Synthesis, characterization, and antimicrobial activity of novel heterocyclic compounds containing a ferrocene unit via Michael addition reaction

Article abstract of DOI:10.1007/s11164-013-1489-1

A series of novel heterocyclic compounds containing a ferrocene unit were synthesized by reacting ferrocenylchalcone with pyrazolyl amine or triazolyl amine via Michael addition reaction. A novel synthetic route of ferrocenylchalcones was developed in whi

Full text of DOI:10.1007/s11164-013-1489-1

Res Chem Intermed
DOI 10.1007/s11164-013-1489-1
Synthesis, characterization, and antimicrobial activity
of novel heterocyclic compounds containing a ferrocene
unit via Michael addition reaction
•
Yuting Liu Hanli Zhang Dawei Yin Dan Chen
•
•
Received: 25 June 2013 / Accepted: 12 November 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract A series of novel heterocyclic compounds containing a ferrocene unit
were synthesized by reacting ferrocenylchalcone with pyrazolyl amine or triaz-
olyl amine via Michael addition reaction. A novel synthetic route of ferroce-
nylchalcones was developed in which cinnamic acid and ferrocene were used as
starting materials and phosphorus pentachloride was used as acylating agent. The
structure of these newly synthesized compounds was confirmed by IR, elemental
analysis, 1H NMR, and 13C NMR. The antibacterial activity and minimum
inhibitory concentration (MIC) of all compounds were screened for Escherichia
coli, Saccharomyces aureus, Streptococcus, Actinomycete, and Saccharomyces
cerevisiae in vitro by filter paper disc diffusion method, and agar dilution method,
respectively. The compounds 4a–c exhibited moderate to excellent antibacterial
activity in comparison to Ampicillin used as reference drug and MIC values
between 1 and 64 lg/mL. Among these tested compounds, 4a, 4b show the best
inhibitory activity.
Keywords Heterocyclic compounds ꢀ Ferrocenylchalcone ꢀ Pyrazolyl
amine ꢀ Triazolyl amine ꢀ Synthesis ꢀ Michael addition reaction ꢀ
Antimicrobial activity
Y. Liu ꢀ H. Zhang (&) ꢀ D. Yin ꢀ D. Chen
Key Laboratory of Auxiliary Chemistry & Technology for Chemical Industry, Ministry of
Education, Shaanxi University of Science & Technology, Xi’an 710021, Shaanxi, China
e-mail: zhanghl1213@126.com
Y. Liu ꢀ H. Zhang ꢀ D. Yin ꢀ D. Chen
School of Chemistry and Chemical Engineering, Shaanxi University of Science & Technology,
Xi’an 710021, Shaanxi, China
123

L. Yuting et al.
Introduction
Bioorganometallics was defined as the study of biomolecules or biologically active
molecules that contain at least one carbon directly bound to a metal or metalloid by
´
Gerard Jaouen in 1985 [1–5].
Ferrocene is known to exhibit a broad spectrum of biological activity and has
become a useful organometallic compound in the field of pharmaceutical sciences due
to its unique structure. Many ferrocenyl compounds display interesting cytotoxic, anti-
tumur [5, 6], antimalarial [7, 8], anticancer, and antifungal HIV and DNA-cleaving
activities [9–11]. On the other hand, the ferrocenylchalcone, an important interme-
diate in organic synthesis, and application more widely, is normally used for Michael
addition reaction with amine compounds, which can introduce other groups having
biological activity into the ferrocene group, such as producing pyrazole derivatives via
reacting with hydrazine [12, 13], pyrimidine derivatives by treating with thiourea [14],
and pyridine derivatives though reacting with nitrile [15], etc.
The Michael addition reaction plays an important role in organic synthesis
reaction of building the carbon–sulfur bond and carbon–nitrogen bond [16–18]. The
Michael addition of amine and ferrocenylchalcone usually requires a certain amount
of strong base or Lewis acid as catalyst.
