Synthesis and antimicrobial evaluation of some halcones and their derived pyrazoles, pyrazolines, isoxazolines, and 5,6-dihydropyrimidine-2-(1H)-thiones

Article abstract of DOI:10.1007/s00706-007-0700-8

Chalcones were synthesized by a base catalyzed Claisen-Schmidt condensation reaction. Bromination of chalcones afforded the dibromo derivatives. Monobromo derivatives could be obtained by treating the corresponding dibromochalcones with dry benzene in the

Full text of DOI:10.1007/s00706-007-0700-8

Monatshefte fu¨r Chemie 138, 889–897 (2007)
DOI 10.1007/s00706-007-0700-8
Printed in The Netherlands
Synthesis and Antimicrobial Evaluation of Some Chalcones
and Their Derived Pyrazoles, Pyrazolines, Isoxazolines,
and 5,6-Dihydropyrimidine-2-(1H)-thiones
Adel A.-H. Abdel-Rahman1;ꢀ, Ahmed E.-S. Abdel-Megied1, Mohamed A. M. Hawata1,
Eman R. Kasem1, and Mohamed T. Shabaan2
1
Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt
2
Department of Botany, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt
Received April 11, 2007; accepted April 20, 2007; published online June 29, 2007
# Springer-Verlag 2007
Summary. Chalcones were synthesized by a base catalyzed
obtained by convenient synthesis methods strongly
Claisen-Schmidt condensation reaction. Bromination of
chalcones afforded the dibromo derivatives. Monobromo
derivatives could be obtained by treating the corresponding
dibromochalcones with dry benzene in the presence of triethyl-
amine. Pyrazole derivatives were obtained by refluxing of
dibromochalcones with phenylhydrazine or 2,4-dinitrophenyl-
hydrazine in dry pyridine. Chalcones were treated with hy-
drazine hydrate or phenyl hydrazine in ethanol to afford
D2-pyrazolines and N-phenyl-D2-pyrazolines. Condensation
of chalcones with hydroxylamine hydrochloride or thiourea
in ethanolic sodium hydroxide solution gave 4,5-dihydro-
isoxazoles and 5,6-dihydropyrimidine-2-(1H)-thiones. The
prepared compounds were tested for antimicrobial activity
against four different bacterial species displaying different
degrees of antibacterial activities or inhibitory actions.
inhibit the polymerization of tubulin by binding to
the colchicine-binding site [9]. The relatively simple
structure and high affinity of chalcones for the col-
chicine-binding site because of similarity of the two-
aryl group placements in the two molecules has led
to the synthesis and subsequent evaluation of a large
number of chalcones [10]. The synthesis of aryl-
pyrazoles is of major interest [11]. Indeed these con-
stitute an important class of heterocyclic compounds
because this ring system is present in numerous
compounds of therapeutic importance including
a number of marketed drugs, such as Celecoxib
(Celebrex+) or Deracoxib (Fig. 1) [12]. Due to the
importance of these pharmacological properties, sig-
nificant efforts toward the synthesis of this kind of
compounds have been carried out in the last years
[13]. Functionalized isoxazoline and isoxazole deriv-
atives are active pharmacophores in several phar-
macologically important molecules [14], and are
also useful intermediates for the synthesis of a wide
variety of bioactive natural products [15]. Thioxo-
pyrimidine is an essential structural unit of several
heterocycles, which display a wide range of inter-
esting biological and pharmacological properties,
such as anticancer and antimicrobial activities [16].
Despite these characteristics there are few synthesis
methodologies for this class of heterocycles [17].
Keywords. Chalcones; Pyrazoles; Pyrazolines; Isoxazolines;
2-Thioxopyrimidines.
Introduction
For a structurally simple group of compounds, chal-
cones have displayed an impressive array of bio-
logical activities, among which anti-malarial [1],
anti-protozoal [2], anti-inflammatory [3], immuno-
modulatory [4], nitric oxide inhibition [5], tyronase
inhibition [6], cytotoxic [7], and anticancer [8] activ-
ities have been cited in literature. These compounds
ꢀ
Corresponding author. E-mail: adelnassar63@hotmail.com

890
A. A.-H. Abdel-Rahman et al.
at 1600 and 1475, while the vinyl CH¼CH appeared
at 1295–1300 cmꢁ1. From 1H NMR spectra, all chal-
cones were geometrically pure and with trans-con-
figuration (JH -H ¼ 15.50–15.60 Hz). Saturation of
ꢀ
ꢁ
the double bond or variation of the aliphatic part re-
sults in loss of the anti-inflammatory activity [20].
So, bromination of chalcones was carried out by ad-
ding bromine dropwise to the clear solution of 1a–1c
in chloroform to afford the corresponding 2,3-dibro-
mochalcones 2a–2c. Monobromo derivatives could
be obtained from the corresponding dibromochal-
cones according to the method described by Holla
et al. [21]. So, treatment of 2a–2c with dry benzene
in the presence of triethylamine afforded 3a–3c
(Scheme 1).
Fig. 1. Structures of Celecoxib and Deracoxib
Our interest in the synthesis of such compounds was
to shed some light on their biological study as anti-
microbial agents as a part of our program aimed at
the development of new heterocyclic compounds with
potential biological activities [18].
