Synthesis and Antimicrobial Activity of Some Novel Quinoline, Chromene, Pyrazole Derivatives Bearing Triazolopyrimidine Moiety

Article abstract of DOI:10.1002/jhet.2645

7-Amino-3-phenyl-[1,2,4]triazolo [4,3-a] pyrimidin-5(1H)-one (5) was utilized as key intermediate for the synthesis of some new, quinolines 9, 10, 11, 12, 13, 14 and 18, 19, 20, acrylonitrile 25 and 28, coumarin 26, and pyrazoles 31, 32, 33, 34 incorporating triazolopyrimidines. The structures of the newly synthesized compounds were confirmed by elemental analysis, IR, ¹H NMR, and mass spectral data. Representative compounds of the synthesized products were tested and evaluated as antimicrobial. Compounds 25, 28, 31, 32, 33, and 34 are the most promising.

Full text of DOI:10.1002/jhet.2645

Month 2016
Synthesis and Antimicrobial Activity of Some Novel Quinoline,
Chromene, Pyrazole Derivatives Bearing Triazolopyrimidine Moiety
A. A. Abu-Hashemc,d and M. A. Goudaa,b
*
aDepartment of Chemistry, Faculty of Science and Arts, Ulla, Taibah University, KSA
bDepartment of Chemistry, Faculty of Science, Mansoura University, El-Gomhoria Street, 35516 Mansoura, Egypt
cDepartment of Photochemistry (Heterocyclic Unit), National Research Center, Dokki, Giza 12622, Egypt
dDepartment of Chemistry, Faculty of Science, Jazan University, 2097 Jezan, Saudi Arabia
*
E-mail: dr_mostafa_chem@yahoo.com
Received December 24, 2015
DOI 10.1002/jhet.2645
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
7-Amino-3-phenyl-[1,2,4]triazolo [4,3-a] pyrimidin-5(1H)-one (5) was utilized as key intermediate for the
synthesis of some new, quinolines 9–14 and 18–20, acrylonitrile 25 and 28, coumarin 26, and pyrazoles
31–34 incorporating triazolopyrimidines. The structures of the newly synthesized compounds were
confirmed by elemental analysis, IR, 1H NMR, and mass spectral data. Representative compounds of
the synthesized products were tested and evaluated as antimicrobial. Compounds 25, 28, 31, 32, 33,
and 34 are the most promising.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
substituents, and include antimalarial [12], anticancer
[13], antimicrobial [14], and anti-inflammatory activities
[15]. Coumarin (2H-chromen-2-one) and its derivatives
are widely distributed in nature and have been reported
to exhibit diverse pharmacological properties such as
anticancer [16], anti-coagulant, estrogenic, dermal,
photosensitizing, antimicrobial, vasodilatory, mollusci-
cidal, antihelminthic, sedative, hypnotic, and analgesic
hypothermic [17,18]. Many biological properties for
pyrazole derivatives have been reported such as anti-
inflammatory [19], antiviral [20], antimicrobial [21], anti-
convulsant [22], antitumor [23], fungicidal activities [24],
and antihistaminic [25].
In view of these facts and as a continuation of our
research program on the chemistry of 6-amino-2,3-
dihydro-2-thioxopyrimidin-4(1H)-one [26–29], the present
investigation aimed to synthesize and characterize newer
quinoline, chromene, and pyrazole derivatives bearing TP
moiety in order to evaluate their anti-microbial activities.
It was found that 7-amino-3-phenyl-[1,2,4]triazolo [4,3-a]
pyrimidin-5(1H)-one (5) is an excellent building block
for the synthesis of the target objectives.
Triazolopyrimidines (TPs), a subtype of purine analogs,
have been the subject of chemical and biological studies
because of their interesting pharmacology including
antibacterial [1], antifungal [2], antihypertensive [3],
anticonvulsant [4], antitumor [5], cytotoxicity [6], potent
and selective ATP site directed inhibition of the EGF-
receptor protein tyrosine kinase [7], and cardiovascular
[8] activities.
In addition, TPs are versatile ligands, and their derived
coordination compounds can be considered as model sys-
tems for metal–ligand interactions observed in biological
systems [9,10]. The simple molecule of Trapidil, the most
widely known TP derivative, acts as a platelet-derived
growth factor antagonist and as a phosphodiesterase inhib-
itor [9]. Essramycin was the first TP antibiotic isolated
from nature. Essramycin represents a class of TP and was
proved to be potent antibiotic agents [11].
Furthermore, Pyrimidoquinolines are important com-
pounds because of their biological properties, which are
known to depend mainly on the nature and position of
© 2016 Wiley Periodicals, Inc.

