Synthesis and antifungal activity of novel (1-arylmethyl-3-aryl-1Hpyrazol- 5-yl)(4-arylpiperazin-1-yl)methanone derivatives

Article abstract of DOI:10.3184/174751913X13734652599909

A series of novel (1-arylmethyl-3-aryl-1H-pyrazol-5-yl)(4-arylpiperazin-1- yl)methanone derivatives were synthesised. Preliminary study of the structure-activity relationship revealed that 4-chlorophenyl, 4-tert-butylphenyl, 4-fluorophenyl and 3-methoxyphenyl had a promising effect on the antifungal activity.

Full text of DOI:10.3184/174751913X13734652599909

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 473
AUGUST, 473–475
Synthesis and antifungal activity of novel (1-arylmethyl-3-aryl-1H-
pyrazol-5-yl)(4-arylpiperazin-1-yl)methanone derivatives
Hong-Shui Lva, Li-Ying Wangb, Xiao-Ling Dingc, Xiu-Hua Wangb, Bao-Xiang Zhaoa* and
Hua Zuob
aInstitute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, P. R. China
bCollege of Pharmaceutical Sciences, Southwest University, Chongqing 400715, P. R. China
cCollege of Advanced ProfessionalTechnology, Qingdao University, Qingdao 266061, P. R. China
A series of novel (1-arylmethyl-3-aryl-1H-pyrazol-5-yl)(4-arylpiperazin-1-yl)methanone derivatives were synthesised.
Preliminary study of the structure–activity relationship revealed that 4-chlorophenyl, 4-tert-butylphenyl, 4-fluorophe-
nyl and 3-methoxyphenyl had a promising effect on the antifungal activity.
Keywords: synthesis, pyrazole carboxamide, piperazine, antifungal activity
Microbial resistance to known antibiotics is increasing and
leads to an increasing incidence of infection.1 Therefore, it is
very necessary to develop new antimicrobial drugs. Pyrazoles
are a class of important heterocyclic compounds that are widely
used in the agrochemical and pharmaceutical industries. Many
pyrazole derivatives are known to exhibit a wide range of
bioactivities such as antimicrobial,2 anti-inflammatory,3 anti-
cancer,4 antidepressant,5 anticonvulsant6 and antiangiogenic7
activities. Some pyrazole derivatives have been used clinically,
such as Celecoxib, a well-known COX-2 inhibitor.8 According
to the literature, many piperazine derivatives exhibit antifungal
activity.9,10 In our previous work, we reported a series of novel
pyrazole derivatives such as ethyl 1-(2-hydroxy-3-aroxypropyl)-
3-aryl-1H-pyrazole-5-carboxylate derivatives, 1-arylmethyl-3-
aryl-1H-pyrazole-5-carbohydrazide derivatives, 1-arylmethyl-
3-aryl-1H-pyrazole-5-carbohydrazide hydrazone derivatives
and 3-aryl-1-(2-(hydroxyimino)-2-arylethyl)-1H-pyrazole-5-
carboxylate derivatives as potential anticancer agents.11–14 We
are also committed to the synthesis of pyrazole derivatives
with antimicrobial activity. The combination of pyrazole and
some heterocyclic compounds can form compounds with good
antifungal activity.15,16 Thus, we focused on the introduction
of piperazine to enhance the antifungal activity of pyrazole
derivatives. A series of novel pyrazole derivatives containing
piperazine moiety was synthesised and evaluated for their
antifungal activity in vitro.
Results and discussion
The synthesis of pyrazole carboxamide 3 was performed as
outlined in Scheme 1. The starting material ethyl 3-aryl-1-
arylmethyl-1H-pyrazole-5-carboxylate 1 was synthesised as
described in a previous paper.17 Pyrazolecarboxylic acids 218,19
were obtained by the alkali hydrolysis of pyrazole esters 1.
Pyrazolecarboxylic acids first reacted with oxalyl chloride
in CH2Cl2 under reflux to give pyrazole carbonyl chlorides.
Then the target compound 3 was obtained by the reactions
of pyrazole carbonyl chlorides with 1-arylpiperazines in the
presence of triethylamine in CH2Cl2 at room temperature in
yield 59.3–98.4%.
Structures of the compounds 3a–l were determined by IR,
1H NMR and HRMS spectroscopy. For example, IR spectrum
of compound 3a showed C=O stretching vibration at 1640 cm−1.
1H NMR spectral of compound 3a showed four singles for
Scheme 1 Synthesis of 3.