The pyrazole derivatives 4a–4c or 5a–5c were
obtained by refluxing of dibromochalcones 2a–2c
with phenylhydrazine or 2,4-dinitrophenylhydrazine
in dry pyridine. The IR spectra of 4a–4c or 5a–5c
showed the characteristic band for C¼N at 1673–1680
and C¼C–Ar at 1598–1600 and 1450–1456 cmꢁ1,
Results and Discussion
Synthesis
1
while the H NMR spectra showed a singlet at ꢂ ¼
Chalcones 1a–1c were synthesized by a base cata-
lyzed Claisen-Schmidt condensation reaction [19] of
appropriately substituted acetophenones and alde-
hydes. The method is attractive since it specifically
generates the (E)-isomer. The IR spectra show the
characteristic band for C¼O at 1690–1695, C¼C Ar
6.84–6.99ppm for the pyrazole-H-4 (Scheme 2).
It has been reported that, ꢀ,ꢁ-unsaturated ketones
can react with hydrazine hydrate or phenylhydra-
zine to give the corresponding pyrazolines [22]. So,
1a–1c were treated with hydrazine hydrate or phenyl
hydrazine in ethanol to afford the D2-pyrazolines
Scheme 1

Synthesis and Antimicrobial Evaluation of Some Chalcones
891
Scheme 2
6a–6c in 73–75% yields, and N-phenyl-D2-pyra-
zolines 7a–7c in 80–89% yields. The IR spectra
of 6a–6c showed the characteristic band for NH
at 3370–3380 and C¼N at 1690–1695 cmꢁ1. The
1H NMR spectra showed two doublets at ꢂ ¼ 3.00–
3.03 and 3.50–3.57ppm for the pyrazoline-H-4, while
pyrazoline-H-5 appeared as a triplet at ꢂ ¼ 4.90–
dro-2-thioxopyrimidine-H-6, and a broad singlet at
ꢂ ¼ 12.74–12.80ppm for the SH group (Scheme 3).
Antimicrobial Activity
The newly synthesized compounds were tested for
their antimicrobial action [23] against four different
bacterial species namely, Pseudomonas sp. (Gram
negative bacterium), Bacillus subtilis (Gram positive
bacterium), Bacillus cereus (Gram positive bacte-
rium), and Streptomyces sp. (one of the important
actinomycetes). All the tested compounds exhibited
different degrees of antibacterial activities or inhibi-
tory actions. The most susceptible organisms were
the two Gram positive bacteria (Bacillus subtilis and
Bacillus cereus) followed by Streptomyces sp., while
the lowest inhibitory effect was encountered in the
case of Pseudomonas sp. The highest degrees of
inhibition were recorded for compounds 4a–4c and
5a–5c followed by 1a–1c, 3a–3c, 6a–6c, 7a–7c,
8a–8c and 9a–9c, while the lowest degree of inhibi-
tion was recorded for the dibromochalcones 2a–2c
(Table 1). The results were compared to amoxicillin
(penicillin) as a reference drug.
1
4.98ppm. The H NMR spectra of 7a–7c showed
two doublets at ꢂ ¼ 3.15–3.18 and 3.87–3.96 ppm
for the pyrazoline-H-4 and a triplet at ꢂ ¼ 5.42–
5.50ppm for the pyrazoline-H-5. Condensation of
1a–1c with hydroxylamine hydrochloride or thiourea
in ethanolic sodium hydroxide solution gave 4,5-
dihydroisoxazoles 8a–8c in 80–86% yields, and 5,6-
dihydropyrimidine-2(1H)-thiones 9a–9c in 75–80%
1
yields. The H NMR spectra of 8a–8c showed two
doublets at ꢂ ¼ 3.58–3.62 and 3.86–3.90 ppm for the
isoxazoline-H-4 and a triplet at ꢂ ¼ 5.91–5.97 ppm for
the isoxazoline-H-5. The IR bands of 9a–9c showed
the characteristic band for NH at 3320–3335, SH at
1
2450–2460, and C¼N at 1690cmꢁ1. The H NMR
spectra showed two doublets at ꢂ ¼ 5.06–5.11 and
5.23–5.25 ppm for the dihydro-2-thioxopyrimidine-
H-5, a triplet at ꢂ ¼ 5.45–5.59 ppm for the dihy-

892
A. A.-H. Abdel-Rahman et al.
Scheme 3
Conclusions
cones 2a–2c to the monobromo derivatives 3a–3c
resulted in the re-appearance of the activity com-
parable to 2a–2c. (d) Converting 2a–2c to the
corresponding pyrazoles 4a–4c and 5a–5c, the anti-
microbial activity was enhanced to its maximum, in
fact higher than that of the chalcones 1a–1c. This
result demonstrated that the introduction of the pyr-
azole nucleus between two aryl rings enhanced the
rigidity besides polarity and solubility in the mole-
cule, which played an integral role for their increase
in antimicrobial activity. (e) Pyrazolines 6a–6c
showed a higher antimicrobial activity than the N-
phenylpyrazolines 7a–7c. This result showed that
the pyrazoline nucleus might be the active bind-
ing site, which becomes deactivated by arylation.
(f) Isoxazolines 8a–8c and 2-thioxopyrimidines 9a–
9c showed moderate antimicrobial activity.
