate in ethanol to yield a series of novel 2-pyrazolines
e-mail: drhamidlatif@[Link] (2a–2l) based on piperidyl–thienyl ring systems. Finally,
all the title compounds with variation of substituents at
M. Johns  M. Detorio  R. F. Schinazi
different positions in the Ar ring were tested for their
Center for AIDS Research, Veterans Affairs Medical Center
and Department of Pediatrics, Emory University School cytotoxic and anti-HIV-1 activities in primary human
of Medicine, Decatur, GA 30033, USA lymphocytes (Table 1).

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Scheme 1 Reaction protocol O O

for the synthesis of 2-pyrazoline (i)
N
derivatives (2a–2l): (i) K2CO3,
NH
+ F
H
CTAB, DMF, 100°C; (ii) H
NaOH, rt, 2 h; (iii) EtOH, reflux
(1)

O O
O
(ii)
Ar
H + Ar

N N

(1) (a-l) (1a-l)

O HN N

(iii)
Ar
+ H2N NH2 Ar

N N

(1a-l) (2a-l)

Table 1 Aryl moiety (Ar) of aromatic ketones (a–l) were precipitated out within the reaction flask, which were
Ketones Ar then filtered washed with water and then with cold meth-
anol. The pure products were obtained after recrystalliza-
a Thien-2-yl tion from methanol.
b Thien-3-yl Selected bands of the IR spectra of the chalcones (1a–1l)
c 3-Methylthien-2-yl showed relevant information about their structures. Two
d 4-Methylthien-2-yl typical stretching bands of chalcone moiety, due to ethyl-
e 5-Methylthien-2-yl enic group C=C and carbonyl group C=O were observed at
f 2,5-Dimethylthien-3-yl 1,590–1,607 and 1,650–1,658 cm-1, respectively. The
g 3-Chlorothien-2-yl characteristic band for thiophene (a–l derivatives) was
h 5-Chlorothien-2-yl observed at 750–700 cm-1. In mass spectra of compounds
i 2,5-Dichlorothien-3-yl (1a–1l), the base peak was exhibited by M? itself. This
j 3-Bromothien-2-yl gives information about the stability of the piperidyl
k 5-Bromothien-2-yl chalcone nucleus. Molecular masses of compounds (1a–1l)
l 5-Iodothien-2-yl were also confirmed by their mass spectra. The 1H-NMR
spectra of the chalcones (1a–1l) show that the Ha and Hb
protons appear in the aromatic region (d 7.09–7.79). As a
Results and discussion result, two very sharp doublets around 7.10 ppm for Ha and
7.79 ppm for Hb, with a coupling constant 15.2–15.6 Hz
Chemistry for the trans chalcones were observed. Here also, the sig-
nals of the Ha, for chalcones (1g and 1j) appeared relatively
The precursor 4-piperidin-1-ylbenzaldehyde was prepared in the downfield at d 7.55. This again was attributed to an
by N-arylation of piperidine with 4-fluorobenzaldehyde in additional (-)I of the groups like Cl/Br in the vicinity, i.e.,
the presence of K2CO3 and CTAB, in DMF as solvent. The on the 30 position of thiophene ring (Fig. 1).
4-piperidin-1-yl-benzaldehyde was then condensed with The pyrazoline derivatives (2a–2l) of the synthesized
various thienyl ketones in alkaline medium with constant piperidyl chalcones (1a–1l) were prepared by refluxing
stirring at room temperature. The title compounds (1a–1l) them with hydrazine hydrate in ethanolic solution. The

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Fig. 1 General structure of Hβ O HN N

chalcones and their pyrazoline H5
8 8
derivatives 7 S 7 S
9 1' 9 1'
2' 5' 2' 5'
Ha Hb
2 10 2 10
12 Hα 3' 12 3'
3 4' 3 4'
N 11 N 11
1 1

