Synthesis of new fluorescent pyrazolo[4,3-a]acridine derivatives having strong antibacterial activities

Article abstract of DOI:10.3184/174751914X13932618023986

New 3H-pyrazolo[4,3-a]acridine derivatives have been prepared by the reaction of 1-alkyl-5-nitro-1H-indazole with phenylacetonitrile and 2-(4-bromophenyl)acetonitrile in basic conditions via the nucleophilic substitution of hydrogen and concomitant cyclisation. The new compounds exhibited potent antibacterial activities and their antibacterial activities against Gram positive (Staphylococcus aureus, methicillin resistant S. aureus and Bacillus subtilis) and Gram negative bacterial (Pseudomonas aeruginosa and Escherichia coli) species were determined. The fluorescence properties of these derivatives were also studied.

Full text of DOI:10.3184/174751914X13932618023986

202 RESEARCH PAPER
VOL. 38 APRIL, 202–207
JOURNAL OF CHEMICAL RESEARCH 2014
Synthesis of new fluorescent pyrazolo[4,3-a]acridine derivatives having
strong antibacterial activities
Leila Rezaei Daghigh, Mehdi Pordel* and Abolghasem Davoodnia
Department of Chemistry, Mashhad Branch, Islamic Azad University, Mashhad, Iran
New 3H‑pyrazolo[4,3‑a]acridine derivatives have been prepared by the reaction of 1‑alkyl‑5‑nitro‑1H‑indazole with
phenylacetonitrile and 2‑(4‑bromophenyl)acetonitrile in basic conditions via the nucleophilic substitution of hydrogen and
concomitant cyclisation. The new compounds exhibited potent antibacterial activities and their antibacterial activities against
Gram positive (Staphylococcus aureus, methicillin resistant S. aureus and Bacillus subtilis) and Gram negative bacterial
(Pseudomonas aeruginosa and Escherichia coli) species were determined. The fluorescence properties of these derivatives
were also studied.
Keywords: 5‑nitro‑1H‑indazole, nucleophilic substitution of hydrogen, pyrazolo[4,3‑a]acridine, antibacterial agents, fluorescence,
emission and absorption spectra
Nitrogen heterocyclic compounds have long interested organic
and inorganic researchers because they constitute an important
class of natural and non‑natural products, many of which
exhibit useful biological activities and unique electrical and
optical properties.1–3 Pyrazoles have attracted much attention
recently because of their synthetic accessibility and their
diverse chemical and biological properties. Some of the most
important biological activities of pyrazoles are the effective
antirheumatoidal (SC‑58635 Celecoxib), antiviral agents
(Pyrazomycin), hormone oxytocin agonists (WAY VNA‑
932) and selective Human C1s inhibitors.4 In addition, the
photophysical properties of pyrazoles have attracted interest in
both aqueous and non‑aqueous solvents as well as in various
microheterogeneous media due to the possibility of charge
transfer (CT) emission.5
As an important type of tricyclic nitrogen heterocycle,
acridine derivatives are one of the oldest classes of photoactive
and bioactive compounds that are widely used for the production
of dyes and some valuable drugs. In particular, some of them are
found to be efficient fluorescent chemosensors for recognition
of transition metal ions such as Hg(II)6 and emitters for
luminescence studies,7 as well as antibacterial,8,9 antiviral,10,11
antiprion,12 and antimalarial13–17 agents. Some work in these
areas continues, but recent research has focused mainly on
their utility as anticancer18,19 and antitumour20,21 drugs. This is
because of the ability of the acridine chromophore to intercalate
within the double‑stranded DNA structure and inhibit
topoisomerase enzymes. A combination of the acridine moiety
with the pyrazole nucleus may enhance these properties.
Prompted by this information and in continuation of
our research work on the synthesis of fluorescent22–27 and
bioactive28–31 nitrogen heterocyclic compounds, we aimed
to obtain new derivatives of the 3‑alkyl‑3H‑pyrazolo[4,3‑a]
acridine‑11‑carbonitrile, via the nucleophilic substitution
of
hydrogen
in
1‑alkyl‑5‑nitro‑1H‑indazoles
with
phenylacetonitrile and with 2‑(4‑bromophenyl)acetonitrile in
basic solution, and to evaluate their spectroscopic properties
and biological activities.