Chalcones and their derived analogues were assayed
for antimicrobial activity against four different bac-
terial species. By comparing the antimicrobial activ-
ity of these compounds, the following conclusions
were drawn: (a) presence of Br-atom on 4-position
of ring B led to a higher antimicrobial activity than a
nitro group in the 3-position as well as no substitu-
tion on the ring. (b) Converting ꢀ,ꢁ-unsaturated
ketones 1a–1c to the corresponding dibromochal-
cones 2a–2c dramatically reduced the antimicrobial
activity. This result demonstrated that the conforma-
tion of the two aryl rings in the molecule has an
essential role to play for the activity of chalcones
and the double bond seems to be a crucial moiety
as reported earlier [24]. (c) Converting dibromochal-

Synthesis and Antimicrobial Evaluation of Some Chalcones
893
Table 1. Antimicrobial activity of the newly synthesized
compounds 1–9
General Procedure for the Preparation of Chalcones 1a–1c
To a solution of 1.96g 4-phenylacetophenone (10 mmol) in
ethanol, an aqueous solution of 10 cm3 10% NaOH or 2 drops
piperidine was added. The resulting solution was heated to
80ꢂC and substituted benzaldehydes (10 mmol) were added
with constant stirring. The reaction mixture was kept stirring
at this temperature for 3–4 h, cooled to room temperature, and
was allowed to stand overnight. The solid product separated
was collected by filtration, dried, and recrystallized from etha-
nol to give 1a–1c in 80–88% yields.
Compd no. Pseudomonas Bacillus Bacillus Streptomyces
sp.
subtilis cereus
sp.
Amoxicillin
(Penicillin)
1a
ꢁ
þþ þþþ
þ
ꢁ
ꢁ
ꢁ
ꢁ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þþþ þþþ
þþþ þþþ
þþþ þþþ
þþ
þ
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
9a
þ
þ
þ
þ
þ
ꢁ
(E)-1-(Biphenyl-4-yl)-3-phenylprop-2-en-1-one
(1a, C21H16O)
þ
þ
þ
ꢁ
þþ
þþ
þ
Pale yellow powder (88%); Rf ¼ 0.33 (petroleum ether:
CH2Cl2, 2:1); mp 143–145ꢂC; IR (KBr): ꢃꢀ¼ 1695 (C¼O),
þþþ þþþ
þ
1600, 1475 (C¼C Ar), 1295 (CH¼CH) cmꢁ1
;
1H NMR
þþ
þþ
þ
þþþþ þþþþ
þþþþ þþþþ
þþþþ þþþþ
þþþþ þþþþ
þþþþ þþþ
þþþþ þþþþ
þþþ þþþ
þþþ þþþ
þþþ þþþ
þþ
þþ
þþ
þ
(DMSO-d6, 250 MHz): ꢂ ¼ 7.33–7.48 (m, Ar–H), 7.50–
7.53 (m, Ar–H), 7.56 (d, J ¼ 15.5 Hz, COCH¼CH), 7.80–
7.90 (m, Ar–H), 7.92 (d, J ¼ 15.5 Hz, COCH¼CH) ppm;
MS (MALDI, positive mode, Matrix: DHB): m=z (%) ¼ 307
[(M þ Na)þ, 59].
þ
þ
þ
(E)-1-(Biphenyl-4-yl)-3-(4-bromophenyl)prop-2-en-1-one
(1b, C21H15BrO)
þþ
þ
Yellow powder (85%); Rf ¼ 0.38 (petroleum ether:CH2Cl2,
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þ
2:1); mp 203–204ꢂC; IR (KBr): ꢃꢀ¼ 1690 (C¼O), 1600, 1475
þ
(C¼C Ar), 1295 (CH¼CH) cmꢁ1
;
1H NMR (DMSO-d6,
þ
250 MHz): ꢂ ¼ 7.46–7.51 (m, Ar–H), 7.58 (d, J ¼ 15.6 Hz,
COCH ¼ CH), 7.70–7.88 (m, Ar–H), 7.90 (d, J ¼ 15.6Hz,
COCH¼CH) ppm; MS (MALDI, positive mode, Matrix:
DHB): m=z (%) ¼ 385 [(M þ Na)þ, 45].
þþ
þ
þ
þ
9b
9c
þ
(E)-1-(Biphenyl-4-yl)-3-(3-nitrophenyl)prop-2-en-1-one
(1c, C21H15NO3)
þ
ꢁ No antibacterial effect
þ Low antibacterial effect
Yellow powder (80%); Rf ¼ 0.32 (petroleum ether:CH2Cl2,
2:1); mp 190–192ꢂC; IR (KBr): ꢃꢀ¼ 1693 (C¼O), 1600, 1475
(C¼C Ar), 1300 (CH¼CH) cmꢁ1
;
1H NMR (DMSO-d6,
þþ Moderate antibacterial effect
þþþ High antibacterial effect
þþþþ Complete antibacterial effect
250 MHz): ꢂ ¼ 7.33–7.53 (m, Ar–H), 7.57–7.63 (m, Ar–H),
7.69–7.85 (m, Ar–H), 7.90–8.18 (m, Ar–H), 8.27 (d, J ¼
15.6Hz, COCH¼CH), 8.54 (d, J ¼ 15.6 Hz, COCH¼CH)
ppm; MS (MALDI, positive mode, Matrix: DHB): m=z (%) ¼
352 [(M þ Na)þ, 33].