4 6 4 6
5 5

products (2a–2l) were precipitated within the reaction In case of pyrazoline derivatives (2a–2l), the unsubsti-
flask, which were filtered, washed (first with water and then tuted thiophenyl derivatives (2a and 2b) showed enhanced
with cold ethanol), and recrystallized from ethanol. activities (EC50 = 7.3 and 11.3 lM, respectively) as
The formation of product (2a–2l) was confirmed by the compared with their chalcones analogs (1a and 1b, EC50 =
disappearance of C=O peak at 1,650–1,658 cm-1 and 73.8 and 56.0 lM, respectively). The compounds 2c and 2g
appearance of characteristic ring stretching bands of C=N also proved to be active anti-HIV-1 agents like their
at 1,610–1,580 cm-1. Moreover, an additional stretching starting analogs (1c and 1g), whereas the activity of 2j
band of N–H at 3,305–3,317 cm-1 confirmed the ring (EC50 = 17.4 lM) decreased than that of 1j (EC50 =
closure at chalcone moiety. The molecular ion M?, 5.8 ± 2.8 lM). The compounds in which methyl and halo
observed in the mass spectra for all the pyrazolines, con- groups are present at position 5 of thiophenyl ring (2e, 2h,
firmed their molecular masses. Again, the base peak, in all 2k and 2l), only 2e and 2k displayed improved anti-HIV-1
of the mass spectra (except for 2g, 2h, and 2k where the activity (EC50 = 7.2 ± 0.5 and 9.0 ± 0.4 lM, respec-
M?–Cl and M?–Br gave the base peak, respectively), was tively) than their corresponding chalcones (1e and 1k,
exhibited by M? itself. In 1NMR spectra, the disappearance EC50 = 17.9 and 46.5 lM, respectively). The rest of the
of signals between d 7.22–8.23 ppm for olefinic protons compounds (2d, 2f, and 2i) showed no or weak anti-HIV-1
and appearance of peaks at d 2.77–3.14, 3.55–4.02, and activities as summarized in Table 2.
5.24–5.39 for CH2 (Ha and Hb, respectively) and H-5 in
pyrazoline ring, further confirmed the formation of target
compounds (2a–2l). The 1H-NMR spectra of pyrazolines Cytotoxic activity
show the presence of two doublets of doublet signals due to
CH2 protons, Ha (upfield H of CH2) at d 2.82–3.21 ppm Among the compounds under investigation, the unsubsti-
region and Hb at 3.64–4.10 ppm. The CH proton appeared tuted thiophenyl derivatives (1a and 1b) of chalcones (1a–
as a triplet at d 5.28–5.40 ppm region. 1l) showed no toxicity in human PBM cells. As in case of
anti-HIV-1 assays, here also the activity was enhanced by
the incorporation of methyl and halo groups at position 3 of
Anti-HIV-1 activity thiophenyl ring (1c, 1g, and 1j). These three compounds
(i.e., 1c, 1g, and 1j) were found to be toxic in PBM, CEM,
According to the results obtained, it is evident that the un- and Vero cells, except that of 1c, which showed no toxicity
substituted thiophenyl derivatives (1a and 1b) of chalcones in Vero cells only. Moreover, both the disubstituted
(1a–1l) demonstrated no anti-HIV-1 activity (EC50 [ derivatives (1f and 1i) showed cytotoxicity in all three
20 lM) while the activity was considerably enhanced by types of cells (i.e., PBM, CEM, and Vero cells). The rest of
the substitution of methyl and halo groups at position 3 of the compounds 1d, 1e, 1h, 1k, and 1l exhibited no toxicity
the thiophenyl ring (1c, 1g, and 1j). However, incorporation in PBM cells, 1k was non-toxic only in CEM cells, while
of these functionalities at position 5 of thiophenyl ring (1e, 1d, 1e, 1k, and 1l displayed no toxicity in Vero cells.
1h, 1k, and 1l) instead of position 3, the chloro- and bromo- In the case of pyrazoline derivatives (2a–2l), only the
derivatives (1h and 1k) displayed no anti-HIV-1 activity, compounds 2a, 2c, 2d, and 2g were cytotoxic in PBM cells.
whereas methyl- and iodo-derivatives (1e and 1l) were All of the pyrazoline derivatives (2a–2l) were cytotoxic
proven to be weakly active anti-HIV-1 agents. Incorpora- except 2h, while four compounds (2e, 2f, 2h, and 2i)
tion of methyl group at position 4 of thiophenyl ring (1d) showed no cytotoxic activity in Vero cells.
also exhibited weak anti-HIV-1 activity. Moreover, the two
disubstituted derivatives (1f and 1i) also showed weak anti-
HIV-1 activity. In short, in the chalcones series (1a–1l), Conclusion
only three compounds (1c, 1g, and 1j) proved to be potential
anti-HIV-1 agents although these compounds also displayed All the compounds (1a–1l and 2a–2l) were tested against
toxicity in human PBM cells. HIV-1LAI in primary human PBM cells for anti-viral and