Results and discussion
As depicted in Scheme 1, the synthesis of the new compounds
commenced with the preparation of 1‑alkyl‑5‑nitro‑1H‑
indazoles 1a–e from 5‑nitro‑1H‑indazole, by treatment with
a variety of different alkyl halides in DMF in the presence
of KOH, according to a literature method.32 The reaction of
1‑alkyl‑5‑nitro‑1H‑indazoles with phenylacetonitrile 2a and
with 2‑(4‑bromophenyl)acetonitrile 2b, in basic MeOH solution,
led to the formation of the new 3‑alkyl‑3H‑pyrazolo[4,3‑a]
acridine‑11‑carbonitriles 3a–h via the nucleophilic substitution
of hydrogen.33 The cyclisation proceeds at room temperature
and in good yields (Scheme 1). As we have previously
reported,22–27 these reactions are accomplished by the
condensation of nitroarenes with different arylacetonitriles
and concomitant cyclisation. The following mechanism is
offered for the formation of compounds 3a–h. The ring closure
proceeds via an electrocyclic pathway following tautomerism
of nitrile A, whereby intermediate B is converted to C
followed by elimination of H2O, to afford 3a–h (Scheme 2).
The simple work‑up procedure was performed by filtration of
the precipitated product after the mixture was concentrated at
reduced pressure.
R'
R'
CH2CN
CN
O2N
2a: R'=H
2b: R'=Br
O2N
R-X
N
N
+
N
KOH, DMF
MeOH, KOH, 24h, rt
N
N
N
3a: R= Me, R'= H (57%)
3b: R= Et, R'= H (70%)
3c: R= n-Pr,R'= H (65%)
3d: R= n-Bu,R'= H (55%)
3e: R= Me,R'= Br (65%)
3f: R= Et, R'= Br (77%)
3g: R= n-Pr, R'= Br (80%)
R
H
N
5-nitro-1H-indazole
R
1a: R=Me
1b: R=Et
1c: R=n-Pr
1d: R=n-Bu
1e: R=iso-Bu
3h: R= iso-Bu, R'= Br (75%)
Scheme 1 Synthesis of new compounds 3a–h.
* Correspondent. E‑mail: mehdipordel58@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2014 203
R'
R'
R'
R'
a
2
b
,
N
H
N
C
N
C
C
π
6
H
O
a-
3
h
N
C
O
N
N
-
H
2O
N
N
-
H
2O
H
H
O
O
N
N
N
O
N
N
N
N
N
R
R
R
R
a-e
1
B
C
A
Scheme 2 Proposed reaction mechanism for the formation of compounds 3a–h.
The structure of products 3a–h was confirmed by NMR and
IRspectroscopyinadditiontomassspectralandmicroanalytical
data. The spectral details of all these are given in experimental
is designated the minimum inhibitory concentration (MIC).
Experimental details of the tests can be found in our earlier
studies.28–30
1
section. For example, in the expanded H NMR spectrum of
The antimicrobial tests performed on pyrazolo[4,3‑a]acridine
derivatives 3a–h confirmed that they are super‑effective
against both Gram‑positive and Gram‑negative bacteria and
some showed greater inhibitory activity against a number of
Gram‑positive and Gram‑negative bacteria than did the well‑
known antibacterial agents ampicillin and sulfamethoxazole.
Also, the results revealed that compounds 3e–h in which
the R′ substituent is a bromine function displayed greater
antibacterial activity than did 3a–d. Compound 3g was the most
potent of the tested compounds against both Gram‑positive and
Gram‑negative bacteria. We propose that the chain lengths and
bromine substituent might change the binding characteristics of
ligands to their respective receptors and, thereby, improve the
biological activities.
compound 3g, there is a doublet of doublets at δ 7.85 and two
doublet signals at 8.24 and 8.45 ppm attributed to the ring A
protons. Two doublet peaks at δ 7.89 and 8.00 are assignable
to the two ring C protons and a singlet peak at 9.10 ppm is
attributed to the D ring (Fig. 1).