Experimental
General Procedure for the Preparation of 2,3-
Melting points were determined using a Kofler block instru-
ment. IR spectra were recorded with a Perkin-Elmer model
Dibromochalcones 2a–2c
Bromine (1.6g, 10mmol) was added dropwise with vigorous
stirring to a solution of 1a–1c (10 mmol) in 10cm3 CHCl3
over 30min. After complete addition of Br2, the reaction
mixture was allowed to stand for 1 h. The dibromo derivatives
were precipitated, filtered off, and washed with 3ꢃ10cm3
ether to remove the excess of Br2. Recrystallization from
ethanol afforded 2a–2c in 85–90% yields.
1
1720 FTIR (KBr), H NMR spectra were recorded with a
Bruker AC 250 FT NMR spectrometer at 250 MHz with
TMS as an internal standard. MALDI-MS were measured with
a KRATOS Analytical Compact, using 2,5-dihydroxybenzoic
acid (DHB) as matrix. The (Mþ Na)þ ions were peak-
matched using ions derived from the 2,5-dihydroxybenzoic
acid matrix. The microanalyses were performed at the micro-
analytical unit, Cairo University, Egypt, and were found to
agree favourably with the calculated values. Antimicrobial
activity of the synthesized compounds was conducted at the
Botany Department, Faculty of Science, Menoufia University,
Shebin El-Koam, Egypt.
1-(Biphenyl-4-yl)-2,3-dibromo-3-phenylpropan-1-one
(2a, C21H16Br2O)
White powder (88%); Rf ¼ 0.68 (petroleum ether:CH2Cl2,
1
2:1); mp 208–210ꢂC; H NMR (DMSO-d6, 250 MHz): ꢂ ¼

894
A. A.-H. Abdel-Rahman et al.
5.65 (d, J ¼ 2.5Hz, CH), 5.77 (d, J ¼ 2.5 Hz, CH), 7.12–7.26
(m, Ar–H), 7.48–7.52 (m, Ar–H), 7.75–7.82 (m, Ar–H),
7.90–8.03 (m, Ar–H) ppm; MS (MALDI, positive mode,
Matrix: DHB): m=z (%) ¼ 464 [(M þ Na)þ, 22].
General Procedure for the Preparation of Pyrazoles 4a–4c
and 5a–5c
A mixture of 2a–2c (10 mmol), phenylhydrazine or 2,4-dini-
trophenylhydrazine (20 mmol) in 20cm3 dry pyridine was
refluxed in an oil bath for 14h (TLC). The reaction mixture
was poured onto crushed ice and the residual oil was extracted
with 3ꢃ100 cm3 CHCl3. The combined organic layers were
dried (Na2SO4) and evaporated under reduced pressure. The
residue was purified by silica gel column chromatography
using 5% CHCl3 in petroleum ether to give 4a–4c in 72–
80% and 5a–5c in 70–75% yields.
1-(Biphenyl-4-yl)-2,3-dibromo-3-(4-bromophenyl)propan-1-
one (2b, C21H15Br3O)
White powder (90%); Rf ¼ 0.72 (petroleum ether:CH2Cl2,
1
2:1); mp 240–242ꢂC; H NMR (DMSO-d6, 250 MHz): ꢂ ¼
5.62 (d, J ¼ 2.5Hz, CH), 5.73 (d, J ¼ 2.5 Hz, CH), 7.02–7.17
(m, Ar–H), 7.48–7.59 (m, Ar–H), 7.72–7.79 (m, Ar–H),
7.97–8.00 (m, Ar–H) ppm; MS (MALDI, positive mode,
Matrix: DHB): m=z (%) ¼ 542 [(M þ Na)þ, 14].
3-(Biphenyl-4-yl)-1,5-diphenyl-1H-pyrazole (4a, C27H20N2)
Pale yellow crystals (80%); Rf ¼ 0.34 (petroleum ether:
CH2Cl2, 2:1); mp 121–123ꢂC; IR (KBr): ꢃꢀ¼ 1677 (C¼N),
1598, 1456 (C¼C Ar) cmꢁ1; 1H NMR (DMSO-d6, 250 MHz):
ꢂ ¼ 6.88 (s, pyrazole-H-4), 7.33–7.46 (m, Ar–H), 7.47–7.77
(m, Ar–H), 7.95–8.04 (m, Ar–H) ppm; MS (MALDI, positive
mode, Matrix: DHB): m=z (%) ¼ 395 [(M þ Na)þ, 32].
1-(Biphenyl-4-yl)-2,3-dibromo-3-(3-nitrophenyl)propan-1-
one (2c, C21H15Br2NO3)
White powder (85%); Rf ¼ 0.72 (petroleum ether:CH2Cl2,
1
2:1); mp 130–131ꢂC; H NMR (DMSO-d6, 250 MHz): ꢂ ¼
5.66 (d, J ¼ 2.5 Hz, CH), 5.77 (d, J ¼ 2.5 Hz, CH), 7.40–7.57
(m, Ar–H), 7.72–7.82 (m, Ar–H), 8.00–8.07 (m, Ar–H) ppm;
MS (MALDI, positive mode, Matrix: DHB): m=z (%) ¼ 509
[(M þ Na)þ, 17].
