Hindawi Publishing Corporation
Journal of Chemistry
Volume 2016, Article ID 5286462, 7 pages
http://dx.doi.org/10.1155/2016/5286462
Research Article
A Synthetic Approach to Pyrazolopyranopyrimidinones and
Pyrazolopyranooxazinones as Antimicrobial Agents
A. K. Elziaty,1 G. Bassioni,2 A. M. A. Hassan,1 H. A. Derbala,1 and M. S. Abdel-Aziz3
1
Department of Chemistry, Faculty of Science, Ain Shams University, Abbassia, Cairo 11566, Egypt
Department of Chemistry, Faculty of Engineering, Ain Shams University, Abbassia, Cairo 11566, Egypt
3
Department of Microbial Chemistry, National Research Centre, 33 El Bohouth St. (Former Tahrir St.), Dokki, Cairo 12622, Egypt
2
Correspondence should be addressed to A. K. Elziaty; [email protected]
Received 12 July 2016; Accepted 6 September 2016
Academic Editor: Mohamed Afzal Pasha
Copyright © 2016 A. K. Elziaty et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The hitherto unknown 6-amino-4-(2-chloro-5-nitrophenyl)-3-methyl-1,4-dihydropyrano[2,3-c] pyrazole-5-carbonitrile 1a was
synthesized. Both 1a and its 2,4 dichlorophenyl derivative 1b were utilized as building blocks for the preparation of novel class of
pyrazolopyrano-[oxazines 2a–d and pyrimidinones 3a–d]. Synthesis of these compounds was achieved by two alternative acylation
steps followed by ammonolysis. The structures of the synthesized compounds were elucidated by spectral data and elemental
analysis. Screening and evaluation of these products as antimicrobial agents showed that the derivatives 1b, 2s, 3b, and 3d possess
a potent activity.
1. Introduction
2-Amino-3-cyano-4-(H)pyran derivatives [1, 2] represent a
group of heterocycles of special interest due to their biological activities as antimicrobial, antioxidant, antifungal, and
antimycobacterial [3–5]. Meanwhile, they have been utilized
as building block for the synthesis of important heterocycles
including pyrazopyranopyrimidines [6], chromenooxazine
[7], and pyrrolopyranopyrazole [8]. Heterocycles containing the oxazine nucleus were found to possess a wide
range of valuable biological properties like analgesic, antiinflammatory antileukemic, antimalarial [9–11], antipyretic,
anticonvulsant, and antimicrobial activities [12–16]. Benzo1,3-oxazines are also known to be biologically active, demonstrating antirheumatic, antianginal, antihypertensive effects,
cytotoxic [17, 18], and antiosteoclastic bone resorption activities [19]. Efavirenz, a trifluoromethyl-1,3-oxazine-2-one, is a
nonnucleoside reverse transcriptase inhibitor which displays
significant activity against HIV-1 mutant strains [20]. 1,3Oxazine derivatives are also known to function as progesterone receptor agonists [21]. Naphthoxazines are found to
possess psychostimulating and antidepressant activity and
are used in the treatment of Parkinson’s disease [22, 23].
Only few reports are available regarding the antimicrobial
activity of pyrazolopyranooxazinones [24]. Based on these
reports, in this paper we devoted our efforts to construct new
pyrazolopyranooxazinones and pyrimidinone heterocycles,
as well as screening and evaluation of their antimicrobial
activity [25, 26].
2. Experimental
All melting points were determined on an electrothermal
apparatus and are uncorrected. The infrared spectra were
recorded in potassium bromide disks on Pye Unicam SP3-300 and Shimdazu FTIR 8101 PC Infrared spectrophotometers. The 1 H-NMR was recorded on a Varian Mercury
VX-300 NMR spectrometer. 1 H-NMR spectra were run at
300 MHz and on a Varian Gemini 200 MHz, Bruker AC200 MHz using TMS as internal standard in deuterated chloroform (CDCl3 ) or deuterated dimethyl sulfoxide (DMSOd6 ). Chemical shifts are quoted in 𝛿 and were related to that of
the solvents. The mass spectra were recorded on a Shimadzu
GC-MS QP1000 EX mass spectrometer at 70 eV. Elemental
analyses were carried out at the Microanalytical Center of
2
Journal of Chemistry
O2 N
12
11
13
14
10
Cl
9
1
7
CN
8
2
6
3
5
N
N
H
4
O
NH2
1a
Scheme 1
Cairo University. All the reactions and the purity of the new
compounds were followed and cheeked by TLC.