The pyrazole ring is a prominent structure found in numerous pharmaceutically active
compounds. Pyrazoles have been implemented as antileukemic [18–22] antiproliferative
[23, 24], antitumor agents [25–29], as insecticides [30], and as anti-inflammatory and
antimicrobial agents [31–33]. On the other hand, the derivatives of 1,2,4-triazole possess
a wide range of antimicrobial [34–36] and antitumor activities [34–37], and as potent
tubulin polymerization inhibitors [38, 39]. The following 1,2,4-triazole derivatives are
applied in medicine: alprazolam (tranquilizer), estazolam (hypnotic, sedative, tranquil-
izer), trapidil (hypotensive), trazodon (antidepressant, anxiolytic), and so on [34].
Recent studies have suggested that a combination of a ferrocenyl moiety with
heterocyclic structures may increase their biological activities or create new medicinal
properties [40]. Heterocyclic compounds containing ferrocenyl have been reported on
less during recent years. For instance, Kumar et al. [41, 42] have synthesized 1,2,3-
triazole tethered b-lactam–ferrocene and b-lactam–ferrocenylchalcone chimeric
scaffolds and evaluated them for anti-tubercular activity. In view of above-mentioned
facts, we envisioned the synthesis of novel heterocyclic compounds containing
ferrocenyl and pyrazolyl or triazolyl derivatives that may have significant biological
activities. Here, a series of novel compounds containing a ferrocenyl group were
synthesized by using ferrocenylchalcone and 1-(tetrahydro-2H-thiopyran-4-yl)-1H–
pyrazol-4-amine, 5-methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazol-4-amine,
or 1-(tetrahydro-2H-thiopyran-4-yl)-1H-1,2,4-triazol-3-amine via Michael addition
reaction in the presence of triethylamine.
Experimental
All the reagents described in this paper are commercially available, and all solvents
were freshly distilled before use. The melting points were recorded on a X-4
123

Novel heterocyclic compounds containing a ferrocene
microscopic melting point meter, apparatus and are uncorrected. Elemental analysis
(C, H and N) was recorded on a Vario EL III. IR spectra were recorded on a
1
VECTOR-22 instrument and using KBr pellets. H NMR and 13C NMR spectra
were recorded on an ADVANCE III 400 MHz instrument and using CDCl3 as
solvent and SiMe4 as an internal reference.
Procedure for synthesis of ferrocenylchalcone (1)
A mixture of 1.48 g (0.01 mol) cinnamic acid and 2.50 g (0.012 mol) phosphorus
pentachloride in a drying three-neck flask (100 mL) was stirred at 20 °C for 2 h. Then,
4.8 mL (0.08 mol) carbon disulfide, 1.48 g (0.008 mol) ferrocene, and 1.33 g
(0.01 mol) anhydrous aluminum chloride were added to the above stirred solution, and
the reaction mixture was kept under stirring for 3 h at 45 °C. Carbon disulfide was
removed by vacuum distillation and 5.5 mL water and sodium bicarbonate were
added, respectivel,y so that no bubbles appeared. The solid obtained by filtration was
washed well with 5 % hydrochloric acid, 5 % sodium hydroxide, and water to pH 7,
finally obtaining a purple red solid. The solid was recrystallized from CH3CH2OH/
H2O (mCH CH OH : mH Oꢁ ¼ ꢁ1 : 1) with the addition of activated carbon, when
3
2
2
2.17 g red needle crystals were obtained. The yield was 85.8 %, m.p. 139–140 °C.
IR (KBr, tmax/cm-1): 3,114, 3,085, 3,055, 3,025, 1,648 (tC=O), 1,611, 1,590
1
(tC=C), 1,496, 1,451; H NMR (CDCl3, 400 M, TMS, d: ppm): 4.25 (s, 5H, Fc–H),
4.63–4.94 (d, 4H, Fc–H),7.14–7.18 (d, 1H, =CH), 7.28–7.69 (m, 5H, Ar–
H),7.81–7.83 (d, 1H, =CH); Anal. Calcd. for C19H16FeO: C, 72.18 %; H, 5.10 %;
Found: C, 72.15 %; H, 5.12 %.