The antibacterial activity of compounds 3a–h was tested
against a panel of strains of Gram positive [Staphylococcus
aureus, methicillin resistant S. aureus (MRSA), clinically
isolated S. aureus and Bacillus subtilis (ATCC 6633)] and
Gram negative bacterial [Pseudomonas aeruginosa (ATCC
27853) and Escherichia coli (ATCC 25922)] species (Table 1)
using a broth microdilution method as previously described.34
Sulfamethoxazole, ampicillin and penicillin G were used as
references. The lowest concentration of the antibacterial agent
that prevents growth of the test organism, as detected by lack
of visual turbidity (matching the negative growth control),
The compounds 3a–h were characterised by both UV‑Vis
and fluorescence spectra. The wavelength range of both
spectrophotometers used was 200–1000 nm. The fluorescence
Fig. 1 The expanded 1H NMR spectrum of compound 3g in the downfield region.

204 JOURNAL OF CHEMICAL RESEARCH 2014
Table 1 Antibacterial activity (MIC, μg mL–1) of references and newly synthesised compounds 3a–h
Staphylococcus aureus
(MRSA)
Bacillus subtilis
(ATCC 6633)
Pseudomonas aeruginosa
(ATCC 27853)
Escherichia coli
(ATCC 25922)
Compound
3a
3b
6
3
10
9
6
3
6
3
3c
3d
3
2
3
4
3
2
3
2
3e
3f
3g
2
2
1
6
2
2
0.50
3
1
1
1
3
1
1
1
3
3h
Sulfamethoxazole
Ampicillin
Penicillin G
16
62
0.06
16
0.50
8
62
125
–
16
8
–
absorption and emission spectra of 3a–h were recorded at
concentrations of 1×10–5 and 1×10–6 mol L–1 respectively in
dichloromethane (DCM). Figures 2 and 3 show the visible
absorption and emission spectra of compounds 3a–h.
The fluorescence intensity in these compounds can be
explained by efficient intramolecular charge transfer (ICT)
states from the donor site (endocyclic N) to the acceptor moiety
(CN group).22–27 Scheme 3 shows neutral and charge‑separated
mesomeric structures of 3a–h.
The fluorescence absorption and emission spectra of
compound 3h were measured in a variety of solvents such
as tetrahydrofuran (THF), dioxane and methanol. As shown
in Figs 4 and 5, the fluorescence absorption and emission
spectra of 3h in polar solvents exhibited a bathochromic shift.
Increasing solvent polarity stabilises the ICT excited‑state
molecule relative to the ground‑state molecule with the observed
redshift of the absorption maximum as the experimentally
observed result (Table 3). For example, in Table 3, one can
see that in the emission spectrum of 3h, λflu shifts from 430 to
458 nm as the solvent is changed from n‑heptane to methanol.
Table 2 shows the wavelengths of maximum absorbance
(λabs/nm), wavelengths of fluorescence excitation (λex/nm),
wavelengths of fluorescence emission (λflu/nm), values of
extinction coefficient (ε) and fluorescence quantum yield ΦF)
data. Values of the extinction coefficient (ε) were calculated as
the slope of the plot of absorbance versus concentration. The
fluorescence excitation (λex) wavelength at 390 nm (λex/nm) was
used for all compounds 3a–h. The fluorescence quantum yields
(ΦF) of compounds 3a–h were determined via comparison
methods, using fluorescein as a standard sample in 0.1 M NaOH
and MeOH solution.35 The absorbance and fluorescence spectral
properties (Table 2) of compounds 3a–d as well as 3e–h are
similar to each other, however, the fluorescence intensity of
compound 3d, having a butyl group had the maximal value.
Fig. 2 Visible absorption spectra of compounds 3a–h in DCM solution (1×10–5 mol L–1).
Fig. 3 Emission spectra of compounds 3a–h in DCM solution (1×10–6 mol L–1).