2.1. Chemistry
2.1.1. General Procedure for Synthesis of Compounds 1a
and 1b. A mixture of 2-chloro-5-nitrobenzaldehyde or 2,4dichlorobenzaldehyde (5 mmol), malononitrile (5 mmol),
hydrazine monohydrate (5 mmol), and ethyl acetoacetate
(5 mmol) in n-butanol (15 ml) containing few drops of piperidine was heated under reflux for 5 h. The separated solid was
filtered off, dried, and crystallized from proper solvent to give
compounds 1a and 1b, respectively.
6-Amino-4-(2-chloro-5-nitrophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1a). Deep yellow crystals,
m.p. 252-253∘ C (n-butanol), yield 70%. Anal. Calcd. for
C14 H10 N5 O3 Cl (331.71): C, 50.69; H, 3.04; Cl, 10.69; N, 21.11;
O, 14.47. Found: C, 50.64; H, 3.01; Cl, 10.66; N, 21.10; O, 14.45.
FTIR (KBr, 𝜐 cm−1 ): 3394 (NH), 3358–3305 (NH2 ), 3095
(CHar ), 2925 (CHaliph ), 2192 (CN). 1 H-NMR (DMSO- d6 ) 𝛿
(ppm): 12.21 (s, 1H, NH, pyrazole, exch. with D2 O), 7.10 (s,
2H, NH2 , exch. with D2 O), 7.09–8.139 (m, 3H, Har ), 5.23 (s,
1H, benzylic), 1.79 (s, 3H, CH3 ). 13 C-NMR (DMSO- d6 ) 𝛿
(ppm): 161.54 (C-5), 154.92 (C-14), 146.62 (C-4), 143.50 (C-9),
139.50 (C-10), 135.74 (C-3), 131.14 (C-11), 125.05 (C-2), 123.47
(C-12), 120.14 (C-13), 95.58 (C-7), 54.44 (C-6), 32.5 (C-8), 9.6
(C-1). MS m/z (%): 331 (M∙+ ; 7.35), 333 (2.56), 305 (1.43), 230
(4.72), 176 (9.73), 175 (100) (see Scheme 1).
6-Amino-4-(2,4-dichlorophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1b) [2].
2.1.2. General Procedure for Synthesis of Compounds 2a and
2b. A solution 1a or 1b (5 mmol) in freshly distilled acetic
anhydride (20 ml) was refluxed on a hot plate for 24 h, and
excess of acetic anhydride was removed using rotary evaporator. The solid remains after evaporation were crystallized
from the proper solvent to give compounds 2a and 2b,
respectively.
4-(2-Chloro-5-nitrophenyl)-3,7-dimethyl-1,4-dihydro-5H-pyrazolo[4󸀠 ,3󸀠 :5,6]pyrano[2,3-d][1,3]oxazin-5-one (2a). Pale
brown crystals, m.p. > 300∘ C (DMF), yield 65%. Anal. Calcd.
for C16 H11 N4 O5 Cl (374.74): C, 51.28; H, 2.96; Cl, 9.46; N,
14.95; O, 21.35. Found: C, 51.26; H, 2.94; Cl, 9.47; N, 14.95;
O, 21.33. IR (KBr, 𝜐 cm−1 ): 3170 (NH), 1735 (C=O), 1626
(C=N). 1 H-NMR (DMSO- d6 ) 𝛿 (ppm): 12.58 (s, 1H, NH,
pyrazole, exch. with D2 O), 7.66–8.09 (m, 3H, Har ), 5.58 (s,
1H, benzylic), 3.72 (s, 3H, CH3 ), 2.21 (s, 3H, CH3 , pyrazole).
MS m/z (%): 374 (M∙+ ; 9.87), 375 (4.28), 322 (100), 338
(63.35), 217 (59.76), 176 (29.75).
4-(2,4-Dichlorophenyl)-3,7-dimethyl-1,4-dihydro-5H-pyrazolo
[4󸀠 ,3󸀠 :5,6]pyrano[2,3-d][1,3]oxazin-5-one (2b). White crystals, m.p. > 300∘ C (ethanol), yield 70%. Anal. Calcd. for
C16 H11 N3 O3 Cl2 (364.18): C, 52.77; H, 3.04; Cl, 19.47; N,
11.54; O, 13.18. Found: C, 52.75; H, 3.02; Cl, 19.51; N, 11.54;
O, 13.19. FTIR (KBr, 𝜐 cm−1 ): 3457 (NH), 1738 (C=O), 1656
(C=N). 1 H-NMR (DMSO- d6 ) 𝛿 (ppm): 12.51 (s, 1H, NH,
pyrazole, exch. with D2 O), 7.48–7.31 (m, 3H, Har ), 5.34 (s, 1H,
benzylic), 3.25 (s, 3H, CH3 ), 2.19 (s, 3H, CH3 , pyrazole). MS
𝑚/𝑧 (%): 364 (M∙+ ; 0.91), 284 (2.95), 270 (4.51), 194 (33.14),
183 (23.48), 107 (100).