General procedure for synthesis of compounds (3a–c)
Two mmol amine (2a–c), 0.28 g (2.4 mmol) tetrahydro-2H-thiopyran-4-alcohol,
0.63 g (2.4 mmol) triphenylphosphine, 0.42 g (2.4 mmol) DEAD and 10 mL THF
were added to a dry three-neck flask (50 mL), and the reaction mixture was stirred
at room temperature overnight. It was then concentrated under reduced pressure and
0.66 g (12 mmol) iron powder and 20 mL 95 % ethanol were added to the stirred
solution, and the reaction mixture was heated at 50 °C. Next, 0.5 mL concentrated
hydrochloric acid was added dropwise, and the reaction mixture was heated to
reflux for 4 h, cooled, and filtered. The solution from reduced pressure condensation
was washed with 30 mL (1 M) hydrochloric acid and ethyl acetate (10 mL 9 2),
and the water phase was adjusted to pH [ 9 with sodium hydroxide and extracted
with ethyl acetate (10 mL 9 2).The combined extract was dried and evaporated to
dryness, to provide a yellow solid. The solid was recrystallized from CH3CH2OH/
H2O with the addition of activated carbon.
1-(Tetrahydro-2H-thiopyran-4-yl)-1H-pyrazol-4-amine (3a)
The product of 3a was white powder 0.27 g, the yield was 91.6 %, m.p.
1
192–194 °C. H NMR (CDCl3, 400 M, TMS, d: ppm): 1.60–1.74 (m, 2H, –CH–
CH2–), 1.93–1.96 (d, 2H, –CH–CH2–), 2.79 (s, 2H, –NH2), 3.85–3.95 (m, 1H, –CH–
123

L. Yuting et al.
); 4.26 (s, 4H, –CH2–S–CH2–), 6.56 (s, 1H, pyrazole-H), 6.65 (s, 1H, pyrazole-
H);13C NMR (CDCl3, 100 M, TMS, d: ppm):28.39, 32.26, 52.51, 111.54, 124.66,
146.88; Anal. Calcd. for C8H13N3S: C, 52.43 %; H, 7.15 %; N, 22.93 %; Found: C,
52.40 %; H, 7.18 %; N, 22.89 %.
5-Methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazol-4-amine (3b)
The product of 3b was white powder 0.26 g, the yield was 65.99 %, m.p. 93–95 °C.
1H NMR (CDCl3, 400 M, TMS, d: ppm): 1.48 (s, 3H, –CH3), 1.66–1.76 (m, 2H, –
CH–CH2–), 1.94–1.98 (d, 2H, –CH–CH2–), 2.82 (s, 2H, –NH2), 3.86–3.92 (m, 1H, –
CH–); 4.267 (s, 4H, –CH2–S–CH2–), 6.67 (s, 1H, pyrazole-H); 13C NMR (CDCl3,
100 M, TMS, d: ppm): 11.08, 28.38, 32.23, 52.51,114.26,146.89, 150.01; Anal.
Calcd. for C9H15N3S: C, 54.79 %; H, 7.66 %; N, 21.30 %; Found: C, 54.82 %; H,
7.64 %; N, 21.28 %.
1-(Tetrahydro-2H-thiopyran-4-yl)-1H-1,2,4-triazol-3-amine (3c)
The product of 3c was white powder 0.17 g, the yield was 46.20 %, m.p. 105–106 °C.