JOURNAL OF CHEMICAL RESEARCH 2014 205
Table 2 Photophysical data for absorption (abs) and fluorescence (flu) of 3a–h
Dye 3a 3b 3c 3d
395 395 395 395
8.7 8.0 7.2 5.5
390 390 390 390
455 455 455 455
0.45 0.47 0.50 0.52
3e
400
9.5
390
440
0.36
3f
398
8.2
390
440
0.37
3g
398
7.3
390
440
0.40
3h
398
5.2
390
440
0.42
λabs/nma
ε×10–4/(mol L–1)–1 cm–1b
λex/nmc
λflu/nmd
e
ΦF
aWavelengths of maximum absorbance.
bExtinction coefficient.
cWavelengths of fluorescence excitation.
dWavelengths of fluorescence emission.
eFluorescence quantum yield.
R'
R'
Table 3 Spectroscopic data for 3h at 298 K in dependence of the solvent
N
N
Solvent
λabs/nm
λflu/nm
C
C
Acetone
Dioxane
Methanol
n‑Heptane
Toluene
THF
410
405
415
390
395
400
410
456
450
458
430
440
450
456
N
N
N
N
N
N
R
R
DMF
Scheme 3 Neutral and charge‑separated mesomeric structures of 3a–h.
spectrometer in CDCl3. Chemical shifts are reported in ppm downfield
from TMS as internal standard; coupling constants J are given in Hz.
The mass spectra were recorded on a Varian Mat, CH‑7 instrument
at 70 eV. Elemental analysis was performed on a Thermo Finnigan
Flash EA microanalyser. All measurements were carried out at room
temperature.
Experimental
Methanol, N,N‑dimethylformamide (DMF), methyl iodide, ethyl
bromide, n‑propyl bromide, n‑butyl bromide, isobutyl bromide,
phenylacetonitrile and 2‑(4‑bromophenyl)acetonitrile were purchased
from Merck. Potassium hydroxide was purchased from Sigma–
Aldrich. All solvents were dried according to standard procedures.
Compounds 1a–e were synthesised as described in the literature.32
The microorganisms Bacillus subtilis ATCC 6633, Pseudomonas
aeruginosa ATCC 27853 and Escherichia coli ATCC 25922 were
purchased from the Pasteur Institute of Iran and S. aureus methicillin
resistant (MRSA) was isolated from different specimens which were
referred to the Microbiological Laboratory of Ghaem Hospital of
Medical University of Mashhad, Iran and its methicillin resistance was
tested according to the NCCLS guidelines.36
Absorption and fluorescence spectra were measured on Varian
Cary 50‑bio UV‑Vis spectrophotometer and Varian Cary Eclipse
spectrofluorophotometer. UV‑Vis and fluorescence scans were
recorded from 200 to 1000 nm. Melting points were measured on an
Electrothermal type‑9100 melting‑point apparatus. The IR spectra
(as KBr discs) were obtained on a Tensor 27 spectrometer and only
noteworthy absorptions are listed. The 13C NMR (100 MHz) and the
1H NMR (400 MHz) were recorded on a Bruker Avance DRX‑400 FT
Synthesis of compounds (3a–h); general procedure
The appropriate 1‑alkyl‑5‑nitro‑1H‑indazoles 1a–e (10 mmol) and
arylacetonitriles 2a–b (12 mmol) were added with stirring to a solution
of KOH (13 g, 238 mmol) in methanol (50 mL). The mixture was stirred
at room temperature for 24 h. After concentration at reduced pressure,
the precipitate was collected by filtration, washed with water, followed
by EtOH, and then air dried to give crude 3a–h.
3-Methyl-3H-pyrazolo[4,3-a]acridine-11-carbonitrile (3a): Shiny
yellow needles (EtOH), yield 57%; m.p. 251–253 °C; IR (KBr disk)
ν
max/cm–1 2223 (CN). 1H NMR (CDCl3): δ 4.30 (3H, s, CH3), 7.87–7.98
(3H, m, ArH), 8.21 (1H, d, J=8.8 Hz, ArH), 8.44 (1H, d, J=8.8 Hz,
ArH), 8.50 (1H, dd, J=8.4, 1.2 Hz, ArH), 9.21 (1H, s, ArH); 13C NMR
(CDCl3): δ 38.49, 113.62, 116.80, 117.29, 120.59, 124.16, 127.22, 128.63,
130.28, 135.75, 135.89, 136.51, 136.76, 137.50, 141.94, 147.21 ppm.