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Table 2 Anti-HIV-1 activity in human PBM cells (EC50) and cyto- Experimental
toxicity in PBM, CEM, and Vero cells (IC50) of the series 1a–1l and
2a–2l
General melting points were obtained on Gallenkamp
Anti-HIV-1 activity in human PBM cells Cytotoxicity (IC50, lM) melting point apparatus and were uncorrected. IR spectra
Code EC50 (lM) EC90 (lM) PBM CEM Vero were recorded in KBr pellets on Perkin Elmer infrared
spectrophotometer. 1H-NMR spectra were recorded in
1a 73.8 C100 [100 11.6 65.5 CDCl3 on Brücker/XWIN NMR (400 MHz) and TMS was
1b 56.0 C100 [100 32.1 34.4 used as internal standard (chemical shifts, d in ppm). Mass
1c 2.5 ± 1.8 19.6 ± 20.4 26.4 9.9 63.9 spectra were recorded on a Jeol MSRoute instrument.
1d 11.6 23.1 68.8 33.3 56.3 Acetyl thiophenes (Alpha Aesar), piperidine (Wako),
1e 17.9 30.9 77.8 21.2 50.5 p-fluorobenzaldehyde (Wako), cetyl trimethylammonium
1f 11.6 ± 4.6 23.6 ± 4.9 38.2 16.6 42.3 bromide (Wako), dimethyl formamide (Aldrich), ethanol
1g 8.4 ± 7.8 29.0 ± 25.4 32.1 12.2 18.1 (Aldrich), and hydrazine hydrate (Aldrich) were used as
1h 35.4 C100 [100 41.5 32.4 received. Elemental analyses were performed by C.S.I.C.,
1i 11.8 ± 2.9 24.7 ± 1.8 42.8 15.0 24.9 Madrid Spain and were within ±0.4% of predicted values
1j 5.8 ± 2.8 27.8 ± 16.8 39.3 12.5 18.0 for all compounds.
1k 46.5 C100 [100 52.8 69.5
1l 11.6 C100 [100 22.0 56.5 General method for the synthesis of piperidyl chalcones
2a 7.3 26.8 20.8 6.9 3.2 (1a–1l)
2b 11.3 C100 [100 27.0 29.5
2c 5.1 ± 3.9 15.5 ± 11.1 11.0 2.3 11.4 A mixture of 4-piperidin-1-ylbenzaldehyde (1) (10 mmol)
2d 13.0 24.9 24.4 16.3 31.6 and an aromatic ketone (a–l, 10 mmol) in methanol (50 ml)
2e 7.2 ± 0.5 52.9 ± 11.9 86.4 15.3 52.0 was stirred at room temperature, followed by dropwise
2f 16.9 ± 11.7 29.8 ± 12.9 77.5 20.1 83.4 addition of aq. NaOH (4 ml, 10%). The stirring was con-
2g 2.4 ± 1.4 13.1 ± 7.8 34.2 10.2 31.6 tinued for 2 h and the reaction mixture was then kept at 0°C
2h 75.3 [100 [100 [100 [100 (24 h). Subsequently, it was poured onto ice-cold water
2i 32.5 [100 59.0 37.7 53.9 (200 ml). The precipitates were collected by filtration,
2j 17.4 30.4 57.0 31.6 24.8 washed with cold water followed by cold MeOH. The
2k 9.0 ± 0.4 33.3 ± 17.5 80.0 21.5 25.8 resulting chalcones (1a–1l) were recrystallized from CHCl3.
2l 14.5 43.6 [100 36.5 15.9
AZT 0.0029 ± 0.0020 0.026 ± 0.013 [100 14.3 56.0
(2E)-3-(4-Piperidin-1-ylphenyl)-1-thiophen-2-ylprop-2-en-
1-one (1a)

cytotoxicity. Assays were conducted using at least two dif- 80% Yield. mp. 141°C. IR (KBr) cm-1: 1652 (C=O), 1598
ferent donor cells in duplicate or triplicate. Eight compounds (C=C). 1H-NMR (CDCl3) d: 1.63–1.68 (6H, m, H3/H4/H5),
(1c, 1g, 1j, 2a, 2c, 2e, 2g, and 2k) were found to be active 3.29–3.30 (4H, m, H2/H6), 6.87 (2H, d, H9/H11,
below 10 lM with no significant cytotoxicity at active J = 8.8 Hz), 7.15 (1H, t, H40 , J = 4.2 Hz), 7.23 (1H, d, Ha,
concentrations, especially at or above the anti-viral con- J = 15.2 Hz), 7.52 (2H, d, H8/H12, J = 8.8 Hz), 7.62 (1H,
centrations. Compounds 1c and 2g demonstrated the most d, H50 , J = 4.8 Hz), 7.79 (1H, d, Hb, J = 15.6 Hz), 7.82
potent anti-HIV-1 activity (median effective concentration, (1H, d, H30 , J = 3.6 Hz). MS (m/z): 297 (M?, 100%).
EC50 = 2.5 and 2.4 lM, respectively) with modest toxicity Anal. Calculated for C18H19NOS: C, 72.69; H, 6.44; N,
above 20 lM in human PBM cells. None of the compounds 4.71. Found: C, 72.62; H, 6.48; N, 4.68.
were more potent than the positive control AZT. Compounds
were also evaluated for cytotoxicity in CEM and Vero cells (2E)-3-(4-Piperidin-1-ylphenyl)-1-thiophen-3-ylprop-2-en-
to determine their spectrum of toxicity. CEM cells are a line 1-one (1b)
of lymphoblastic cells originally derived from a child with
acute lymphoblastic leukemia, whereas Vero cells are 85% Yield. mp. 160°C. IR (KBr) cm-1: 1655 (C=O), 1596
derived from African Green monkey kidney cells. In general, (C=C). 1H-NMR (CDCl3) d: 1.63–1.68 (6H, m, H3/H4/H5),
the eight compounds listed above were found to be more 3.29–3.31 (4H, m, H2/H6), 6.87 (2H, d, H9/H11,
toxic in CEM and Vero than PBM cells. Modification of the J = 8.8 Hz), 7.21 (1H, d, Ha, J = 15.2 Hz), 7.33 (1H, t,
chemical structure of compounds that were found to be H40 , J = 4.0 Hz), 7.51 (2H, d, H8/H12, J = 8.4 Hz), 7.64
active against HIV-1 merits exploration to improve their (1H, d, H50 , J = 4.8 Hz), 7.76 (1H, d, Hb, J = 15.6 Hz),
potency and reduce their cytotoxicity. 8.10 (1H, s, H20 ). MS (m/z): 297 (M?, 100%). Anal.