1H NMR (CDCl3, 400 M, TMS,d: ppm): 1.84–1.91 (m, 2H,–CH–CH2–), 2.08–2.11 (d,
2H, –CH–CH2–), 2.87 (s, 2H, –NH2), 4.06–4.23 (m, 5H,–CH–,–CH2–S–CH2–
coupling superimpose), 7.70 (s, 1H, triazole-H); 13C NMR (CDCl3, 100 M, TMS, d:
ppm): 28.39, 31.77, 57.03, 139.95, 163.21; Anal. Calcd. for C7H12N4S: C, 45.63 %; H,
6.56 %; N, 30.41 %; Found: C, 45.60 %; H, 6.52 %; N, 30.38 %.
General procedure for synthesis of compounds (4a–c)
A mixture of 1 mmol compound 3a–c, 0.32 g (1 mmol) compound 1, 10.01 g
triethylamine and 10 mL ethanol in a drying three-neck flask (50 mL) was stirred at
room temperature overnight. Then, the black solid was obtained by concentration
under reduced pressure. The crude product was purified by column chromatography
on silica gel eluted with (mmethanol:mdichloromethane = 1:10) to give the compound 4a–
c as needle crystals.
1-Ferrocenyl-3-phenyl-3-((1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazol-4-
yl)amino)propan-1-ketone (4a)
The product of 4a was yellow needle crystals (0.18 g), the yield was 36.07 %, m.p.
1
156–158 °C. H NMR (DMSO, 400 M, TMS, d: ppm): 1.70–1.78 (m, 2H,–CH–
CH2–), 1.91–1.94 (d, 2H, –CH–CH2–), 2.50–2.51 (m, 2H, S–CH2–), 2.87–2.89/
5.39–5.48 (m, 2H, C–CH2–CH), 3.02–3.04 (d, 2H, –S–CH2–), 3.62–3.67 (m, 1H,
CH–Ar),4.03 (s, 5H, Fc–H), 4.12 (m, 1H, C–CH–C), 4.13 (brs, 1H, N–H), 4.14–4.69
(m, 4H, Fc–H), 7.25–7.43 (m, 5H, Ar–H), 7.53/7.89 (s, 2H, pyrazole-H); 13C NMR
(DMSO, 100 M, TMS, d: ppm): 29.23, 43.60, 46.00, 48.35, 59.43, 67.26, 67.86,
69.48, 70.59, 70.70, 74.89, 119.49, 124.56, 127.04, 130.24, 131.42, 143.88, 154.21;
Anal. Calcd. for C27H29FeN3OS: C, 64.93 %; H, 5.85 %; N, 8.41 %; Found: C,
64.90 %; H, 5.88 %; N, 8.38 %.
123

Novel heterocyclic compounds containing a ferrocene
1-Ferrocenyl-3-phenyl-3-((5-methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazol-
4-yl)amino) propan-1-ketone (4b)
The product of 4b was yellow needle crystals (0.18 g), the yield was 31.19 %, m.p.
1
166–167 °C. H NMR (DMSO, 400 M, TMS, d: ppm): 1.70–1.74 (m, 2H, –CH–
CH2–), 1.89–1.91 (d, 2H,–CH–CH2–), 2.13 (s, 3H, –CH3), 2.50–2.51 (m, 2H, S–
CH2–), 2.76–2.81/5.38–5.46 (m, 2H, C–CH2–CH), 3.00–3.03 (d, 2H, S-CH2–),
3.48–3.57 (m, 1H, CH–Ar), 3.95 (s, 5H, Fc–H), 4.02 (m, 1H, C–CH–C), 4.04 (brs,
1H, N–H), 4.05–4.54 (m, 4H, Fc–H), 7.87 (s, 1H, pyrazole-H);13C NMR (DMSO,
100 M, TMS, d: ppm): 11.16, 29.02, 43.65, 46.07, 48.32, 59.44, 67.24, 67.82, 69.48,
70.57, 70.72, 74.89, 120.64, 124.34, 127.05, 130.25, 143.85, 153.99; Anal. Calcd.
for C28H31FeN3OS: C,65.49 %; H, 6.09 %; N, 8.18 %; Found: C,65.54 %; H,
6.06 %; N, 8.21 %.