3-(Biphenyl-4-yl)-5-(4-bromophenyl)-1-phenyl-1H-pyrazole
(4b, C27H19BrN2)
Pale brown crystals (78%); Rf ¼ 0.39 (petroleum ether:
CH2Cl2, 2:1); mp 145–147ꢂC; IR (KBr): ꢃꢀ¼ 1680 (C¼N),
1600, 1456 (C¼C Ar) cmꢁ1; 1H NMR (DMSO-d6, 250 MHz):
ꢂ ¼ 6.85 (s, pyrazole-H-4), 7.40–7.50 (m, Ar–H), 7.60–7.80
(m, Ar–H), 7.90–8.07 (m, Ar–H) ppm; MS (MALDI, positive
mode, Matrix: DHB): m=z (%) ¼ 473 [(M þ Na)þ, 30].
General Procedure for the Preparation of 2-Bromochalcones
3a–3c
Triethylamine (4.04 g, 40 mmol) in 30cm3 dry benzene was
added to a solution of 2a–2c (10 mmol) in 100 cm3 dry ben-
zene with stirring. The reaction mixture was stirred at room
temperature for 24 h. After removal of the separated triethyl-
amine hydrobromide, the filtrate was concentrated under re-
duced pressure. The residue was recrystallized from ethanol to
give 3a–3c in 86–90% yields.
3-(Biphenyl-4-yl)-5-(3-nitrophenyl)-1-phenyl-1H-pyrazole
(4c, C27H19N3O2)
Pale yellow crystals (72%); Rf ¼ 0.38 (petroleum ether:
CH2Cl2, 2:1); mp 153–155ꢂC; IR (KBr): ꢃꢀ¼ 1679 (C¼N),
1600, 1450 (C¼C Ar) cmꢁ1; 1H NMR (DMSO-d6, 250 MHz):
ꢂ ¼ 6.84 (s, pyrazole-H-4), 7.43–7.59 (m, Ar–H), 7.88–8.03
(m, Ar–H) ppm; MS (MALDI, positive mode, Matrix: DHB):
m=z (%) ¼ 440 [(M þ Na)þ, 19].
(Z)-1-(Biphenyl-4-yl)-2-bromo-3-phenylprop-2-en-1-one
(3a, C21H15BrO)
Brown powder (87%); Rf ¼ 0.16 (petroleum ether:CH2Cl2,
1
2:1); mp 100–102ꢂC; H NMR (DMSO-d6, 250 MHz): ꢂ ¼
7.30–7.43 (m, Ar–H), 7.75–7.83 (m, Ar–H), 8.44 (s, CH)
ppm; MS (MALDI, positive mode, Matrix: DHB): m=z (%) ¼
385 [(M þ Na)þ, 76].
3-(Biphenyl-4-yl)-1-(2,4-dinitrophenyl)-5-phenyl-1H-
pyrazole (5a, C27H18N4O4)
Yellow crystals (75%); Rf ¼ 0.34 (petroleum ether:CH2Cl2,
2:1); mp 175–177ꢂC; IR (KBr): ꢃꢀ¼ 1675 (C¼N), 1600,
1450 (C¼C Ar) cmꢁ1
;
1H NMR (DMSO-d6, 250 MHz):
(Z)-1-(Biphenyl-4-yl)-2-bromo-3-(4-bromophenyl)prop-2-en-
1-one (3b, C21H14Br2O)
ꢂ ¼ 6.94 (s, pyrazole-H-4), 7.33–7.69 (m, Ar–H), 7.85–7.93
(m, Ar–H), 8.35–8.44 (m, Ar–H), 8.74–8.79 (m, Ar–H) ppm;
MS (MALDI, positive mode, Matrix: DHB): m=z (%) ¼ 485
[(M þ Na)þ, 29].
Pale brown powder (90%); Rf ¼ 0.18 (petroleum ether:CH2Cl2,
1
2:1); mp 109–111ꢂC; H NMR (DMSO-d6, 250 MHz): ꢂ ¼
7.19–7.33 (m, Ar–H), 7.45–7.49 (m, Ar–H), 7.75–7.89 (m,
Ar–H), 8.47 (s, CH) ppm; MS (MALDI, positive mode,
Matrix: DHB): m=z (%) ¼ 462 [(M þ Na)þ, 43].
3-(Biphenyl-4-yl)-5-(4-bromophenyl)-1-(2,4-dinitrophenyl)-
1H-pyrazole (5b, C27H17BrN4O4)
(Z)-1-(Biphenyl-4-yl)-2-bromo-3-(3-nitrophenyl)prop-2-en-
1-one (3c, C21H14BrNO3)
Yellow crystals (74%); Rf ¼ 0.38 (petroleum ether:CH2Cl2,
2:1); mp 166–168ꢂC; IR (KBr): ꢃꢀ¼ 1679 (C¼N), 1600,
Pale brown gum (86%); Rf ¼ 0.12 (petroleum ether:CH2Cl2,
2:1); 1H NMR (DMSO-d6, 250 MHz): ꢂ ¼ 7.40–7.46–7.33 (m,
Ar–H), 7.69–7.88 (m, Ar–H), 8.15–8.28 (m, Ar–H), 8.58
(s, CH) ppm; MS (MALDI, positive mode, Matrix: DHB):
m=z (%) ¼ 430 [(M þ Na)þ, 53].