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Calculated for C18H19NOS: C, 72.69; H, 6.44; N, 4.71. (2E)-1-(3-Chlorothiophen-2-yl)-3-(4-piperidin-1-

Found: C, 72.60; H, 6.40; N, 4.64. ylphenyl)prop-2-en-1-one (1g)

(2E)-1-(3-Methylthiophen-2-yl)-3-(4-piperidin-1- 82% Yield. mp. 85°C. IR (KBr) cm-1: 1658 (C=O), 1600
ylphenyl)prop-2-en-1-one (1c) (C=C). 1H-NMR (CDCl3) d: 1.64–1.68 (6H, m, H3/H4/H5),
3.30–3.32 (4H, m, H2/H6), 6.87 (2H, d, H8/H12,
90% Yield. mp. 125°C. IR (KBr) cm-1: 1654 (C=O), 1590 J = 8.8 Hz), 7.02 (1H, d, H50 , J = 5.2 Hz), 7.51 (1H, d,
(C=C). 1H-NMR: (CDCl3) d: 1.63–1.68 (6H, m, H3/H4/H5), H40 , J = 5.2 Hz), 7.52 (2H, d, H9/H11, J = 8.8 Hz), 7.55
2.56 (3H, s, Me), 3.29–3.31 (4H, m, H2/H6), 6.87 (2H, d, (1H, d, Ha, J = 15.6 Hz), 7.80 (1H, d, Hb, J = 15.2 Hz).
H9/H11, J = 8.4 Hz), 7.12 (1H, d, H50 , J = 5.2 Hz), 7.18 MS (m/z): 331 (M?, 48%), 333 (M??2, 12%), 331 (M?-
(1H, d, Ha, J = 15.2 Hz), 7.52 (2H, d, H8/H12, 1, 100%). Anal. Calculated for C18H18ClNOS: C, 65.15; H,
J = 8.4 Hz), 7.60 (1H, d, H40 , J = 5.2 Hz), 7.78 (1H, d, 5.47; N, 4.22. Found: C, 65.18; H, 5.43; N, 4.19.
Hb, J = 15.2 Hz) MS (m/z): 311 (M?, 100%). Anal. Cal-
culated for C19H21NOS: C, 73.27; H, 6.80; N, 4.50. Found:
(2E)-1-(5-Chlorothiophen-2-yl)-3-(4-piperidin-1-
C, 73.22; H, 6.78; N, 4.44.
ylphenyl)prop-2-en-1-one (1h)
(2E)-1-(4-Methylthiophen-2-yl)-3-(4-piperidin-1-
76% Yield. mp. 162°C. IR (KBr) cm-1: 1656 (C=O), 1602
ylphenyl)prop-2-en-1-one (1d)
(C=C). 1H-NMR (CDCl3) d: 1.65–1.68 (6H, m, H3/H4/H5),
3.29–3.31 (4H, m, H2/H6), 6.87 (2H, d, H9/H11,
82% Yield. mp. 110°C. IR (KBr) cm-1: 1652 (C=O), 1600
J = 8.8 Hz), 6.97 (1H, d, H40 , J = 4.0 Hz), 7.12 (1H, d,
(C=C). 1H-NMR: (CDCl3) d: 1.63–1.68 (6H, m, H3/H4/H5),
Ha, J = 15.2 Hz), 7.51 (2H, d, H8/H12, J = 8.4 Hz), 7.58
2.30 (3H, s, Me), 3.29–3.31 (4H, m, H2/H6), 6.87 (2H, d,
(1H, d, H30 , J = 3.6 Hz), 7.77 (1H, d, Hb, J = 15.2 Hz).
H9/H11, J = 8.8 Hz), 7.20 (1H, d, Ha, J = 15.2 Hz), 7.21
MS (m/z): 331 (M?, 44%), 333 (M?-1, 100%). Anal.
(1H, s, H50 ), 7.52 (2H, d, H8/H12, J = 8.8 Hz), 7.63 (1H, s,
Calculated for C18H18ClNOS: C, 65.15; H, 5.47; N, 4.22.
H30 , J = 4.8 Hz), 7.77 (1H, d, Hb, J = 15.2 Hz). MS (m/z):
Found: C, 65.27; H, 5.42; N, 4.26.