1-Ferrocenyl-3-phenyl-3-((1-(tetrahydro-2H-thiopyran-4-yl)-1H-1,2,4-triazol-3-
yl)amino)propan-1-ketone (4c)
The product of 4c was yellow needle crystals (0.23 g), the yield was 46.00 %, m.p.
1
188–190 °C. H NMR (DMSO, 400 M, TMS, d: ppm): 1.74–1.82 (m, 2H, –CH–
CH2–), 1.96–1.98 (d, 2H, –CH–CH2–), 2.55–2.60 (m, 2H, S–CH2–), 2.74–2.78/
5.40–5.49 (m, 2H, C–CH2–CH), 3.02–3.04 (d, 1H, S–CH2–), 3.48–3.57 (m, 1H,
CH–Ar), 4.04 (s, 5H, Fc–H), 4.19–4.20 (m, 1H, C–CH–C), 4.21 (brs, 1H, N–H),
4.23–4.62 (m, 4H, Fc–H), 8.37 (s, 1H, triazole-H); 13C NMR (DMSO, 100 M, TMS,
d: ppm): 28.98, 43.74, 45.75, 48.30, 59.24, 67.11, 67.70, 69.27, 69.32, 70.06, 70.72,
75.01, 127.07, 124.34, 127.99, 130.26, 142.46, 143.78, 153.87, 155.49; Anal. Calcd.
for C26H28FeN4OS: C, 62.40 %; H, 5.64 %; N, 11.20 %; Found: C,62.38 %; H,
5.68 %; N, 11.15 %.
Antimicrobial activity
Antibacterial activity
Antibacterial activity was determined in acetone by the filter paper disc method
[43]. Five bacterial strains (Escherichia coli, Saccharomyces aureus, Streptococcus,
Actinomycete, and Saccharomyces cerevisiae) were selected for the test.
Beef extract in agar medium was prepared by dissolving peptone (10 g), beef
extract (5 g), sodium chloride (5 g), and agar (20 g) in distilled water (1,000 mL)
and adjusting the pH to 7.5 or 7.6, and sterilized by dry heat at 120 °C for 30 min.
Normal saline was used to make a suspension of strains for lawning. A loopful of a
particular strain was transferred to normal saline to get a suspension of the
corresponding species (106 cfu/mL). Agar medium (15 mL) was poured into each
sterile Petri dish. Sterile filter paper discs (6 mm in diameter) saturated with the
solution of test compounds (0.01 g of the synthesized compounds were dissolved
separately in acetone to get a concentration of 5 mg/mL) were placed on the surface
of an agar plate inoculated with 0.1 mL suspension. To ensure that the solvent had
no effect on the bacterial growth, a control was performed with the test medium
123

L. Yuting et al.
Table 1 Antimicrobial activity of the compounds 1, 3a–c and 4a–c
Compound no.
(5 mg/mL)
Zone of Inhibition (mm)
E. coli
S. aureus
Streptococcus
Actinomycete
S. cerevisiae
1
18.3
26.7
24.6
20.3
32.1
30.0
28.2
-
5.6
6.9
6.2
5.5
12.2
11.1
8.4
-
8.3
8.9
6.1
9.7
8.7
6.3
13.7
12.5
10.0
-
6.5
7.4
3a
3b
8.0
6.9
3c
7.1
5.5
4a
15.5
14.8
11.3
-
12.9
11.8
10.6
-
4b
4c
Acetone
Ampicillin
28.4
7.8
10.4
8.7
15.5
The data in the table are average values of three experiments, Acetone as blank, - indicates no antimi-
crobial activity, Ampicillin was used as reference drug
supplemented with the filter paper discs (6 mm in diameter) saturated with acetone
and treated as blank in the experiments. The plates were prepared in triplicate and
were incubated at 37 °C for 2–4 days for evaluating antimicrobial activity. The
diameters of inhibition zones (in mm) of triplicate sets were measured and the
results are given in Table 1. Ampicillin was used as reference drug.