2.1.3. General Procedure for Synthesis of Compounds 2c and
2d. A solution of 1a or 1b (5 mmol) and benzoyl chloride
(20 ml) was refluxed on a hot plate for 24 h, and excess
of benzoyl chloride was removed using rotary evaporator.
The solid remains after evaporation were crystallized to give
compounds 2c and 2d, respectively.
1-Benzoyl-4-(2-chloro-5-nitrophenyl)-3,methy-7,phenyll-4-hydro-5H-pyrazolo-[4󸀠 ,3󸀠 :5,6]pyrano[2,3-d][1,3]oxazin-5-one
(2c). Pale brown crystals, m.p. > 300∘ C (toluene), yield 60%.
Anal. Calcd. for C28 H17 N4 O6 -Cl (540.91): C, 62.17; H, 3.17;
Cl, 6.55; N, 10.36; O, 17.75. Found: C, 62.16; H, 3.15; Cl, 6.57; N,
10.36; O, 17.76. FTIR (KBr, 𝜐 cm−1 ): 1758 (C=O), 1715 (C=O),
1613 (C=N). 1 H-NMR (DMSO- d6 ) 𝛿 (ppm): 8.33–7.17 (m,
13H, Har ), 6.15 (s, 1H, benzylic), 1.23 (s, 3H, CH3 ). MS 𝑚/𝑧
(%): 540 (M∙+ ;1.53), 445 (29.38), 327 (22.16), 230 (44.69), 175
(100).
Journal of Chemistry
1-Benzoyl-4-(2,4-dichlorophenyl)-3,methy-7,phenyll-4-hydro5H-pyrazolo-[4󸀠 ,3󸀠 :5,6]pyrano[2,3-d][1,3]oxazin-5-one (2d).
Brown crystals, m.p. > 300∘ C (benzene), yield 54%. Anal.
Calcd. for C28 H17 N3 O4 Cl2 (530.36): C, 63.40; H, 3.21; Cl,
13.40; N, 7.92; O, 12.08. Found: C, 63.41; H, 3.23; Cl, 13.37; N,
7.92; O, 12.07. FTIR (KBr, 𝜐 cm−1 ): 1754 (C=O), 1704 (C=O),
1582 (C=N). 1 H-NMR (DMSO- d6 ) 𝛿 (ppm): 7.98–7.30 (m,
13H, Har ), 5.28 (s, 1H, benzylic), 1.22 (s, 3H, CH3 ). MS 𝑚/𝑧
(%): 530 (M∙+ ; 1.42), 534 (0.70), 281 (72.36), 222 (44.33),
118.99 (100).
2.1.4. General Procedure for Synthesis of Compounds 3c and
3d. A mixture of 2a and/or 2b (5 mmol) and ammonium
acetate (15 mmol) was refluxed on a hot plate for 20 h,
and the reaction mixture was cooled and then poured into
cold water. The separated solid was filtered off, dried, and
crystallized from the proper solvent to give products 3a and
3d, respectively.
4-(2-Chloro-5-nitrophenyl)-3,7-dimethyl-4,6-dihydropyrazolo[4󸀠 ,3󸀠 :5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (3a). Pale
yellow crystals, m.p. > 300∘ C (ethanol), yield 59%. Anal.
Calcd. for C16 H12 N5 O4 -Cl (373.75): C, 51.42; H, 3.24; Cl,
9.49; N, 18.74; O, 17.12. Found: C, 51.41; H, 3.21; Cl, 9.50; N,
18.74; O, 17.14. FTIR (KBr, 𝜐 cm−1 ): 3420 (NH), 1646 (C=O),
1609 (C=N). 1 H-NMR (DMSO- d6 ) 𝛿 (ppm): 12.43 (s, 1H,
NH, pyrazole, exch. with D2 O), 12.23 (s, 1H, NH, exch. with
D2 O), 8.05–7.07 (m, 3H, Har ), 5.49 (s, 1H, benzylic), 2.29
(s, 3H, CH3 ), 1.87 (s, 3H, CH3 , pyrazole). MS 𝑚/𝑧 (%): 373
(M∙+ ; 5.32), 376 (0.96), 338 (100), 217 (30.19), 145 (39.19).
4-(2,4-Dichlorophenyl)-3,7-dimethyl-4,6-dihydropyrazolo[4󸀠 ,
3󸀠 :5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (3b). White crystals, m.p. > 300∘ C (1, 4-dioxane), yield 61%. Anal. Calcd. for
C16 H12 N4 O2 -Cl2 (363.2): C, 52.89; H, 3.31; Cl, 19.56; N, 15.43;
O, 8.82. Found: C, 52.91; H, 3.33; Cl, 19.52; N, 15.43; O, 8.81.