311 (M?, 100%). Anal. Calculated for C19H21NOS: C,
73.27; H, 6.80; N, 4.50. Found: C, 73.32; H, 6.83; N, 4.48.
(2E)-1-(2,5-Dichlorothiophen-3-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (1i)
(2E)-1-(5-Methylthiophen-2-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (1e)
62% Yield. mp. 84°C. IR (KBr) cm-1: 1654 (C=O), 1594
(C=C). 1H-NMR (CDCl3) d: 1.64–1.67 (6H, m, H3/H4/H5),
79% Yield. mp. 90°C. IR (KBr) cm-1: 1656 (C=O), 1606
3.30–3.31 (4H, m, H2/H6), 6.85 (2H, d, H9/H11,
(C=C). 1H-NMR: (CDCl3) d: 1.62–1.67 (6H, m, H3/H4/H5),
J = 8.8 Hz), 7.11 (1H, s, H40 ), 7.13 (1H, d, Ha,
2.54 (3H, s, Me), 3.28–3.30 (4H, m, H2/H6), 6.81 (1H, d,
J = 15.6 Hz), 7.48 (2H, d, H8/H12, J = 8.4 Hz), 7.67 (1H,
H40 , J = 3.2 Hz), 6.87 (2H, d, H9/H11, J = 8.4 Hz), 7.19
d, Hb, J = 15.6 Hz). MS (m/z): 367 (M??2, 24%),
(1H, d, Ha, J = 15.2 Hz), 7.51 (2H, d, H8/H12,
364 (M?-1, 100%). Anal. Calculated for C18H17Cl2NOS:
J = 8.4 Hz), 7.64 (1H, d, H30 , J = 3.2 Hz), 7.75 (1H, d,
C, 59.02; H, 4.68; N, 3.82. Found: C, 58.70; H, 4.70; N,
Hb, J = 15.6 Hz). MS (m/z): 311 (M?, 100%). Anal.
3.75.
Calculated for C19H21NOS: C, 73.27 H, 6.80; N, 4.50.
Found: C, 73.21; H, 6.76; N, 4.53.
(2E)-1-(3-Bromothiophen-2-yl)-3-(4-piperidin-1-
(2E)-1-(2,5-Dimethylthiophen-3-yl)-3-(4-piperidin-1- ylphenyl)prop-2-en-1-one (1j)
ylphenyl)prop-2-en-1-one (1f)
69% Yield. mp. 93°C. IR (KBr) cm-1: 1655 (C=O), 1596
-1
72% Yield. mp. 115–117°C. IR (KBr) cm : 1650 (C=O), (C=C). 1H-NMR (CDCl3) d: 1.64–1.67 (6H, m, H3/H4/H5),
1607 (C=C). 1H-NMR (CDCl3) d: 1.63–1.67 (6H, m, H3/ 3.30–3.32 (4H, m, H2/H6), 6.87 (2H, d, H9/H11,
H4/H5), 2.42–2.67 (3H, s, 2xMe), 3.30–3.31 (4H, m, H2/ J = 8.4 Hz), 7.10 (1H, d, H50 , J = 5.2 Hz), 7.48 (1H, d,
H6), 6.86 (2H, d, H9/H11, J = 8.8 Hz), 7.10 (1H, s, H40 ), H40 , J = 5.2 Hz), 7.52 (2H, d, H8/H12, J = 8.8 Hz), 7.55
7.09 (1H, d, Ha, J = 15.6 Hz), 7.48 (2H, d, H8/H12, (1H, d, Ha, J = 15.6 Hz), 7.79 (1H, d, Hb, J = 15.6 Hz).
J = 8.4 Hz), 7.67 (1H, d, Hb, J = 15.6 Hz). MS (m/z): 325 MS (m/z): 375 (M?, 100%). Anal. Calculated for
(M?, 100%). Anal. Calculated for C20H23NOS: C, 73.86; C18H18BrNOS: C, 57.45; H, 4.82; N, 3.72. Found: C,
H, 7.97; N, 4.10. Found: C, 73.82; H, 7.10; N, 4.12. 57.54; H, 4.76; N, 3.76.