For the antibacterial activity, the compounds were dissolved in acetone. Further
dilutions of the compounds and reference drug in the test medium were prepared at
the required quantities of 256, 128, 64, 32, 16, 8, 4, 2, and 1 lg/mL concentrations
with Mueller–Hinton agar. The minimum inhibitory concentrations (MIC) were
determined using the agar dilution method. A control test was also performed
containing inoculated broth supplemented with just acetone at the same dilutions
used in our experiments and found to be inactive in the culture medium. All the
compounds were tested for their in vitro growth inhibitory activity against different
bacteria and the results are summarized in Table 2.
Table 2 Minimum inhibitory concentrations (MIC) of the compounds 1, 3a–c and 4a–c in lg/mL
Compounds no.
E. coli
S. aureus
Streptococcus
Actinomycete
S. cerevisiae
1
8
2
128
64
64
64
64
64
16
16
32
32
64
64
64
64
32
32
32
64
64
64
3a
3b
4
64
64
3c
8
128
32
128
32
4a
1
4b
2
32
32
4c
64
2
64
32
Ampicillin
64
16
Acetone as blank; Ampicillin was used as reference drug
123

Novel heterocyclic compounds containing a ferrocene
Results and discussion
In this study, we report the synthesis of novel heterocyclic compounds containing a
ferrocene unit. The synthetic strategy for desired compounds 4a–c in three steps is
depicted in Scheme 1. The compound 1 (ferrocenylchalcone) was traditionally
synthesized by using acetylferrocene and aromatic aldehyde as starting materials. In
order to avoid problems in the purification process of acetylferrocene, we designed
one-pot synthesis of compound 1 by Friedel–Crafts acylation of cinnamic acid with
ferrocene using phosphorus pentachloride as acylating agent in 85.84 % yields. This
method had the advantage of easily available starting materials, easy procedure, and
good yields. The characteristic vibration of the carbonyl group in the ferrocenyl-
1
chalcone scaffold was observed at 1,648/cm. In the H NMR spectra of compound
1, the olefinic Ha and Hb protons have two bound doublets at d (7.81–7.83) and
(7.14–7.18) ppm. These indicate that the carbonyl group and olefinic group are
present in the ferrocenylchalcone scaffold. The rest of the signals for protons
appeared in the expected regions. In addition, protons of the amino group of
compounds 3a–c appeared as a singlet at d 2.79, 2.82, and 2.87 ppm in the 1H NMR
spectra, respectively. The synthesized compounds 3a–c were then treated with
Scheme 1 Synthesis route of compounds 1, 3a–c, and 4a–c. R:a,-H:b,-CH3. Reaction reagents and
conditions: (1) PCl5, 20 °C, 2 h; (2) CS2/AlCl3, 45 °C, 3 h; (3) i: DEAD, PPh3, THF, rt; ii: Fe,
95 %ethanol, HCl, reflux 4 h; (4) triethylamine, ethanol, rt
123

L. Yuting et al.
compound 1 to obtain target compounds 4a–c. Successful synthesis of compounds
4a–c was confirmed by the disappearance of the signals at d (7.81–7.83) and
(7.14–7.18) ppm in H NMR spectra of the compound 1 which are related to the
1
olefinic Ha and Hb protons, respectively, coupled with two broad multiplet d
(1.70–1.78) and (1.91–1.94) ppm, d (1.70–1.74) and (1.89–1.91) ppm, d (1.74–1.79)
and (1.96–1.98) ppm in H NMR spectra of the compounds 4a–c which are related
1
1
to –CH-CH2-, respectively. In H NMR spectra of compounds 4a–c, a broad single
at d 4.13, 4.04, and 4.21 ppm due to N–H protons, respectively. The target
compounds were well characterized by data of 13C NMR.