MS (m/z) 258 (M+). Anal. calcd for C16H10N4 (258.3): C, 74.41; H, 3.90;
N, 21.69; found: C, 74.09; H, 3.84; N, 21.43%.
Fig. 4 Visible absorption spectra of compound 3h in different solvents
Fig. 5 Emission spectra of compound 3h in different solvents
(1×10–5 mol L–1).
(1×10–6 mol L–1).

206 JOURNAL OF CHEMICAL RESEARCH 2014
3-Ethyl-3H-pyrazolo[4,3-a]acridine-11-carbonitrile (3b): Shiny
yellow needles (EtOH), yield 70%; m.p. 209–211 °C; IR (KBr disk):
νmax/cm–1 2223 (CN). 1H NMR (CDCl3): δ 1.65 (3H, t, J=7.6 Hz,
CH2CH3), 4.62 (2H, q, J=7.6 Hz, CH2CH3), 7.84–7.94 (3H, m, ArH),
8.13 (1H, d, J=9.0 Hz, ArH), 8.39 (1H, d, J=9.0 Hz, ArH), 8.45 (1H,
dd, J=8.0, 1.2 Hz, ArH), 9.18 (1H, s, ArH); 13C NMR (CDCl3): δ 15.50,
44.49, 113.61, 116.40, 117.09, 119.04, 125.76, 127.20, 127.69, 130.10,
134.14, 135.09, 136.61, 136.81, 137.55, 141.83, 147.54; MS (m/z) 272
(M+). Anal. calcd for C17H12N4 (272.3): C, 74.98; H, 4.44; N, 20.57;
found: C, 74.62; H, 4.35; N, 20.39%.
3-Propyl-3H-pyrazolo[4,3-a]acridine-11-carbonitrile (3c): Shiny
yellow needles (EtOH), yield 65%; m.p. 208–209 °C; IR (KBr disk):
νmax/cm–1 2225 (CN). 1H NMR (CDCl3): δ 1.03 (3H, t, J=7.2 Hz,
CH2CH2CH3), 2.11 (2H, m, CH2CH2CH3), 4.54 (2H, t, J=7.2 Hz,
CH2CH2CH3), 7.87–7.95 (3H, m, ArH), 8.18 (1H, d, J=9.0 Hz, ArH),
8.43 (1H, d, J=9.0 Hz, ArH), 8.49 (1H, dd, J=8.0, 1.2 Hz, ArH), 9.22
(1H, s, ArH); 13C NMR (CDCl3): δ 11.38, 23.76, 51.20, 110.13, 115.54,
117.10, 117.16, 122.53, 124.53, 125.96, 129.34, 129.61, 129.98, 130.32,
135.06, 137.71, 145.98, 147.41; MS (m/z) 286 (M+). Anal. calcd for
C18H14N4 (286.3): C, 75.51; H, 4.93; N, 19.57; found: C, 75.32; H, 4.88;
N, 19.82%.
3-Butyl-3H-pyrazolo[4,3-a]acridine-11-carbonitrile (3d): Shiny
yellow needles (EtOH), yield 55%; m.p. 200–201 °C; IR (KBr disk):
νmax/cm–1 2225 (CN). 1H NMR (CDCl3): δ 1.01 (3H, t, J=7.2 Hz,
CH2CH2CH2CH3), 1.43 (2H, m, CH2CH2CH2CH3), 2.05 (2H, m,
CH2CH2CH2CH3), 4.58 (2H, t, J=7.2 Hz, CH2CH2CH2CH3), 7.87–7.97
(3H, m, ArH), 8.20 (1H, d, J=9.0 Hz, ArH), 8.45 (1H, d, J=9.0 Hz,
ArH), 8.50 (1H, dd, J=8.4, 1.2 Hz, ArH), 9.22 (1H, s, ArH; 13C NMR
(CDCl3): δ 13.50, 20.01, 33.50, 42.76, 112.05, 113.97, 115.84, 119.64,
125.25, 127.88, 128.15, 130.33, 136.81, 136.90, 137.01, 137.86, 138.04,
142.60, 146.37; MS (m/z) 300 (M+). Anal. calcd for C19H16N4 (300.4): C,
75.98; H, 5.37; N, 18.65; found: C, 75.65; H, 5.32; N, 18.41%.