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(2E)-1-(5-Bromothiophen-2-yl)-3-(4-piperidin-1- 1-[4-(3-Thiophen-3-yl-4,5-dihydro-1H-pyrazol-5-
ylphenyl)prop-2-en-1-one (1k) yl)phenyl]piperidine (2b)

88% Yield. mp. 162°C. IR (KBr) cm-1: 1650 (C=O), 1595 69% Yield. mp. 125°C. IR (KBr) cm-1: 3312 (N–H) 1596
(C=C). 1H-NMR (CDCl3) d: 1.64–1.67 (6H, m, H3/H4/H5), (C=N). 1H-NMR (CDCl3) d: 1.61–1.65 (6H, m, H3/H4/H5),
3.29–3.31 (4H, m, H2/H6), 6.86 (2H, d, H9/H11, 2.94 (1H, dd, J = 16.4, 9.4 Hz, 4-Ha), 3.27–3.29 (4H, m,
J = 8.4 Hz), 7.11 (1H, d, H40 , J = 4.0 Hz), 7.12 (1H, d, H2/H6), 3.71 (1H, dd, J = 16.2, 10.2 Hz, 4-Hb), 5.39 (1H,
Ha, J = 15.2 Hz), 7.50 (2H, d, H8/H12, J = 8.4 Hz), 7.54 t, J = 9.8 Hz, 5-H), 6.81 (2H, d, H9/H11, J = 8.7 Hz), 7.23
(1H, d, H30 , J = 3.6 Hz), 7.78 (1H, d, Hb, J = 15.2 Hz). (1H, t, H40 , J = 4.0 Hz), 7.42 (2H, d, H8/H12, J = 8.4 Hz),
MS (m/z): 374 (M?-1, 100%) 375 (M?, 67%). Anal. 7.51 (1H, d, H50 , J = 4.8 Hz), 8.02 (1H, s, H20 ). MS (m/z):
Calculated for C18H18BrNOS: C, 57.45; H, 4.82; N, 3.72. 311 (M?, 100%). Anal. Calculated for C18H21N3S: C,
Found: C, 57.38; H, 4.16; N, 3.61. 69.42; H, 6.80; N, 13.49. Found: C, 69.47; H, 6.72; N,
13.44.
(2E)-1-(5-Iodothiophen-2-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (1l) 1-{4-[3-(3-Methylthiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]phenyl}piperidine (2c)
92% Yield. mp. 142°C. IR (KBr) cm-1: 1652 (C=O), 1602
(C=C). 1H-NMR (CDCl3) d: 1.64–1.67 (6H, m, H3/H4/H5), 61% Yield. mp. 119–120°C. IR (KBr) cm-1: 3307 (N–H)
3.30–3.32 (4H, m, H2/H6), 6.86 (2H, d, H9/H11, 1610 (C=N). 1H-NMR (CDCl3) d: 1.62–1.66 (6H, m, H3/
J = 8.4 Hz), 7.31 (1H, d, H40 , J = 3.6 Hz), 7.11 (1H, d, H4/H5), 2.51 (3H, s, Me), 2.81 (1H, dd, J = 16.1, 9.3 Hz,
Ha, J = 15.2 Hz), 7.50 (2H, d, H8/H12, J = 8.8 Hz), 7.43 4-Ha), 3.30–3.31 (4H, m, H2/H6), 3.62 (1H, dd, J = 16.1,
(1H, d, H30 , J = 4.0 Hz), 7.77 (1H, d, Hb, J 15.2 Hz). MS 10.2 Hz, 4-Hb), 5.28 (1H, t, J = 9.8 Hz, 5-H), 6.81 (2H, d,
(m/z): 423 (M?, 100%). Anal. Calculated for C18H16INOS: H9/H11, J = 8.4 Hz), 7.04 (1H, d, H50 , J = 5.2 Hz), 7.42
C, 51.94; H, 5.05, N, 3.19. Found: C, 52.04; H, 5.12; N, (2H, d, H8/H12, J = 8.4 Hz), 7.48 (1H, d, H40 , J = 5.2 Hz).
3.26. MS (m/z): 325 (M?, 100%). Anal. Calculated for
C19H23N3S: C, 70.11; H, 7.12; N, 12.91. Found: C, 70.09;
General method for the synthesis of 2-pyrazolines of 4- H, 7.07; N, 12.84.
piperidin-1-ylbenzaldehyde (2a–2l)
1-{4-[3-(4-Methylthiophen-2-yl)-4,5-dihydro-1H-pyrazol-
A mixture of Chalcone (1a–1l, 1.0 mmol) and hydrazine 5-yl]phenyl}piperidine (2d)
hydrate (3.0 mmol) in ethanol (10 ml) was refluxed. After
completion of the reaction (4–6 h, TLC monitoring), the 74% Yield. mp. 145°C. IR (KBr) cm-1: 3315 (N–H) 1602
crude product was precipitated out when the reaction (C=N). 1H-NMR (CDCl3) d: 1.62-1.66 (6H, m, H3/H4/H5),
mixture was poured onto ice-cold water (50 ml). The 2.26 (3H, s, Me), 2.84 (1H, dd, J = 16.3, 9.3 Hz, 4-Ha),
precipitates were collected by filtration, washed with cold 3.30-3.32 (4H, m, H2/H6), 3.60 (1H, dd, J = 16.3, 10.4 Hz,
water followed by cold EtOH to obtain 2-pyrazolines 4-Hb), 5.28 (1H, t, J = 9.9 Hz, 5-H), 6.77 (2H, d, H9/H11,
which were recrystallized from EtOH (95%) to obtain pure J = 8.5 Hz), 7.21 (1H, s, H50 ), 7.43 (2H, d, H8/H12,
compounds 2a–2l. J = 8.6 Hz), 7.54 (1H, s, H30 , J = 4.8 Hz). MS (m/z): 325
(M?, 100%). Anal. Calculated C19H23N3S: C, 70.11; H,
1-[4-(3-Thiophen-2-yl-4,5-dihydro-1H-pyrazol-5- 7.12; N, 12.91. Found: C, 70.14; H, 7.07; N, 12.88.
yl)phenyl]piperidine (2a)
1-{4-[3-(5-Methylthiophen-2-yl)-4,5-dihydro-1H-pyrazol-
65% Yield. mp. 132°C. IR (KBr) cm-1: 3313 (N–H) 1585 5-yl]phenyl}piperidine (2e)
(C=N). 1H-NMR (CDCl3) d: 1.60–1.65 (6H, m, H3/H4/H5),
2.87 (1H, dd, J = 16.3, 9.3 Hz, 4-Ha), 3.30–3.31 (4H, m, 75% Yield. mp. 157°C. IR (KBr) cm-1: 3310 (N–H) 1589
H2/H6), 3.68 (1H, dd, J = 16.2, 10.2 Hz, 4-Hb), 5.33 (1H, (C=N). 1H-NMR: (CDCl3) d: 1.62–1.67 (6H, m, H3/H4/
t, J = 9.8 Hz, 5-H), 6.85 (2H, d, H9/H11, J = 8.8 Hz), 7.10 H5), 2.53 (3H, s, Me), 2.84 (1H, dd, J = 16.2, 9.1 Hz,
(1H, t, H40 , J = 4.2 Hz), 7.49 (2H, d, H8/H12, J = 8.8 Hz), 4-Ha), 3.30–3.32 (4H, m, H2/H6), 3.57 (1H, dd, J = 16.2,
7.55 (1H, d, H50 , J = 4.8 Hz), 7.75 (1H, d, H30 , 10.0 Hz, 4-Hb), 5.23 (1H, t, J = 9.8 Hz, 5-H), 6.72 (1H, d,
J = 3.6 Hz). MS (m/z): 311 (M?, 100%). Anal. Calculated H40 , J = 3.2 Hz), 6.77 (2H, d, H9/H11, J = 8.4 Hz),
for C18H21N3S: C, 69.42; H, 6.80; N, 13.49. Found: C, 7.41 (2H, d, H8/H12, J = 8.4 Hz), 7.51 (1H, d, H30 ,
69.35; H, 6.86; N, 13.56. J = 3.2 Hz). MS (m/z): 325 (M?, 100%). Anal. Calculated