FTIR (KBr, 𝜐 cm−1 ): 3426 (NH), 1658 (C=O), 1611 (C=N).
1
H-NMR (DMSO- d6 ) 𝛿 (ppm): 12.32 (s, 1H, NH, pyrazole,
exch. with D2 O), 12.11 (s, 1H, NH, exch. with D2 O), 7.47–7.11
(m, 3H, Har ), 5.31 (s, 1H, benzylic), 3.27 (s, 3H, CH3 ), 2.26 (s,
3H, CH3 , pyrazole). MS 𝑚/𝑧 (%): 363 (M∙+ ; 3.36), 365 (1.35),
310 (22.67), 300 (32.89), 257 (14.44), 217 (100), 220 (21.94).
2.1.5. General Procedure for Synthesis of Compounds 3c and 3d.
A mixture of 2c and/or 2d (5 mmol) and ammonium acetate
(30 mmol) was refluxed on a hot plate for 17 h, the reaction
mixture was cooled and then poured into cold water, and the
separated solid was filtered off, dried, and crystallized from
proper solvent to give compounds 3c and 3d, respectively.
4-(2-Chloro-5-nitrophenyl)-3-methyl-7-phenyl-4,6-dihydropyrazolo[4󸀠 ,3󸀠 :5,6]-pyrano[2,3-d]pyrimidin-5(1H)-one (3c).
Pale yellow crystals, m.p. > 300∘ C (ethanol), yield 63%. Anal.
Calcd. for C21 H14 N5 O4 -Cl (435.82): C, 57.87; H, 3.24; Cl,
8.13; N, 16.07; O, 14.68. Found: C, 57.86; H, 3.23; Cl, 8.11; N,
16.07; O, 14.67. FTIR (KBr, 𝜐 cm−1 ): 3311 (NH), 1662 (C=O),
1605 (C=N). 1 H-NMR (DMSO- d6 ) 𝛿 (ppm): 12.75 (s, 1H,
NH, pyrazole, exch. with D2 O), 12.24 (s, 1H, NH, exch. with
D2 O), 8.11–7.51 (m, 8H, Har ), 5.31 (s, 1H, benzylic), 3.28(s,
3
3H, CH3 ). MS 𝑚/𝑧 (%): 436 (M∙+ ; 9.01), 400.03 (36.80), 297
(73.08), 279 (100).
4-(2,4-Dichlorophenyl)-3-methyl-7-phenyl-4,6-dihydropyrazolo[4󸀠 ,3󸀠 :5,6]-pyrano[2,3-d]pyrimidin-5(1H)-one (3d). Pale
brown crystals, m.p. > 300∘ C (ethanol), yield 60%. Anal.
Calcd. for C21 H14 N4 O2 Cl2 (425.27): C, 59.31; H, 3.32; Cl,
16.67; N, 13.17; O, 7.52. Found: C, 59.30; H, 3.30; Cl, 16.65; N,
13.15; O, 7.51. FTIR (KBr, 𝜐 cm−1 ): 3392 (NH), 1673 (C=O),
1559 (C=N). 1 H-NMR (DMSO- d6 ) 𝛿 (ppm): 12.57 (s, 1H,
NH, pyrazole, exch. with D2 O), 12.15 (s, 1H, NH, exch. with
D2 O), 8.21–7.22 (m, 8H, Har ), 5.42 (s, 1H, benzylic), 3.26 (s,
3H, CH3 ). MS 𝑚/𝑧 (%): 425 (M∙+ ; 22.7), 424.05 (100), 426
(63.9).
2.2. Antimicrobial Assay by Agar Cup Plate Method. The
sample was prepared by dissolving 0.005 g in 2 ml of DMSO
and 100 𝜇l (containing 250 𝜇g) was used in this test. The
antimicrobial activity of different samples was investigated
by the agar cup plate method. Four different test microbes,
namely, Staphylococcus aureus (G+ve), Pseudomonas aeruginosa (G−ve), Candida albicans (yeast), and Aspergillus niger
(fungus), were used. Nutrient agar plates were heavily seeded
uniformly with 1 ml of 105 –106 cells/ml in case of bacteria
and yeast. A potato dextrose agar plate seeded by the fungus
was used to evaluate the antifungal activities. Then a hole was
made in media by gel cutter (cork borer number 4) in sterile
condition. Then one drop of melted agar was poured into hole
and allowed to solidify to make a base layer. After that specific
amount of culture filtrate (0.1 ml) was poured into the hole.