1450 (C¼C Ar) cmꢁ1
;
1H NMR (DMSO-d6, 250 MHz):
ꢂ ¼ 6.99 (s, pyrazole-H-4), 7.30–7.65 (m, Ar–H), 7.85–7.90
(m, Ar–H), 8.30–8.40 (m, Ar–H), 8.70–8.80 (m, Ar–H) ppm;
MS (MALDI, positive mode, Matrix: DHB): m=z (%) ¼ 563
[(M þ Na)þ, 29].

Synthesis and Antimicrobial Evaluation of Some Chalcones
895
7.20 (m, Ar–H), 7.29–7.35 (m, Ar–H), 7.40–7.55 (m, Ar–
H), 7.70–7.85 (m, Ar–H) ppm; MS (MALDI, positive mode,
Matrix: DHB): m=z (%) ¼ 397 [(M þ Na)þ, 70].
3-(Biphenyl-4-yl)-1-(2,4-dinitrophenyl)-5-(3-nitrophenyl)-
1H-pyrazole (5c, C27H17N5O6)
Yellow crystals (70%); Rf ¼ 0.41 (petroleum ether:CH2Cl2,
2:1); mp 155–157ꢂC; IR (KBr): ꢃꢀ¼ 1673 (C¼N), 1600,
1450 (C¼C Ar) cmꢁ1
;
1H NMR (DMSO-d6, 250 MHz):
3-(Biphenyl-4-yl)-5-(4-bromophenyl)-1-phenyl-4, 5-dihydro-
1H-pyrazole (7b, C27H21BrN2)
ꢂ ¼ 6.92 (s, pyrazole-H-4), 7.30–7.60 (m, Ar–H), 7.80–7.94
(m, Ar–H), 8.42–8.65 (m, Ar–H), 8.73–8.86 (m, Ar–H) ppm;
MS (MALDI, positive mode, Matrix: DHB): m=z (%) ¼ 530
[(M þ Na)þ, 25].
Yellow powder (89%); Rf ¼ 0.66 (petroleum ether:CH2Cl2,
1
2:1); mp 190–192ꢂC; H NMR (DMSO-d6, 250 MHz): ꢂ ¼
3.15, 3.87 (2dd, J ¼ 8.0, 3.6 Hz, pyrazoline-H-4), 5.46 (t,
J ¼ 3.6 Hz, pyrazoline-H-5), 6.84–6.95 (m, Ar–H), 7.21–7.33
(m, Ar–H), 7.39–7.45 (m, Ar–H), 7.49–7.73 (m, Ar–H),
7.79–7.87 (m, Ar–H) ppm; MS (MALDI, positive mode,
Matrix: DHB): m=z (%) ¼ 475 [(M þ Na)þ, 51].
General Procedure for the Preparation of Pyrazolines 6a–6c
and N-Phenylpyrazolines 7a–7c
A mixture of 1a–1c (5mmol), 0.13 cm3 N2H4 ꢄ H2O (5 mmol)
and=or 0.27 cm3 phenylhydrazine (5 mmol) in 25 cm3 ethanol
was refluxed for 8 h (TLC). The reaction mixture was cooled,
the precipitate was filtered off, and recrystallized from ethanol
to give 6a–6c in 73–75% yields, and 7a–7c in 80–89% yields.
3-(Biphenyl-4-yl)-5-(3-nitrophenyl)-1-phenyl-4,5-dihydro-
1H-pyrazole (7c, C27H21N3O2)
Yellow powder (80%); Rf ¼ 0.54 (petroleum ether:CH2Cl2,
1
2:1); mp 164–166ꢂC; H NMR (DMSO-d6, 250 MHz): ꢂ ¼
3.18, 3.96 (2dd, J ¼ 8.0, 3.6 Hz, pyrazoline-H-4), 5.42 (t,
J ¼ 3.6Hz, pyrazoline-H-5), 6.85–6.99 (m, Ar–H), 7.19–7.29
(m, Ar–H), 7.39–7.50 (m, Ar–H), 7.59–7.66 (m, Ar–H), 7.79–
7.85 (m, Ar–H), 8.13–8.25 (m, Ar–H) ppm; MS (MALDI,
positive mode, Matrix: DHB): m=z (%) ¼ 442 [(M þ Na)þ, 45].
3-(Biphenyl-4-yl)-5-phenyl-4,5-dihydro-1H-pyrazole
(6a, C21H18N2)
Pale yellow powder (75%); Rf ¼ 0.30 (petroleum ether:
CH2Cl2, 2:1); mp 125–127ꢂC; IR (KBr): ꢃꢀ¼ 3375 (NH),
1690 (C¼N) cmꢁ1
;
1H NMR (DMSO-d6, 250 MHz): ꢂ ¼
3.00, 3.51 (2dd, J ¼ 8.0, 3.6Hz, pyrazoline-H-4), 4.98 (t,
J ¼ 3.6 Hz, pyrazoline-H-5), 7.08 (br s, NH), 7.12–7.23 (m,
Ar–H), 7.33–7.50 (m, Ar–H), 7.70–7.84 (m, Ar–H), 7.90–
7.99 (m, Ar–H) ppm; MS (MALDI, positive mode, Matrix:
DHB): m=z (%) ¼ 321 [(M þ Na)þ, 66].