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for C19H23N3S : C, 70.11; H, 7.12; N, 12.91. Found: C, 379 (M?, 100%). Anal. Calculated for C18H19Cl2N3S: C,
70.03; H, 7.18; N, 12.97. 56.84; H, 5.04; N, 11.05. Found: C, 56.74; H, 5.14; N,
11.09.
1-{4-[3-(2,5-Dimethylthiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]phenyl}piperidine (2f) 1-{4-[3-(3-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]phenyl}piperidine (2j)
73% Yield. mp. 144°C. IR (KBr) cm-1: 3316 (N–H) 1582
(C=N). 1H-NMR: (CDCl3) d: 1.62–1.66 (6H, m, H3/H4/ 77% Yield. mp. 180°C. IR (KBr) cm-1: 3317 (N–H) 1600
H5), 2.39–2.60 (3H, s, 2xMe), 2.77 (1H, dd, J = 16.3, (C=N). 1H-NMR (CDCl3) d: 1.63–1.66 (6H, m, H3/H4/H5),
9.5 Hz, 4-Ha), 3.30–3.32 (4H, m, H2/H6), 3.55 (1H, dd, 3.14 (1H, dd, J = 16.5, 10.2 Hz, 4-Ha), 3.25-3.28 (4H, m,
J = 16.3, 10.2 Hz, 4-Hb), 5.24 (1H, t, J = 10.0 Hz, 5-H), H2/H6), 4.02 (1H, dd, J = 16.5, 10.6 Hz, 4-Hb), 5.35 (1H,
6.78 (2H, d, H9/H11, J = 8.7 Hz), 7.02 (1H, s, H40 ), 7.45 t, J = 10.4 Hz, 5-H), 6.78 (2H, d, H9/H11, J = 8.4 Hz),
(2H, d, H8/H12, J = 8.4 Hz). MS (m/z): 339 (M?, 100%). 7.05 (1H, d, H50 , J = 5.2 Hz), 7.46 (1H, d, H40 ,
Anal. Calculated for C20H25N3S: C, 70.76; H, 7.42; N, J = 5.2 Hz), 7.49 (2H, d, H8/H12, J = 8.6 Hz). MS (m/z):
12.38. Found: C, 70.69; H, 7.37; N, 12.37. 389 (M?, 100%). Anal. Calculated for C18H20BrN3S: C,
55.39; H, 5.16; N, 10.76. Found: C, 55.30; H, 5.20; N,
1-{4-[3-(3-Chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol- 10.72.
5-yl]phenyl}piperidine (2g)
1-{4-[3-(5-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
65% Yield. mp. 151°C. IR (KBr) cm-1: 3308 (N–H) 1597 5-yl]phenyl}piperidine (2k)
(C=N). 1H-NMR (CDCl3) d: 1.62–1.66 (6H, m, H3/H4/H5),
3.12 (1H, dd, J = 16.6, 10.2 Hz, 4-Ha), 3.30–3.32 (4H, m, 78% Yield. mp. 140°C. IR (KBr) cm-1: 3305 (N–H) 1586
H2/H6), 3.96 (1H, dd, J = 16.7, 10.2 Hz, 4-Hb), 5.37 (1H, (C=N). 1H-NMR (CDCl3) d: 1.62–1.66 (6H, m, H3/H4/H5),
t, J = 10.2 Hz, 5-H), 6.80 (2H, d, H8/H12, J = 8.7 Hz), 2.85 (1H, dd, J = 16.2, 9.6 Hz, 4-Ha), 3.30–3.32 (4H, m,
7.02 (1H, d, H50 , J = 5.2 Hz), 7.47 (1H, d, H40 , H2/H6), 3.65 (1H, dd, J = 16.2, 9.6 Hz, 4-Hb), 5.32 (1H, t,
J = 5.2 Hz), 7.49 (2H, d, H9/H11, J = 8.8 Hz). MS (m/z): J = 10.3 Hz, 5-H), 6.82 (2H, d, H9/H11, J = 8.4 Hz), 7.05
345 (M?, 12%), 310 (M?-Cl, 100%). Anal. Calculated for (1H, d, H40 , J = 4.0 Hz), 7.49 (2H, d, H8/H12, J = 8.4 Hz),
C18H20ClN3S : C, 62.50; H, 5.83; N, 12.15. Found: C, 7.39 1H, d, H30 , J = 3.6 Hz). MS (m/z): 389 (M?, 8%), 310
62.48; H, 5.76; N, 12.21. (M?-Br, 100%). Anal. Calculated for C18H20BrN3S: C,
55.39; H, 5.16; N, 10.76. Found: C, 55.34; H, 5.14; N,
1-{4-[3-(5-Chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol- 10.71.
5-yl]phenyl}piperidine (2h)
1-{4-[3-(5-Iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
80% Yield. mp. 147°C. IR (KBr) cm-1: 3314 (N–H) 1606 yl]phenyl}piperidine (2l)
(C=N). 1H-NMR (CDCl3) d: 1.64–1.68 (6H, m, H3/H4/H5),
2.86 (1H, dd, J = 16.3, 10.1 Hz, 4-Ha), 3.29–3.30 (4H, m, 72% Yield. mp. 167°C. IR (KBr) cm-1: 3312 (N–H), 1608
H2/H6), 3.65 (1H, dd, J = 16.3, 10.4 Hz, 4-Hb), 5.35 (1H, (C=N). 1H-NMR (CDCl3) d: 1.63–1.66 (6H, m, H3/H4/H5),
t, J = 10.3 Hz, 5-H), 6.86 (2H, d, H9/H11, J = 8.7 Hz), 2.86 (1H, dd, J = 16.3, 9.7 Hz, 4-Ha), 3.30–3.32 (4H, m,
6.92 (1H, d, H40 , J = 4.0 Hz), 7.47 (2H, d, H8/H12, H2/H6), 3.64 (1H, dd, J = 16.2, 10.1 Hz, 4-Hb), 5.29 (1H,
J = 8.4 Hz), 7.53 (1H, d, H30 , J = 3.6 Hz). MS (m/z): 345 t, J = 10.2 Hz, 5-H), 6.79 (2H, d, H9/H11, J = 8.4 Hz),
(M?, 18%), 310 (M?-Cl, 100%). Anal. Calculated for 7.15 (1H, d, H40 , J = 3.6 Hz), 7.50 (2H, d, H8/H12,
C18H20ClN3S: C, 62.50; H, 5.83; N, 12.15. Found: C, J = 8.5 Hz), 7.32 (1H, d, H30 , J = 4.0 Hz). MS (m/z): 437
62.42; H, 5.91; N, 12.09. (M?, 100%). Anal. Calculated for C18H20IN3S: C, 49.43;
H, 4.61; N, 9.61. Found: C, 49.47; H, 4.55; N, 9.56.
1-{4-[3-(2,5-Dichlorothiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]phenyl}piperidine (2i)
Anti-HIV-1 assay
65% Yield. mp. 175°C. IR (KBr) cm-1: 3311 (N–H) 1605
(C=N). 1H-NMR (CDCl3) d: 1.63–1.66 (6H, m, H3/H4/H5), The assay was performed as described by Schinazi et al.
3.14 (1H, dd, J = 16.3, 10.0 Hz, 4-Ha), 3.30–3.32 (4H, m, (1990) with modifications. Primary human PBM cells
H2/H6), 3.95 (1H, dd, J = 16.4, 9.5 Hz, 4-Hb), 5.35 (1H, t, obtained from LifeSouth Community Blood Centers
J = 10.3 Hz, 5-H), 6.82 (2H, d, H9/H11, J = 8.5 Hz), 7.09 (Atlanta, GA), were isolated by Histopaque (Sigma-Aldrich,
(1H, s, H40 ), 7.46 (2H, d, H8/H12, J = 8.4 Hz). MS (m/z): [Link], MO) and discontinuous gradient centrifugation