8-Bromo-3-isobutyl-3H-pyrazolo[4,3-a]acridine-11-carbonitrile
(3h): Shiny yellow needles (EtOH), yield 75%; m.p. 192–194 °C; IR
1
(KBr disk): νmax/ cm–1 2222 (CN). H NMR (CDCl3): δ 1.01 [6H, d,
J=6.8 Hz, CHCH2(CH3)2], 2.44–2.53 [1H, m, CHCH2(CH3)2], 4.33
[2H, d, J=6.8 Hz, CHCH2(CH3)2], 7.85 (1H, dd, J=8.8, 1.6 Hz, ArH),
7.88 (1H, d, J=9.6 Hz, ArH), 7.99 (1H, d, J=9.6 Hz, ArH), 8.23 (1H,
d, J=8.8 Hz, ArH), 8.44 (1H, d, J=1.6 Hz, ArH), 9.11 (1H, s, ArH);
13C NMR (CDCl3): δ 13.63, 19.87, 33.55, 43.10, 115.61, 115.73, 116.30,
118.02, 123.87, 124.12, 126.20, 130.21, 132.54, 133.19, 134.71,
136.96, 142.19, 146.14, 147.98; MS (m/z) 381 (M+ +2). Anal. calcd for
C19H15BrN4 (379.3): C, 60.17; H, 3.99; N, 14.77; found: C, 59.77; H, 3.93;
N, 14.49%.
Conclusions
We have successfully designed, synthesised and characterised
new derivatives of pyrazolo[4,3‑a]acridine by the reaction of
1‑alkyl‑5‑nitro‑1H‑indazoles with different arylacetonitriles
in basic media. The results clearly show that these compounds
have fluorescent properties in addition to strong antibacterial
activities and provide an excellent opportunity for the study
of physiological functions of bacteria at single‑cell level.37
Because of the promising antibacterial activity of our new
derivatives, we are undertaking further synthetic and biological
studies on similar substrates to expand this field of knowledge
and establish sound conclusions.
Received 11 October 2013; accepted 6 February 2014
Paper 1302227 doi: 10.3184/174751914X13932618023986
Published online: 2 April 2014
References
1
2
F. Bellina, S. Cauteruccio and R. Rossi, Tetrahedron, 2007, 63, 4571.
Z.J. Hu, J.X. Yang, Y.P. Tian, H.P. Zhou, X.T. Tao, G.B. Xu et al., J. Mol.
Struct., 2007, 839, 50.
Y.Z. Cui, Q. Fang, Z.L. Huang, G. Xue, W.T. Yu and H. Lei, Opt. Mater.,
2005, 27, 1571.
A.R. Katritzky, A.V. Vakulenko, R.A. Gedu and J.W. Rogers, Arkivoc,
2007, i, 8555.
Z.R. Grabowski and K. Rotkiewicz, Chem. Rev., 2003, 103, 3899.
F. Karagöz, O. Güney, M. Kandaz and A.T. Bilgiçli, J. Lumin., 2012, 132,
2736.
A.P.G. Ferreira, R. Frederice, K.P.F. Janssen and M.H. Gehlen, J. Lumin.,
2011, 131, 888.
O. Tabarrini, V. Cecchetti, A. Fravolini, G. Nocentini, A. Barzi, S.
Sabatini, H. Miao and C. Sissi, J. Heterocycl. Chem., 1999, 42, 2136.
W.A. Denny, Curr. Med. Chem., 2002, 9, 1655.