General Procedure for the Preparation of Isoxazolines 8a–8c
A mixture of 1a–1c (5mmol), 0.16 g HONH2 ꢄ HCl (5 mmol),
and 0.5g NaOH (12 mmol) in 60cm3 ethanol was refluxed for
8 h (TLC). The reaction mixture was cooled and poured onto
crushed ice. The precipitate was filtered off, washed with H2O,
and purified by silica gel column chromatography using
CH2Cl2 in petroleum ether (3:7 v=v) to give 8a–8c in 80–
86% yields.
3-(Biphenyl-4-yl)-5-(4-bromophenyl)-4,5-dihydro-1H-
pyrazole (6b, C21H17BrN2)
Pale yellow powder (75%); Rf ¼ 0.34 (petroleum ether:
CH2Cl2, 2:1); mp 144–145ꢂC; IR (KBr): ꢃꢀ¼ 3380 (NH),
1695 (C¼N) cmꢁ1
;
1H NMR (DMSO-d6, 250 MHz): ꢂ ¼
3-(Biphenyl-4-yl)-5-phenyl-4,5-dihydroisoxazole
(8a, C21H17NO)
3.03, 3.57 (2dd, J ¼ 8.0, 3.6Hz, pyrazoline-H-4), 4.90 (t,
J ¼ 3.6 Hz, pyrazoline-H-5), 7.00 (br s, NH), 7.10–7.20 (m,
Ar–H), 7.30–7.40 (m, Ar–H), 7.60–7.70 (m, Ar–H), 7.80–
7.90 (m, Ar–H) ppm; MS (MALDI, positive mode, Matrix:
DHB): m=z (%) ¼ 399 [(M þ Na)þ, 45].
White powder (85%); Rf ¼ 0.34 (petroleum ether:CH2Cl2,
1
2:1); mp 130–132ꢂC; H NMR (DMSO-d6, 250 MHz): ꢂ ¼
3.58, 3.86 (2dd, J ¼ 8.0, 3.5 Hz, isoxazoline-H-4), 5.92 (t,
J ¼ 3.5 Hz, isoxazoline-H-5), 7.19–7.25 (m, Ar–H), 7.37–
7.50 (m, Ar–H), 7.69–7.83 (m, Ar–H), 7.89–7.98 (m, Ar–
H) ppm; MS (MALDI, positive mode, Matrix: DHB): m=z
(%) ¼ 322 [(M þ Na)þ, 45].
3-(Biphenyl-4-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazole
(6c, C21H17N3O2)
Pale yellow powder (73%); Rf ¼ 0.32 (petroleum ether:
CH2Cl2, 2:1); mp 173–175ꢂC; IR (KBr): ꢃꢀ¼ 3370 (NH),
3-(Biphenyl-4-yl)-5-(4-bromophenyl)-4,5-dihydroisoxazole
(8b, C21H16BrNO)
1694 (C¼N) cmꢁ1
;
1H NMR (DMSO-d6, 250 MHz):
ꢂ ¼ 3.00, 3.50 (2dd, J ¼ 8.0, 3.6 Hz, pyrazoline-H-4), 4.95 (t,
J ¼ 3.6 Hz, pyrazoline-H-5), 7.02 (br s, NH), 7.15–7.25 (m,
Ar–H), 7.37–7.50 (m, Ar–H), 7.70–7.80 (m, Ar–H), 7.90–
7.95 (m, Ar–H), 8.05–8.17 (m, Ar–H) ppm; MS (MALDI, pos-
itive mode, Matrix: DHB): m=z (%) ¼ 366 [(M þ Na)þ, 66].
White powder (86%); Rf ¼ 0.37 (petroleum ether:CH2Cl2,
1
2:1); mp 144–146ꢂC; H NMR (DMSO-d6, 250 MHz): ꢂ ¼
3.60, 3.90 (2dd, J ¼ 8.0, 3.5 Hz, isoxazoline-H-4), 5.97 (t,
J ¼ 3.5Hz, isoxazoline-H-5), 7.00–7.11 (m, Ar–H), 7.22–
7.33 (m, Ar–H), 7.40–7.59 (m, Ar–H), 7.89–7.92 (m, Ar–
H) ppm; MS (MALDI, positive mode, Matrix: DHB): m=z
(%) ¼ 400 [(M þ Na)þ, 33].
3-(Biphenyl-4-yl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole
(7a, C27H22N2)
3-(Biphenyl-4-yl)-5-(3-nitrophenyl)-4,5-dihydroisoxazole
(8c, C21H16N2O3)
Yellow powder (85%); Rf ¼ 0.52 (petroleum ether:CH2Cl2,
1
2:1); mp 205–207ꢂC; H NMR (DMSO-d6, 250 MHz): ꢂ ¼
3.15, 3.95 (2dd, J ¼ 8.0, 3.6Hz, pyrazoline-H-4), 5.50 (t,
J ¼ 3.6 Hz, pyrazoline-H-5), 6.71–6.90 (m, Ar–H), 7.07–
Pale yellow powder (80%); Rf ¼ 0.39 (petroleum ether:CH2Cl2,
1
2:1); mp 166–167ꢂC; H NMR (DMSO-d6, 250 MHz): ꢂ ¼

896
A. A.-H. Abdel-Rahman et al.
3.62, 3.87 (2dd, J ¼ 8.0, 3.5Hz, isoxazoline-H-4), 5.91 (t,
J ¼ 3.5 Hz, isoxazoline-H-5), 7.50–7.69 (m, Ar–H), 7.80–
7.95 (m, Ar–H), 8.18–8.28 (m, Ar–H) ppm; MS (MALDI,
positive mode, Matrix: DHB): m=z (%) ¼ 367 [(M þ Na)þ,
40].