* Correspondent. E-mail: bxzhao@sdu.edu.cn

474 JOURNAL OF CHEMICAL RESEARCH 2013
drops of DMF in CH2Cl2 (10 mL) was refluxed for 4 h. After cooling,
the solvent was removed. The residue was dissolved in CH2Cl2 (5 mL)
and added dropwise to a solution of 1-arylpiperazine in CH2Cl2
(10 mL) with Et3N (0.5 mL) at room temperature. The mixture was
stirred for 2–4 h. The end of reaction was detected by TLC. After
which the solution was washed by water (20 mL × 2), the water phase
was extracted with CH2Cl2 (15 mL × 1). The combined organic phase
was dried over MgSO4. After filtration, the solvent was removed under
reduced pressure. The residue was purified by column chromatogra-
phy on silica gel using PE/EtOAc (2:1, v/v) as an eluent to afford title
compound 3 in 44.8–82.9%.
[1-(4-tert-Butylbenzyl)-3-phenyl-1H-pyrazol-5-yl](4-phenylpipe-
razin-1-yl)methanone (3a): White solid, yield 59.3%; m.p. 178–181 °C;
IR (νmax cm−1): 1640 (C=O); 1H NMR (CDCl3, 400 MHz): 1.14 (s, 9H,
C(CH2)3), 2.57 (s, 2H, CH2), 3.07 (s, 2H, CH2), 3.44 (s, 2H, CH2), 3.82
(s, 2H, CH2), 5.53 (s, 2H, CH2), 6.60 (s, 1H, pyrazole–H), 6.83 (d, 2H,
J = 7.8 Hz, ArH), 6.89 (t, 1H, J = 7.2 Hz, ArH), 7.17–7.29 (m, 6H,
ArH), 7.31–7.36 (m, 1H, ArH), 7.42 (t, 2H, J = 7.6 Hz, ArH), 7.83 (d,
2H, J = 7.0 Hz, ArH). HRMS calcd for [M+H]+ C31H35N4O: 479.2811,
found 479.2805.
CH2 of piperazine ring. A singlet at 6.60 was observed for
pyrazole–H. The CH2 connected with the pyrazole ring showed
a singlet at δ 5.53. In the HRMS, compound 3a gave a [M+H]-
ion peak at m/z 479.2805 in accordance with the molecular
structure of C31H35N4O.
In vitro antifungal activity
Fluconazole was used as the reference drug for C. albicans
(CMCC(B) 98001). The result of anti-Candida activity showed
that all the synthesised compounds had no activity against the
pathogenic strains of C. albicans.
Anti-Aspergillus activity of the synthesised compounds was
tested against pathogenic fungal strain Aspergillus flavus
(CGMCC 3.3950). The anti-Aspergillus activity of all the syn-
thesised compounds was evaluated by the microbroth dilution
(MDA) assays.20 Amphotericin B was used as a standard drug.
The minimum inhibitory concentrations (MICs) of the tested
compounds against pathogenic fungi are shown in Table 1.
Results of anti-Aspergillus activity demonstrated that 3c, 3d,
3e, 3i and 3j showed mild to moderate anti-Aspergillus activity
against the pathogenic strains used in the experiments. Com-
pounds 3a, 3b, 3g, 3h, 3k and 3l were found to be potential
inhibitor of Aspergillus flavus. They have significant MIC
value at 64 µg mL−1 in MDA assay (Table 1). By comparing the
anti-Aspergillus activity of 3e–h and 3i–l, it can be seen that
1-arylmethyl has no effect on the anti-Aspergillus activity,
while 4-arylpiperazine shows significant impact. Compounds
3e, 3i and 3j with phenyl and 2-fluorophenyl groups respec-
tively show mild to moderate anti-Aspergillus activitiy, while
compounds 3g, 3h, 3k and 3l with 4-fluorophenyl and
3-methoxyphenyl groups respectively are potential inhibitors
of Aspergillus flavus.
[1-(4-tert-Butylbenzyl)-3-phenyl-1H-pyrazol-5-yl][4-(2-fluoro-
phenyl)piperazin-1-yl]methanone (3b): White solid, yield 65.0%;
1
m.p. 155–158 °C; IR (νmax cm−1): 1627 (C=O); H NMR (CDCl3,
400 MHz): 1.16 (s, 9H, C(CH2)3), 2.46 (s, 2H, CH2), 2.98 (s, 2H,
CH2), 3.43 (s, 2H, CH2), 3.84 (s, 2H, CH2), 5.53 (s, 2H, CH2), 6.60 (s,
1H, pyrazole–H), 6.81 (t, 1H, J = 8.0 Hz, ArH), 6.92–7.07 (m, 3H,
ArH), 7.18–7.30 (m, 4H, ArH), 7.30–7.36 (m, 1H, ArH), 7.42 (t, 2H,
J = 7.6 Hz, ArH), 7.82 (d, 2H, J = 7.4 Hz, ArH). HRMS calcd for
[M+H]+ C31H34FN4O: 497.2717, found 497.2704.