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3748 Med Chem Res (2012) 21:3741–3749

from healthy seronegative donors. Cells were activated with Cytotoxic assay
6 lg/ml phytohemagglutinin A (Associates of Cape Cod,
Inc., East Falmouth, MA) in 500 ml of RPMI-1640 Human PBM, CEM, and VERO cells were cultured in
(Mediatech Inc., Herndon, VA) containing 100 ml heat- 96-well plates (5 9 104 cells per well) along with increasing
inactivated fetal bovine serum (Hyclone, Logan, Utah), concentrations of the test compound (Stuyver et al., 2002).
83.3 IU/ml penicillin, 83.3 lg/ml, streptomycin (Mediatech Cell viability was measured after 5-day incubation period
Inc., Herndon, VA), 1.6 mM L-glutamine (Mediatech Inc., using the Cell Titer 96 Aqueous One Solution cell prolif-
Herndon, VA), for 2–3 days prior to use. HIV-1LAI obtained eration assay (Promega, Madison, WI) by incubating in an
from the Centers for Disease Control and Prevention was incubator at 37°C with 5% CO2 for human PBM cells. The
used as the standard reference virus for the anti-viral assays. results are summarized in Table 2.
A multiplicity of infection (MOI) of 0.1, as determined by a
limiting dilution method in PBM cells, was selected for the Acknowledgments The author is grateful to Higher Education
Commission, Pakistan and Institute of Chemistry, University of the
assays. This represented about 50% tissue culture infectious Punjab, Lahore, for financial assistance. We are also thankful to Inter-
doses per 24-well plate per 2 9 106 cells per 2 ml. Using national Centre for Chemical and Biological Sciences, HEJ Research
this MOI, peak reverse transcriptase (RT) levels occurred Institute of Chemistry, University of Karachi, Karachi, for spectral
within 5–7 days. Cells were exposed to virus for 1 h prior to measurements. This work was also supported in part by NIH grant
2P30-AI-050409 and the Department of Veterans Affairs (to RFS).
addition of the compound. RPMI-1640 medium (500 ml)
supplemented with 100 ml heat-inactivated fetal bovine
serum, 1.6 mM L-glutamine, 83.3 IU/ml penicillin, 83.3 lg/
ml streptomycin, 0.0008% DEAE–Dextran (Sigma-Aldrich, References
St. Louis, MO), 0.047% sodium bicarbonate, and 26 IU/ml
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