The antimicrobial activity of test compounds was assessed in side-by-side
comparisons with blank experiments and reference drug. The investigation of
combined data revealed that some tested compounds showed moderate to excellent
antibacterial activities against five tested strains and the synthesized compounds 1,
3a–c, and 4a–c showing MIC values between 8 and 128, 2 and 128, and 1 and
64 lg/mL, respectively. Compounds 3a and 4c exhibited the best inhibitory
activities against E. coli besides reference drug; their zones of inhibition were 26.7
and 28.2 mm, respectively. Compounds 3a and 3b showed better inhibitory
activities against Actinomycete than reference drug; their zones of inhibition were
9.7 and 8.9 mm, respectively. Compounds 4a–c showed stronger inhibitory
activities against S. aureus, Streptococcus, and Actinomycete in comparison to
reference drug and MIC values between 1 and 64 lg/mL. Among these tested
compounds, compounds 4a and 4b exhibited the broadest spectrum and stronger
inhibitory activities.
From what has been discussed above, we draw out from these novel heterocyclic
compounds containing a ferrocene unit some speculative antimicrobial mechanisms.
Ferrocenylchalcone had a relatively strong inhibitory effect on microbials, while
heterocyclic compounds containing a ferrocene unit displayed a stronger antibac-
terial activity than ferrocenylchalcone due to the group of heterocyclic compounds
of pyrazolyl or triazolyl derivatives being introduced. On the other hand, 4a and 4b
showed different antimicrobial activities against the five tested strains since the
substituent’s steric hindrance of 4a is less than for 4b.
Conclusion
In summary, we have developed a simple and efficient method for the synthesis of
ferrocenylchalcone. A series of novel heterocyclic compounds containing a
ferrocene unit were synthesized and their antimicrobial activity has been tested.
Compounds 4a and 4b showed the best inhibitory activity. This work offers an
excellent framework in this field, which may lead to the discovery of potent
antibacterial agents.
Acknowledgments This work was supported by the Natural Science Foundation of Shaanxi Province,
People’s Republic of China (Project no.: 2009JZ002). The authors gratefully acknowledge Dr. Liu
Baojian, Analytical Center, Shaanxi University of Science & Technology, China, for his help in
characterization of the structure; The authors also thank Professor Zhang Zhiwei, Micro Lab, Shaanxi
University of Science & Technology, China, for her help in performing the antibacterial activities.
123

Novel heterocyclic compounds containing a ferrocene
References
1. M. Patra, G. Gasser, N. Metzler-Nolte, Dalton Trans. 41, 6350–6358 (2012)
2. G. Gasser, N. Metzler-Nolte, Curr. Opin. Chem. Biol. 16(1–2), 84 (2012)
3. N. Chavain, C. Biot, Curr. Med. Chem. 17(25), 2729 (2010)
4. C.G. Hartinger, P.J. Dyson, Chem. Soc. Rev. 38(2), 391 (2009)
5. C. Ornelas, J. New, New J. Chem. 35, 1973 (2011)
6. P. Messina, E. Labb, O. Buriez et al., Chemistry 18(21), 6581 (2012)