8-Bromo-3-methyl-3H-pyrazolo[4,3-a]acridine-11-carbonitrile (3e):
Shiny yellow needles (EtOH), yield 65%; m.p. 266–268 °C; IR (KBr
disk): νmax/cm–1 2219 (CN). 1H NMR (CDCl3): δ 4.27 (3H, s, CH3), 7.89
(1H, dd, J=8.8, 2.0 Hz, ArH), 7.91 (1H, d, J=9.2 Hz, ArH), 8.06 (1H, d,
J=9.2 Hz, ArH), 8.28 (1H, d, J=8.8 Hz, ArH), 8.51 (1H, d, J=2.0 Hz,
ArH), 9.12 (1H, s, ArH); 13C NMR (CDCl3): δ 38.54, 115.49, 115.89,
116.93, 117.34, 124.56, 124.76, 125.12, 129.16, 132.05, 132.19, 135.45,
137.34, 142.60, 146.65, 148.25; MS (m/z) 339 (M+ +2). Anal. calcd for
C16H9BrN4 (337.2): C, 57.00; H, 2.69; N, 16.62; found: C, 56.65; H, 2.62;
N, 16.35%.
8-Bromo-3-ethyl-3H-pyrazolo[4,3-a]acridine-11-carbonitrile (3f):
Shiny yellow needles (EtOH), yield 77%; m.p. 233–235 °C; IR (KBr
disk): νmax/cm–1 2219 (CN). 1H NMR (CDCl3): δ 1.66 (3H, t, J=7.2 Hz,
CH2CH3), 4.61 (2H, q, J=7.2 Hz, CH2CH3), 7.87 (1H, dd, J=8.8, 2.0 Hz,
ArH), 7.91 (1H, d, J=9.2 Hz, ArH), 8.02 (1H, d, J=9.2 Hz, ArH), 8.26
(1H, d, J=8.8 Hz, ArH), 8.48 (1H, d, J=2.0 Hz, ArH), 9.11 (1H, s, ArH);
13C NMR (CDCl3): δ 15.54, 44.61, 115.61, 115.70, 116.77, 117.60, 124.28,
124.49, 125.77, 129.50, 132.36, 132.77, 135.12, 137.21, 142.40, 146.21,
148.11; MS (m/z) 353 (M+ +2). Anal. calcd for C17H11BrN4 (351.2): C,
58.14; H, 3.16; N, 15.95; found: C, 57.83; H, 3.11; N, 16.23%.
3
4
5
6
7
8
9
10 J.R. Goodell, A.A. Madhok, H. Hiasa and D.M. Ferguson, Bioorg. Med.
Chem., 2006, 14, 5467.
11 O. Tabarrini, G. Manfroni, A. Fravolini, V. Cecchetti, S. Sabatini, E. De
Clercq, J. Rozenski, B. Canard, H. Dutartre, J. Paeshuyse and J. Neyts, J.
Med. Chem., 2006, 49, 2621.
12 M. Kukowska‑Kaszuba and K. Dzierzbicka, Curr. Med. Chem., 2007, 14,
3079.
13 R.W. Winter, J.X. Kelly, M.J. Smilkstein, R. Dodean, D. Hinrichs and
M.K. Riscoe, Exp. Parasitol., 2008, 118, 487.
14 A.A. Joshi and C.L. Viswanathan, Anti-Infect. Agents. Med. Chem., 2006,
5, 105.
8-Bromo-3-propyl-3H-pyrazolo[4,3-a]acridine-11-carbonitrile (3g):
Shiny yellow needles (EtOH), yield 80%; m.p. 228–229 °C; IR (KBr
disk): νmax/cm–1 2223 (CN). 1H NMR (CDCl3): δ 1.01 (3H, t, J=7.2 Hz,
CH2CH2CH3), 2.08 (2H, m, CH2CH2CH3), 4.51 (2H, t, J=7.2 Hz,
CH2CH2CH3), 7.85 (1H, dd, J=9.0, 1.6 Hz, ArH), 7.89 (1H, d, J=9.6 Hz,
ArH), 8.00 (1H, d, J=9.6 Hz, ArH), 8.24 (1H, d, J=9.0 Hz, ArH), 8.45
(1H, d, J=1.6 Hz, ArH), 9.10 (1H, s, ArH); 13C NMR (CDCl3): δ 11.43,
23.59, 51.71, 115.54, 115.84, 116.34, 118.04, 123.94, 124.38, 126.11,
129.70, 132.37, 133.07, 134.89, 137.07, 142.38, 146.16, 148.04; MS (m/z)
367 (M+ +2). Anal. calcd for C18H13BrN4 (365.2): C, 59.19; H, 3.59; N,
15.34; found: C, 58.79; H, 3.52; N, 15.04%.