Then plates were kept at low temperature (4∘ C) for 2–4 hours
to allow maximum diffusion. The plates were then incubated
at 37∘ C for 24 hours for bacteria and at 30∘ C for 48 hours in
upright position to allow maximum growth of the organisms.
The antimicrobial activity of the test agent was determined
by measuring the diameter of zone of inhibition expressed in
millimeter. The experiment was carried out more than once
and mean of reading was recorded [27, 28].
3. Results and Discussion
3.1. Chemistry. In order to study their utility as precursors to annulated heterocycles, 6-amino-4-aryl-3-methyl
pyranopyrazole-5-carbonitrile derivatives 1a,b were synthesized employing the previously reported [29] multicomponent reaction (Scheme 2).
Examination of IR spectrum of 1a showed absorption
frequencies at 𝜐 3393, 3305, and 3141 cm−1 due to NH and NH2
groups, respectively, in addition to a strong absorption band
which appeared at 2192 cm−1 referring to the presence of the
cyano (C≡N) group. A compelling evidence for this observation was provided by 13 C-NMR spectrum that showed a
singlet at 𝛿 95.58 ppm. In addition, 1 H-NMR spectrum of
the assigned compound displayed signals at 𝛿 12.21 ppm and
7.10 ppm due to absorption of the former NH and NH2 group
protons, respectively (which disappeared upon deuteration).
Further, the mass spectrum showed the EI-fragment at 𝑚/𝑧 =
331 due to the molecular ion peak. Meanwhile, the structure
4
Journal of Chemistry
Ar
O
CN
O
n-Butanol
pip
+ Ar–CHO + CH2 (CN)2 + H2 N–NH2
O
N
N
H
NH2
O
1a, b
1a: Ar = 2-chloro-5-nitrophenyl
1b: Ar = 2,4-dichlorophenyl
Scheme 2
Ar
Ar
N
N
H
O
CN
AC2 O
NH2
Reflux
N
H
N
2a, b
O
NH
N
N
H
O
N
3a, b
Ar
O
N
O
O
O
PhCOCl
Ar
N
Amm. acetate
or
formamide
O
N
1a, b
Reflux
Ar
O
O
N
Ph
Amm. acetate
or
formamide
Ph
2c, d
O
NH
N
N
H
O
N
Ph
3c, d
2a, 3a, 2c and 3c: Ar = 2-chloro-5-nitrophenyl
2b, 3b, 2d and 3d: Ar = 2,4-dichlorophenyl
Scheme 3
of the previously reported derivative 1b was confirmed by
identity of melting point and IR spectrum data with the
literature [29].
With the aim of constructing new annulated heterocycles containing pyranooxazine moiety, these prepared
compounds were subjected to reaction with acetic anhydride at the reflux temperature. Successfully, this reaction
went readily to afford 4-(2-chloro-5-nitrophenyl)- and 4(2,4-dichlorophenyl)-3,7-dimethyl-1,4-dihydro-5H pyrazolo
[4󸀠 ,3󸀠 :5,6] pyrano [2,3-d][1,3]oxazin-5-one 2a and 2b, respectively (Scheme 3). The suggested mechanism for the formation of the latter compounds could be visualized as shown in
Scheme 4.
The IR spectra of 2a and 2b displayed the band characteristic to the 6-membered oxazinone carbonyl group at 𝜐
1738–1735 cm−1 , however, they lack the bands corresponding
to both the amino and nitrile functionalities. The 1 H-NMR
spectra showed the disappearance of the former group protons signal. This means that these groups have been involved
in acylation and ring closure processes (Scheme 4). Further,
the mass spectra showed the EI-fragment at 𝑚/𝑧 = 374
and 364 due to the molecular ion peaks of both 2a and 2b,
respectively.
On the other hand, in treatment of 1a and 1b with benzoyl
chloride as a coreactant and a cosolvent, the products 1benzoylpyrazolopyranooxazinones 2c and 2d were obtained.
The 1 H-NMR spectra showed the absence of a signal characteristic to NH proton indicating that the reaction might
involve benzoylation of the latter group. This has been
confirmed from the molecular ion peak shown at 𝑚/𝑧 = 540
and 530 of 2c and 2d, respectively (cf. Section 2).
Ammonolysis of 2a and 2b was carried out either by
fusion with amm. acetate or by boiling with formamide.
Both reactions yielded the corresponding 3,7-dimethylpyrazolopyranopyrimidinones 3a and 3b, respectively. However, the 3-methyl-7-phenyl derivatives 3c and 3d were
produced via ammonolysis using ammonium acetate or
formamide of the lactonic carbonyl and the N-benzoyl
functionalities of derivatives 2c and 2d, respectively (cf.