[1-(4-tert-Butylbenzyl)-3-phenyl-1H-pyrazol-5-yl][4-(4-fluoro-
phenyl)piperazin-1-yl]methanone (3c): White solid, yield 89.9%;
1
m.p. 190–192 °C; IR (νmax cm−1): 1640 (C=O); H NMR (CDCl3,
400 MHz): 1.13 (s, 9H, C(CH2)3), 2.47 (s, 2H, CH2), 2.98 (s, 2H,
CH2), 3.45 (s, 2H, CH2), 3.82 (s, 2H, CH2), 5.53 (s, 2H, CH2), 6.60 (s,
1H, pyrazole–H), 6.77 (dd, 2H, J1 = 8.4 Hz, J2 = 4.4 Hz, ArH), 6.95
(t, 2H, J = 8.4 Hz, ArH), 7.19 (d, 2H, J = 8.1 Hz, ArH), 7.26 (d, 2H,
J = 8.1 Hz, ArH), 7.34 (t, 1H, J = 7.4 Hz, ArH), 7.42 (t, 2H, J = 7.6 Hz,
ArH), 7.82 (d, 2H, J = 7.4 Hz, ArH). HRMS calcd for [M+H]+
C31H34FN4O: 497.2717, found 497.2710.
In conclusion, a series of novel pyrazole carboxamide deriv-
atives containing a piperazine moiety 3a–l were synthesised
1
and characterised by IR, H NMR and HRMS spectroscopy.
[1-(4-tert-Butylbenzyl)-3-phenyl-1H-pyrazol-5-yl][4-(3-meth-
oxyphenyl)piperazin-1-yl]methanone (3d): White solid, yield 98.4%;
m.p. 151–154 °C. IR (νmax cm−1): 1640 (C=O); 1H NMR (CDCl3,
400 MHz): 1.14 (s, 9H, C(CH2)3), 2.58 (s, 2H, CH2), 3.07 (s, 2H,
CH2), 3.43 (s, 2H, CH2), 3.78 (s, 3H, OCH3), 3.81 (s, 2H, CH2), 5.53
(s, 2H, CH2), 6.35 (s, 1H, ArH), 6.40–6.47 (m, 2H, ArH), 6.59 (s, 1H,
pyrazole–H), 7.15 (t, 1H, J = 8.2 Hz, ArH), 7.20 (d, 2H, J = 8.2 Hz,
ArH), 7.27 (d, 2H, J = 8.2 Hz, ArH), 7.33 (t, 1H, J = 7.6 Hz, ArH),
7.42 (t, 2H, J = 7.6 Hz, ArH), 7.82 (d, 2H, J = 7.6 Hz, ArH). HRMS
calcd for [M+H]+ C32H37N4O2: 509.2917, found 509.2922.
{3-(4-Chlorophenyl)-1-[(6-chloropyridin-3-yl)methyl]-1H-pyrazol-
5-yl}(4-phenylpiperazin-1-yl)methanone (3e):White solid, yield 79.1%;
m.p. 168–170 °C. IR (νmax cm−1): 1745 (C=N), 1630 (C=O); 1H NMR
(CDCl3, 400 MHz): 2.93 (s, 2H, CH2), 3.18 (s, 2H, CH2), 3.72 (s, 2H,
CH2), 3.89 (s, 2H, CH2), 5.54 (s, 2H, CH2), 6.63 (s, 1H, pyrazole–H),
6.88–6.98 (m, 3H, ArH), 7.27–7.34 (m, 3H, ArH), 7.39 (d, 2H, J =
8.6 Hz, ArH), 7.68 (dd, 1H, J1 = 8.3 Hz, J2 = 2.4 Hz, ArH), 7.72 (d, 2H,
J = 8.6 Hz, ArH), 8.39 (d, 1H, J = 2.4 Hz, ArH). HRMS calcd for
[M+H]+ C26H24Cl2N5O: 492.1358, found 492.1362.