7. C. Roux, C. Biot, Future Med. Chem. 4(6), 783 (2012)
´
8. C. Biot, W. Castro, C.Y. Botte, M. Navarro, Dalton Trans. 41(21), 6335 (2012)
9. C. Biot, N. Franc, L. Maciejewski ois et al., Bioorg. Med. Chem. Lett. 10, 839 (2000)
10. J. Zhang, Appl. Organomet. Chem. 22, 6 (2008)
11. A.K. Kondapi, N. Satyanarayana, A.D. Saikrishna et al., Arch. Biochem. Biophys. 450, 123 (2006)
12. F. Shan, L. Hen-Dong, G. Yong et al., Appl. Chem. 27(4), 474 (2010)
13. Jinming Y. Suzhou: Suzhou University. 11–31 (2006)
14. W. Bing, G. JianBo, N. Yan et al., Org. Chem. 28(5), 791 (2008)
15. S. Toma, M. Putala, M. Salisova et al., Collect. Czech. Chem. C 52, 395 (1987)
16. K. Shibata, I. Katsuyama, M. Matsui et al., B.Chem. Soc. Jap. 63, 3710 (1990)
17. Z. Weijuan, J. Shunjun, S. Zhiliang et al., J. Organomet. Chem. 691(7), 1356 (2006)
18. J. Shunjun, S. Zhiliang, G. Dagong et al., J. Organomet. Chem. 689(10), 1843 (2004)
19. F. Marguerite, N.M. Frederick et al., J. Am. Chem. Soc. 69(10), 2466 (1947)
20. C. Licen, H. Lijiao, Y. Jiaxin et al., Bioorg. Med. Chem. 15(4), 1732 (2007)
21. F. Manetti, C. Brullo, M. Magnani et al., J. Med. Chem. 51, 1252 (2008)
22. G.M. Nitulescu, C. Draghici, A.V. Missir et al., Eur. J. Med. Chem. 45(11), 4914 (2010)
23. R.E. Sammelson, P. Caboni, K.A. Durkin et al., Bioorg. Med. Chem. 12(12), 3345 (2004)
24. G. Daidone, D. Raffa, B. Maggio et al., Eur. J. Med. Chem. 39(3), 219 (2004)
25. L. Juan, Z. Yanfang, Z. Xianglin et al., Archiv der Pharmazie Chem. life Sci. 339(11), 593 (2006)
26. S. Schenone, O. Bruno, A. Ranise et al., Bioorg. Med. Chem. Lett. 14, 2511 (2004)
27. X. Yong, F. Chuandong, Z. Baoxiang et al., Eur. J. Med. Chem. 43(11), 2347 (2008)
28. A.M. Farag, A.S. Mayhoub, S.E. Barakat et al., Bioorg. Med. Chem. 16(8), 4569 (2008)
29. X. Yong, D. Zhiwu, Z. Baoxiang et al., Bioorg. Med. Chem. 15(22), 6893 (2007)
30. A.A. Bekhit, H.T. Fahmy, S.A. Rostom et al., Eur. J. Med. Chem. 38(1), 27 (2003)
31. A.B. Adnan, T. Abdel-Aziem et al., Bioorg. Med. Chem. 12(8), 1935 (2004)
32. A.A. Bekhit, A. Hymete, A.B.A. El-Din et al., Mini-Rev. Med. Chem. 10(11), 1014 (2010)
33. G.B. Pier, B. Italo, C. Paolo et al., Bioorg. Med. Chem. 11(6), 965 (2003)
34. K. Sztanke, T. Tuzimski, J. Rzymowska et al., Eur. J. Med. Chem. 43(2), 404 (2008)
´
35. K. Sztanke, K. Pasternak, A. Sidor-Wojtowicz et al., Bioorg. Med. Chem. 14(11), 3635 (2006)
36. H. Bayrak, A. Demirbas, S.A. Karaoglu et al., Eur. J. Med. Chem. 44(3), 1057 (2009)
37. R. Romagnoli, P.G. Baraldi, O. Cruz-Lopez et al., J. Med. Chem. 53, 4248 (2010)
38. Q. Zhang, Y. Peng, X.I. Wang et al., J. Med. Chem. 50(4), 749 (2007)
39. O. Xiaohu, C. Xiaoling et al., Bioorg. Med. Chem. Lett. 15(23), 5154 (2005)
40. T.C. Gu¨nseli, D. Seda, C. Abban et al., J. Organomet. Chem. 696, 613 (2011)
41. K. Kumar, P. Singh, L. Kremer et al., Dalton Trans. 41(19), 5778 (2012)
`
42. K. Kumar, S. Carrere-Kremer, L. Kremer et al., Dalton Trans. 42(5), 1492 (2013)
43. R. Cruickshank, J.P. Duguid, B.P. Marion, Medicinal Microbiology, vol. 2 12th edn. (Churchill
Livingstone, London, 1975), p. 196
123