Scheme 5). The IR spectra of the assigned products 3a–d
Journal of Chemistry
C
5
N
C
N
AC2 O
C
O
NH2
N
C
CH3
N
NH
N
+
∼H
∙∙ ∙
∙ OH
C
CH3
O
6-exo-dig
cyclization
N
H
+
H
Hydrolysis
O
O
N
Scheme 4
Ar
NH3
O
N
N
O
−
O
+
H3 N
O
N
Ph
O
O
N
O
NH
∙∙ 2
Ph
N C Ph
H O
O
Ph
+
∼H
NH
Ph
OH
N
6-exo-trig
cyclization
H
2c, d
−H2 O
∙∙
NH3
Ar
+
∼H
N
N
+ C Ph
O
H3 N
−
−PhCONH2
O
NH
N
N
H
O
N
Ph
3c, d
Scheme 5
Table 1: The antimicrobial activities of the synthesized compounds as inhibition zone in mm diameter per mg sample.
Sample code number
Control: DMSO
Neomycin
3d
2d
2c
2a
1a
3a
3c
3b
1b
2b
Staphylococcus aureus
0.0
22
17
18
14
16
16
13
16
18
25
13
Slandered drug (neomycin 100 micrograms per 100 microliters).
Clear zone (𝜙mm)
Pseudomonas aeruginosa
Candida albicans
0.0
0.0
28
30
16
17
20
18
15
0
12
0
13
0
14
17
13
14
17
16
25
32
14
13
Aspergillus niger
0.0
0.0
15
15
12
0
0
0
0
10
15
0
6
showed the disappearance of the lactone carbonyl absorption
and instead the lactam carbonyl frequency was exhibited
at the range of 𝜐 1662–1646 cm−1 , in addition to the band
displayed at 𝜐 3420–3311 cm−1 due to the cyclic lactam NH
functionality. The 1 H-NMR spectra of the latter NH group
proton appeared at 𝛿 12.2 ppm (cf. Section 2). The suggested
mechanism for the formation of 3c, d could be visualized as
shown in Scheme 5.
3.2. Antimicrobial Study. Antibiotic resistance is a growing
problem; some of this is due to the overuse of antibiotics
in human, but some of it is probably due to the use of
antibiotics as growth promoters in food of animals, so there is
a growing demand for new antibiotics. The synthesized new
pyrazolopyranopyrimidines and pyrazolopyranooxazinones
were evaluated for their in vitro antimicrobial efficacy against
four strains, namely, Staphylococcus aureus (G+ve), Pseudomonas aeruginosa (G−ve), Candida albicans (yeast), and
Aspergillus niger (fungus). Neomycin was used as standard
drug. Based on the results of zone of inhibition, data in Table 1
revealed that compounds 1b, 3b, 2d, and 3d exhibit strong
activities and compounds 2a, 2b, and 1a exhibit moderate
activities, whereas 3a, 2c, and 2b exhibit week antimicrobial
activities compared with neomycin as standard drug.
Journal of Chemistry
[7]
[8]
[9]
[10]
[11]
[12]
[13]
Competing Interests
The authors declare that they have no competing interests.
References
[1] S. Tabassum, S. Govindaraju, R.-U. Khan, and M. A. Pasha,
“Ultrasound mediated, iodine catalyzed green synthesis of
novel 2-amino-3-cyano-4H-pyran derivatives,” Ultrasonics
Sonochemistry, vol. 24, pp. 1–7, 2015.
[2] S. S. Mansoor, K. Logaiya, K. Aswin, and P. N. Sudhan, “An appropriate one-pot synthesis of 3,4-dihydropyrano[c]chromenes and 6-amino-5-cyano-4-aryl-2-methyl-4Hpyrans with thiourea dioxide as an efficient, reusable organic
catalyst in aqueous medium,” Journal of Taibah University for
Science, vol. 9, no. 2, pp. 213–226, 2015.
[3] A. R. Saundane, K. Vijaykumar, and A. V. Vaijinath, “Synthesis of novel 2-amino-4-(5󸀠 -substituted 2󸀠 -phenyl-1H- indol-3󸀠 yl)-6-aryl-4H-pyran-3-carbonitrile derivatives as antimicrobial
and antioxidant agents,” Bioorganic and Medicinal Chemistry
Letters, vol. 23, no. 7, pp. 1978–1984, 2013.
[4] T. Nakib, V. Bezjak, S. Rashid, B. Fullam, and M. Meegan,
“The synthesis and antifungal activity of 2-amino-4-aryl4H,5H-[1]benzothiopyrano[4,3-b]pyran-3-carbonitriles and 2alkoxy-4-aryl-5H-[1]benzothiopyrano[4,3-b]pyridine-3-carbonitriles,” European Journal of Medicinal Chemistry, vol. 26, no.