[3] a) Ballesteros JF, Sanz MJ, Ubeda A, Miranda MA,
Iborra S, Paya M, Alcaraz M (1995) J Med Chem 38:
2794; b) Hsieh HK, Lee TH, Wang JP, Wang JJ, Lin CN
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Immunopharm 2: 545
[5] Rajas J, Paya M, Dominguez JN, Ferrandiz ML (2002)
Bioorg Med Chem Lett 12: 1951
General Procedure for the Preparation of 5,6-
Dihydropyrimidine-2(1H)-thiones 9a–9c
[6] Nerya O, Musa R, Khatib S, Tamir S, Jacob O (2004)
Phytochemistry 65: 1389
A mixture of 1a–1c (10 mmol), 0.1 g thiourea (14 mmol), and
1.0 g NaOH (25 mmol) in 30 cm3 ethanol was refluxed for 6 h.
The reaction mixture was concentrated, cooled, and filtered.
The precipitate was recrystallized from ethanol to give 9a–9c
in 75–80% yields.
[7] a) Dimmock JR, Kandepu NM, Hetherington M, Quail
JW, Pugazhenthi U, Sudom AM, Chamankhah M, Rose
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Leynadier D, Sarrazin M, Briand C, Menendez M,
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NJ, Mcgown AT, Rennison D (1998) Bioorg Med Chem
Lett 8: 1051
4-(Biphenyl-4-yl)-6-phenyl-5,6-dihydropyrimidine-2(1H)-
thione (9a, C22H18N2S)
Pale yellow crystals (80%); Rf ¼ 0.52 (petroleum ether:
CH2Cl2, 2:1); mp 198–199ꢂC; IR (KBr): ꢃꢀ¼ 3320 (NH),
2450 (SH), 1690 (C¼N) cmꢁ1
;
1H NMR (DMSO-d6,
250 MHz): ꢂ ¼ 5.06, 5.23 (2dd, J ¼ 7.0, 3.0 Hz, dihydro-2-
thioxopyrimidine-H-5), 5.45 (t, J ¼ 3.0 Hz, dihydro-2-thioxo-
pyrimidine-H-6), 7.20–7.38 (m, Ar–H), 7.49–7.65 (m, Ar–H),
12.76 (br s, SH) ppm; MS (MALDI, positive mode, Matrix:
DHB): m=z (%) ¼ 365 [(M þ Na)þ, 40].
4-(Biphenyl-4-yl)-6-(4-bromophenyl)-5,6-dihydropyrimidine-
2(1H)-thione (9b, C22H17BrN2S)
Pale yellow crystals (80%); Rf ¼ 0.55 (petroleum ether:
CH2Cl2, 2:1); mp 207–209ꢂC; IR (KBr): ꢃꢀ¼ 3330 (NH),
2455 (SH), 1690 (C¼N) cmꢁ1
;
1H NMR (DMSO-d6,
250 MHz): ꢂ ¼ 5.11, 5.25 (2dd, J ¼ 7.0, 3.0 Hz, dihydro-2-
thioxopyrimidine-H-5), 5.53 (t, J ¼ 3.0 Hz, dihydro-2-thioxo-
pyrimidine-H-6), 7.20–7.40 (m, Ar–H), 7.50–7.63 (m, Ar–H),
12.74 (br s, SH) ppm; MS (MALDI, positive mode, Matrix:
DHB): m=z (%) ¼ 443 [(M þ Na)þ, 22].
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SM, Bronk BS, Rafka RJ, Jaynes BH, Ziegler CB,
Kilroy C, Mann DW, Nimz EK, Lynch MP, Haven
ML, Kolosko NL, Minich ML, Li C, Dutra JK, Rast
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4-(Biphenyl-4-yl)-6-(3-nitrophenyl)-5,6-dihydropyrimidine-
2(1H)-thione (9c, C22H17N3O2S)
Yellow crystals (75%); Rf ¼ 0.55 (petroleum ether:CH2Cl2,
2:1); mp 222–224ꢂC; IR (KBr): ꢃꢀ¼ 3335 (NH), 2460 (SH),
1690 (C¼N) cmꢁ1; 1H NMR (DMSO-d6, 250 MHz): ꢂ ¼ 5.09,
5.23 (2dd, J ¼ 7.0, 3.0 Hz, dihydro-2-thioxopyrimidine-H-5),
5.59 (t, J ¼ 3.0Hz, dihydro-2-thioxopyrimidine-H-6), 7.20–
7.40 (m, Ar–H), 7.50–7.69 (m, Ar–H), 8.10–8.19 (m, Ar–
H), 12.80 (br s, SH) ppm; MS (MALDI, positive mode, Matrix:
DHB): m=z (%) ¼ 410 [(M þ Na)þ, 22].
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