15 J.P. Dheyongera, W.J. Geldenhuys, T.G. Dekker, M.G. Matsabisa and C.J.
Van Der Schyf, Bioorg. Med. Chem., 2005, 13, 1653.
16 S.J. Kesten, M.J. Degnan, J. Hung, D.J. Mc Namara, D.F. Ortwine, S.E.
Uhlendorf and L.M. Werbel, J. Med. Chem., 1992, 35, 3429.
17 W. Raether, B. Enders, J. Hofmann, U. Schwannecke, H. Seidenath, H.
Hanel and M. Uphoff, Parasitol. Res., 1989, 75, 619.
18 P. Belmont, J. Bosson, T. Godet and M. Tiano, Anti-Cancer Agents Med.
Chem., 2007, 7, 139.
19 A. Kamal, O. Srinivas, P. Ramulu, G. Ramesh and P.P. Kumar, Bioorg.
Med. Chem. Lett., 2004, 14, 4107.
20 M. Demeunynck, Expert. Opin. Ther. Pat., 2004, 14, 55.
21 I.G.C. Robertson, B.D. Palmer, M. Officer, D.J. Siegers, J.W. Paxton and
G.J. Shaw, Biochem. Pharmacol., 1991, 42, 1879.

JOURNAL OF CHEMICAL RESEARCH 2014 207
22 M. Rahimizadeh, M. Pordel, M. Bakavoli and H. Eshghi, Dyes Pigm.,
2010, 86, 266.
30 A. Sadeghian, M. Pordel, H. Safdari, M.A. Fahmidekar and H. Sadeghian,
Med. Chem. Res., 2012, 21, 3897.
23 R. Sahraei, M. Pordel, H. Behmadi and B. Razavi, J. Lumin., 2013, 136,
334.
24 V. Pakjoo, M. Roshani, M. Pordel and T. Hoseini, Arkivoc, 2012, 9, 195.
25 M. Pordel, J. Chem. Res., 2012, 36, 595.
26 M. Rahimizadeh, M. Pordel, M. Ranaei and M. Bakavoli, J. Heterocycl.
Chem., 2012, 49, 208.
27 T. Hoseini‑Hesar, M. Pordel, M. Roshani and A. Shams, J. Chem. Res.,
2013, 37, 438.
28 M. Rahimizadeh, M. Pordel, M. Bakavoli, Sh. Rezaeian and A. Sadeghian,
World. J. Microbiol. Biotechnol., 2010, 26, 317.
29 H. Sadeghian, A. Sadeghian, M. Pordel, M. Rahimizadeh, P. Jahandari, A.
Orafaie and M. Bakavoli, Med. Chem. Res., 2010, 19, 103.
31 M. Rahimizadeh, M. Pordel, M. Bakavoli, Z. Bakhtiarpoor and A. Orafaie,
Monatsh. Chem., 2009, 140, 633.
32 L. Bouissane, S.E. Kazzouli, J.M. Leger, C. Jarry, E.M. Rakib, M. Khouili
and G. Guillaumet, Tetrahedron, 2005, 61, 8218.
33 R.B. Davis and L.C. Pizzini, J. Org. Chem., 1960, 25, 1884.
34 F. Sztaricskai, G. Pintér, E. Röth, P. Herczegh, S. Kardos, F. Rozgonyi and
Z. Boda, J. Antibiot., 2007, 60, 529.
35 J.Q. Umberger and V.K. Lamer, J. Am. Chem. Soc., 1945, 67, 1099.
36 S.M. Finegold, L. Garrod, in Bailey and Scott’s diagnostic microbiology,
8th edn. C.V. Mosby Co., Toronto, 1995, pp. 171.
37 F. Joux and P. Lebaron, Microbes Infect., 2000, 2, 1523.