2, pp. 221–230, 1991.
[5] R. R. Kumar, S. Perumal, P. Senthilkumar, P. Yogeeswari, and
D. Sriram, “An atom efficient, solvent-free, green synthesis and
antimycobacterial evaluation of 2-amino-6-methyl-4-aryl-8[(E)-arylmethylidene]-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]
pyridine-3-carbonitriles,” Bioorganic & Medicinal Chemistry
Letters, vol. 17, no. 23, pp. 6459–6462, 2007.
[6] M. M. Heravi, F. Mousavizadeh, N. Ghobadi, and M. Tajbakhsh,
“A green and convenient protocol for the synthesis of novel
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
pyrazolopyranopyrimidines via a one-pot, four-component
reaction in water,” Tetrahedron Letters, vol. 55, no. 6, pp. 1226–
1228, 2014.
H. M. F. Madkour, A. A. E. Afify, G. A. Elsayed, and M. S.
Salem, “Use of enaminonitrile moiety in heterocyclic synthesis,”
Bulgarian Chemical Communications, vol. 40, no. 2, pp. 147–159,
2008.
A. K. Elziaty, O. E. A. Mostafa, E. A. El-Bordany, M. Nabil, and
H. M. F. Madkour, “Access to new pyranopyrazoles and related
heterocycles,” International Journal of Scientific & Engineering
Research, vol. 5, no. 1, pp. 727–735, 2014.
C. H. Takimoto and E. Calvo, “Principles of oncologic pharmacotherapy,” in Cancer Management: A Multidisciplinary
Approach, pp. 42–58, UBM Medica, London, UK, 2008.
R. Kalirajan, S. U. Sivakumar, S. Jubie, B. Gowramma, and
B. Suresh, “Synthesis and biological evaluation of some heterocyclic derivatives of Chalcones,” International Journal of
ChemTech Research, vol. 1, no. 1, pp. 27–34, 2009.
J. L. Vennerstrom, M. T. Makler, C. K. Angerhofer, and J.
A. Williams, “Antimalarial dyes revisited: xanthenes, azines,
oxazines, and thiazines,” Antimicrobial Agents and Chemotherapy, vol. 39, no. 1, pp. 2671–2677, 1995.
C. Singh, H. K. Parwana, and G. Singh, “Synthesis of 3,6diaryl-2H, 3H, 4H, 5H, 6H-[1,3]-oxazine-2-thiones as potential
anticonvulsants,” Indian Journal of Pharmaceutical Sciences, vol.
57, no. 5, pp. 198–202, 1995.
N. Latif, N. Mishriky, and F. M. Assad, “Carbonyl and thiocarbonyl compounds. XIX. Intramolecular cyclization of (2nitroethenyl)aryl N-arylcarbamates: synthesis of newer series
of 3,4-dihydro-2H-1,3-oxazin-2-ones and their antimicrobial
activities,” Australian Journal of Chemistry, vol. 35, no. 5, pp.
1037–1043, 1982.
J. M. Cassady, K. K. Chan, H. G. Floss, and E. Leistner, “Recent
developments in the maytansinoid antitumor agents,” Chemical
and Pharmaceutical Bulletin, vol. 52, no. 1, pp. 1–26, 2004.
Z. Turgut, E. Pelit, and A. Köycü, “Synthesis of new 1,3disubstituted-2,3-dihydro-1H-naphth-[1,2e][1,3] oxazines,” Molecules, vol. 12, no. 3, pp. 345–352, 2007.
S. F. Mohamed, M. M. Youssef, A. E.-G. E. Amr, and E. R.
Kotb, “Antimicrobial activities of some synthesized pyridines,
oxazines and thiazoles from 3-aryl-1-(2-naphthyl)prop-2-en-1ones,” Scientia Pharmaceutica, vol. 76, no. 2, pp. 279–303, 2008.
V. Verma, K. Singh, D. Kumar et al., “Synthesis, antimicrobial
and cytotoxicity study of 1,3-disubstituted-1H- naphtho[1,2e][1,3]oxazines,” European Journal of Medicinal Chemistry, vol.
56, pp. 195–202, 2012.
L. Benameur, Z. Bouaziz, P. Nebois, M.-H. Bartoli, M. Boitard,
and H. Fillion, “Synthesis of furonaphth[1,3]oxazine and
furo[1,3]oxazinoquinoline derivatives as precursors for an oquinonemethide structure and potential antitumor agents,”
Chemical and Pharmaceutical Bulletin, vol. 44, no. 3, pp. 605–
608, 1996.