{3-(4-Chlorophenyl)-1-[(6-chloropyridin-3-yl)methyl]-1H-pyrazol-
5-yl}[4-(2-fluorophenyl) piperazin-1-yl]methanone (3f): White solid,
yield 72.2%; m.p. 130–132 °C; IR (νmax cm−1): 1744 (C=N), 1629
(C=O); 1H NMR (CDCl3, 400 MHz): 2.77 (s, 2H, CH2), 3.05 (s, 2H,
CH2), 3.71 (s, 2H, CH2), 3.90 (s, 2H, CH2), 5.55 (s, 2H, CH2), 6.62 (s,
1H, pyrazole–H), 6.90 (t, 1H, J = 8.0 Hz, ArH), 6.96–7.12 (m, 3H,
ArH), 7.28 (d, 1H, J = 8.4 Hz, ArH), 7.38 (d, 2H, J = 8.5 Hz, ArH),
7.68 (dd, 1H, J1 = 8.2 Hz, J2 = 2.3 Hz, ArH), 7.72 (d, 2H, J = 8.5 Hz,
ArH), 8.40 (d, 1H, J = 2.3 Hz, ArH). HRMS calcd for [M+H]+
C26H23Cl2FN5O: 510.1264, found 510.1271.
Preliminary evaluation for antifungal activity in vitro showed
that the compounds 3c, 3d, 3e, 3i and 3j had moderate anti-
Aspergillus activity against the pathogenic strains used in the
experiments. While 3a, 3b, 3g, 3h, 3k and 3l were found to be
potential inhibitors of the growth of Aspergillus flavus with
significant MIC value at 64 µg mL−1 in MDA assay. Structure–
activity relationships analysis showed that the 4-fluorophenyl
and 3-methoxyphenyl groups significantly enhanced the
anti-Aspergillus activity.
Experimental
All reagents were of analytical grade or chemically pure. TLC was
performed on silica gel 60F254 plates (Merck KGaA). Melting point
was determined on an XD-4 digital micro melting point apparatus. 1H
NMR spectra were recorded on a Bruker Avance 400 spectrometer,
using CDCl3 as solvent and TMS as internal standard. IR spectra
were recorded with an IR spectrophotometer Avtar 370 FT-IR (Termo
Nicolet). HRMS spectra were recorded on a LTQ Orbitrap Hybrid
mass spectrometer.
General procedure
KOH (30 mmol) was added to a solution of 1 (10 mmol) in ethanol
(50 mL). The mixture was refluxed for 2 h. After cooling, ethanol
was removed under reduced pressure. The residue was dissolved in
50 mL water. The solution was added to hydrochloric acid (3 M) until
pH = 4–5. The precipitate was filtered and dried to give 2 as pure
product. A solution of 2 (1 mmol), oxalyl chloride (0.5 mL) and two
Table 1 Antimicrobial activity of pyrazole carboxamide derivatives 3a–l expressed as MIC (µg mL−1)
Compound
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
Amphotericin B
1
Aspergillus
64
64
128
128
128
–
64
64
128
128
64
64
–No activity.

JOURNAL OF CHEMICAL RESEARCH 2013 475
{3-(4-Chlorophenyl)-1-[(6-chloropyridin-3-yl)methyl]-1H-pyrazol-
5-yl}[4-(4-fluorophenyl) piperazin-1-yl]methanone (3g): White solid,
yield 88.2%; m.p. 199–202 °C; IR (νmax cm−1): 1745 (C=N), 1623
(C=O); 1H NMR (CDCl3, 400 MHz): 2.79 (s, 2H, CH2), 3.06 (s, 2H,
CH2), 3.69 (s, 2H, CH2), 3.88 (s, 2H, CH2), 5.55 (s, 2H, CH2), 6.62
(s, 1H, pyrazole–H), 6.87 (dd, 2H, J1 = 8.4 Hz, J2 = 4.5 Hz, ArH), 7.00
(t, 2H, J = 8.4 Hz, ArH), 7.27 (d, 1H, J = 7.0 Hz, ArH), 7.39 (d, 2H,
J = 8.3 Hz, ArH), 7.68 (dd, 1H, J1 = 8.2 Hz, J2 = 2.3 Hz, ArH), 7.72 (d,
2H, J = 8.3 Hz, ArH), 8.39 (d, 1H, J = 2.3 Hz, ArH). HRMS calcd for
[M+H]+ C26H23Cl2FN5O: 510.1264, found 510.1259.
98001) was obtained from American Type Culture Collection. Asper-
gillus flavus (CGMCC 3.3950) was obtained from China General
Microbiological Culture Collection Center.