Y. Tabuchi, Y. Ando, H. Kanemura et al., “Preparation of
novel (Z)-4-ylidenebenzo[b]furo[3,2-d][1,3]oxazines and their
biological activity,” Bioorganic and Medicinal Chemistry, vol. 17,
no. 11, pp. 3959–3967, 2009.
M. E. Pierce, R. L. Parsons Jr., L. A. Radesca et al., “Practical
asymmetric synthesis of Efavirenz (DMP 266), an HIV-1 reverse
transcriptase inhibitor,” Journal of Organic Chemistry, vol. 63,
no. 23, pp. 8536–8543, 1998.
P. Zhang, E. A. Terefenko, A. Fensome, J. Wrobel, R. Winneker, and Z. Zhang, “Novel 6-aryl-1, 4-dihydrobenzo[d][and
Journal of Chemistry
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
oxazine-2thiones as potent, selective, and orally active nonsteroidal progesterone receptor agonists,” Bioorganic & Medicinal Chemistry Letters, vol. 13, no. 7, pp. 1313–1316, 2003.
. M JMillan, B. Di Cara, M. Hill et al., “A.Gobert, J.L.Peglion
and M.Brocco, Novel naphtoxazine agonist at Dopamine D3/D2
receptors: I. cellular, electrophysiological, and neurochemical
profile in comparison with Ropinirole,” J. Pharmacol. Expl. Ther,
vol. 309, pp. 921–935, 2004.
J. N. Joyce, S. Presgraves, L. Renish et al., “Neuroprotective
effects of the novel D3/D2 receptor agonist and antiparkinson
agent, S32504, in vitro against 1-methyl-4- phenylpyridinium
(MPP+) and in vivo against 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP): a comparison to ropinirole,” Journal of
Experimental Neurology, vol. 184, no. 1, pp. 393–407, 2003.
D. Sunil, H. Upadhya Sadhana, Savitha, and M. Rama, “Synthesis, characterization and QSAR studies of some new 1, 3oxazines as potent antimicrobial agents,” Research Journal of
Pharmaceutical Sciences, vol. 2, no. 2, pp. 15–19, 2013.
W. S. I. Abou-Elmagd, A. K. El-Ziaty, and A. A. Abdalha, “Ring
transformation and antimicrobial activity of indolyl-substituted
2(3H)-furanones,” Heterocyclic Communications, vol. 21, no. 3,
pp. 179–185, 2015.
N. S. El-Sayed, A. N. Shirazi, M. G. El-Meligy et al., “Synthesis of
4-aryl-6-indolylpyridine-3-carbonitriles and evaluation of their
antiproliferative activity,” Tetrahedron Letters, vol. 55, no. 6, pp.
1154–1158, 2014.
The Antimicrobal Susceptibility Test, Principle and Practices,
ELBS, London, UK, 4th edition, 1976.
M. S. Abdel-Aziz, M. S. Shaheen, A. A. El-Nekeety, and M. A.
Abdel-Wahhab, “Antioxidant and antibacterial activity of silver
nanoparticles biosynthesized using Chenopodium murale leaf
extract,” Journal of Saudi Chemical Society, vol. 18, no. 4, pp.
356–363, 2014.
H. Kiyani, H. A. Samimi, F. Ghorbani, and S. Esmaieli,
“One-pot, four-component synthesis of pyrano[2,3-c]pyrazoles
catalyzed by sodium benzoate in aqueous medium,” Current
Chemistry Letters, vol. 2, no. 4, pp. 197–206, 2013.
7
International Journal of
Medicinal Chemistry
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Photoenergy
International Journal of
Organic Chemistry
International
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
International Journal of
Analytical Chemistry
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Advances in
Physical Chemistry
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
International Journal of
Carbohydrate
Chemistry
Hindawi Publishing Corporation
http://www.hindawi.com
Journal of
Quantum Chemistry
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Volume 2014
Submit your manuscripts at
http://www.hindawi.com
Journal of
The Scientific
World Journal
Hindawi Publishing Corporation
http://www.hindawi.com
Journal of
International Journal of
Inorganic Chemistry
Volume 2014
Journal of
Theoretical Chemistry
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Spectroscopy
Hindawi Publishing Corporation
http://www.hindawi.com
Analytical Methods
in Chemistry
Volume 2014
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Chromatography Research International
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
International Journal of
Electrochemistry
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Journal of
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Journal of
Catalysts
Hindawi Publishing Corporation
http://www.hindawi.com
Journal of
Applied Chemistry
Hindawi Publishing Corporation
http://www.hindawi.com
Bioinorganic Chemistry
and Applications
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
International Journal of
Chemistry
Volume 2014
Volume 2014
Spectroscopy
Volume 2014
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014