Candida albicans was grown on Modified Martin Broth at 28 °C
and Aspergillus flavus was grown on Czapek’s medium at 28 °C.
Antifungal activity assay
All the compounds were assayed by microbroth dilution.
Microbroth dilution
{3-(4-Chlorophenyl)-1-[(6-chloropyridin-3-yl)methyl]-1H-pyrazol-
5-yl}[4-(3-methoxyphenyl) piperazin-1-yl]methanone (3h): White
solid, yield 80.1%; m.p. 154–157 °C; IR (νmax cm−1): 1745 (C=N),
Test compounds were dissolved in distilled dimethylsulfoxide
and then were plated in 96-well microplates. Each tested compound
(256 µg mL−1 in DMSO) was transferred to each microplate well, to
be diluted in 100 µL of broth and 100 µL of inocula to obtain final
concentrations at 128, 64, 32, 16, 8, 4, 2, 1, 0.5 and 0.25 µg mL−1,
respectively. Dimethylsulfoxide never exceeded 1% v/v. After incuba-
tion at 28 °C for 48 h, the last tube remaining clear with no growth of
microorganism was recorded to represent MIC. The MICs were read
after incubation at 28 °C for 48 h. Growth controls consisting of media
and media with 1% v/v dimethylsulfoxide were employed.
1
1627 (C=O); H NMR (CDCl3, 400 MHz): 2.95 (s, 2H, CH2), 3.18
(s, 2H, CH2), 3.70 (s, 2H, CH2), 3.80 (s, 3H, OCH3), 3.87 (s, 2H, CH2),
5.54 (s, 2H, CH2), 6.44 (s, 1H, ArH), 6.48–6.53 (m, 2H, ArH), 6.62
(s, 1H, pyrazole–H), 7.20 (t, 1H, J = 8.2 Hz, ArH), 7.27 (d, 1H, J =
6.8 Hz, ArH), 7.39 (d, 2H, J = 8.5 Hz, ArH), 7.68 (dd, 1H, J1 = 8.2 Hz,
J2 = 2.5 Hz, ArH), 7.72 (d, 2H, J = 8.5 Hz, ArH), 8.39 (d, 1H, J =
2.5 Hz, ArH). HRMS calcd for [M+H]+ C27H26Cl2N5O2: 522.1464,
found 522.1468.
[1-(4-tert-Butylbenzyl)-3-(4-chlorophenyl)-1H-pyrazol-5-yl](4-
phenylpiperazin-1-yl)methanone (3i): White solid, yield 79.9%; m.p.
205–208 °C; IR (νmax cm−1): 1637 (C=O); 1H NMR (CDCl3, 400 MHz):
1.14 (s, 9H, C(CH2)3), 2.58 (s, 2H, CH2), 3.08 (s, 2H, CH2), 3.43 (s,
2H, CH2), 3.82 (s, 2H, CH2), 5.52 (s, 2H, CH2), 6.57 (s, 1H, pyra-
zole–H), 6.82 (d, 2H, J = 8.2 Hz, ArH), 6.90 (t, 1H, J = 7.2 Hz, ArH),
7.17–7.24 (m, 3H, ArH), 7.24–7.28 (m, 3H, ArH), 7.38 (d, 2H, J =
8.4 Hz, ArH), 7.76 (d, 2H, J = 8.4 Hz, ArH). HRMS calcd for [M+H]+
C31H34ClN4O: 513.2421, found 513.2419.
This work was supported the Independent Innovation Founda-
tion of Shandong University (2009JC007).
Received 29 March 2013; accepted 3 June 2013
Paper 1301866 doi: 10.3184/174751913X13734652599909
Published online: 9 August 2013
References
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(2-fluorophenyl)piperazin-1-yl]methanone (3j): White solid, yield
64.0%; m.p. 167–169 °C; IR (νmax cm−1): 1639 (C=O); 1H NMR
(CDCl3, 400 MHz): 1.16 (s, 9H, C(CH2)3), 2.46 (s, 2H, CH2), 2.98 (s,
2H, CH2), 3.42 (s, 2H, CH2), 3.84 (s, 2H, CH2), 5.52 (s, 2H, CH2), 6.57
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m.p. 220–222 °C; IR (νmax cm−1): 1638 (C=O); H NMR (CDCl3,
400 MHz): 1.14 (s, 9H, C(CH2)3), 2.47 (s, 2H, CH2), 2.97 (s, 2H,
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