A. A. Abu-Hashem and M. A. Gouda
Vol 000
Scheme 1. Preparation of 7-amino-3-phenyl-[1,2,4]triazolo [4,3-a] pyrimidin-5(1H)-one (5). [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
Scheme 2. Synthesis of [1,2,4]triazolo[4′,3′:1,2]pyrimido[4,5-b]quinoline derivatives 9–14. [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
Scheme 3. Synthesis of [1,2,4]triazolo[4′,3′:1,2]pyrimido[4,5-b]quinoline derivatives 18–20.
RESULTS AND DISCUSSION
derivative (5), was prepared via heating under reflux of
6-aminothiouracil (1) with benzohydrazide (3) in
dimethyl formamide, followed by stirring under reflux of
the formed N′-(pyrimidin-2-yl)benzohydrazide derivative
4 in sodium ethoxide. In another route compound
Chemistry. The reaction sequences used for synthesis of
the title compounds are depicted in Schemes 1, 2, 3, 4, and 5.
The starting compound, 7-aminopyrimidin-5(1H)-one
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Novel Bioactive Triazolopyrimidines
Scheme 4. Synthesis of acrylonitrile derivatives 25, 28, iminocoumarin 28.
Scheme 5. Synthesis of pyrazole derivatives (31–34). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
4 was prepared by alkylation of 1 with methyl
iodide in ethanolic potassium hydroxide solution to
afford 6-amino-2-(methylthio) pyrimidin-4(3H)-one (2)
[30], which reacted with benzohydrazide (3) in absolute
ethanol to give the corresponding 4 (Scheme 1).
The starting compound, 7-amino-3-phenyl-[1,2,4]triazolo
[4,3-a] pyrimidin-5(1H)-one (5) was used as versatile
precursor to react with common reagents to obtain a
variety of heterocyclic compounds. Thus, compound 5
reacted with cyclic α,β-unsaturated ketones type (6–8) in
dimethylformamide for 6–7h afforded compounds (9–11)
in good yield. Whereas, triazolo pyrimido[4,5-b]quinolines
12–14 were achieved when the reaction mixture was
refluxed for a longer time of 45 h. In another route com-
pounds 12 were prepared by refluxing of compound 9 in
DMF for 15h (Scheme 2).
Moreover, cyanoacetylation of compound 5 with
ethylcyanoacetate 21 afforded the cyanoacetamide 22.
Knovenagel condensation of 22 with bezaldehyde 23 or
salicyaldehyde 24 afforded the corresponding arylidine
25 and iminocoumarin 26, respectively. Also, fusion of
22 with acetophenone 27 in the presence of ammonium
acetate afford the corresponding arylidine 28 (Scheme 4).
Condensation of compound 25 with hydrazine deriva-
tives 29, 30 afforded the 3-amino-N-(1,5-dihydro-5-oxo-
3-phenyl
[1,2,4]triazolo[4,3-a]pyrimidin-7-yl)-5-phe-nyl-
1H-pyrazole-4-carboxamide (31) and 3-amino-N-(1,5-
dihydro-5-oxo-3-phenyl [1,2,4]triazolo[4,3-a]pyrimidin-7-
yl)-1,5-diphenyl-1H-pyrazole-4-carboxamide (32) as the ma-
jor products. The formation of the pyrazole derivatives 31,
32 proceed via β-attack of hydrazine derivatives 29, 30 on
the C¼C moiety in 25 to give the non-isolable intermediates
I and II which underwent 1,5-intramolecular dipolar cycliza-
tion and concomitant aromatization. Minor products 33, 34
were obtained in the mother liquor which proceeds via the
condensation of hydrazine derivatives 29, 30 with the
Furthermore, reaction of compound 5 with 2,4-
dichlorobenzoic acid 15, o-fluorobenzaldehyde 16, 2-
chlorocyclohexene carboxaldehyde 17 in glacial acetic acid
produced the triazolopyrimidoquinolines 18–20 (Scheme 3).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. A. Abu-Hashem and M. A. Gouda
Vol 000
carbonyl followed by addition on the cyano group afforded
the pyrazole derivatives 33, 34; similar behaviors were re-
ported [31] (Scheme 5).
Comparing the results obtained for the antimicrobial
activities of the compounds reported in this study with their
structures, the following SAR are postulated (Fig. 1): (i) it
seems that most of the quinolines, cyanoacetamid, couma-
rin, and pyrazole derivatives are more potent than the
starting TP 5 which may be because of the presence of the
quinoline, NHCOCH2CN, coumarin, and pyrazole moieties
respectively. (ii) The antimicrobial activities of quinoline
9–13 follow the order 9 <11 < 10, which may be
attributed to the electronic effect of the p-substituents,
i.e. Cl > OCH3 > H by +M. (iii) Compounds 25 and 28
have good antimicrobial activities which may be attributed
to presence of acrylonitrile moiety. (iv) Compound 33, 34
and 35,36, have good antimicrobial activities than compound
5, which may be attributed to the presence of aminopyrazole
and iminopyrazole moieties respectively (Fig. 1).
Assignment of the new synthesized compounds was
1
based on elemental analyses, IR, H, 13C NMR, and mass
spectral data (c.f. Exp. Part).
Biological evaluation. The new synthesized compounds
were screened in vitro for their antimicrobial activity. The
diameter of inhibition zone was measured as an indicator
for the activity of the compounds. The results for
antibacterial activities depicted in Table 1 revealed that
compounds 10, 11, 25, 28, 31, 32, 33, and 34 were
the most effective against Staphylococcus aureus and
Bacillus subtilis and have moderate activity against
Pseudomonas aeruginosa, and Escherichia coli. On the
other hand, most of the prepared compounds exhibited
low to moderate antifungal activities against the reference
drugs, whereas compounds 25, 28, 31, 32, 33, and 34
were the most effective against Aspergillus fumigatus and
Geotrichum candidum and have moderate activity against
Candida albicans, and Syncephalastrum racemosum
(Table 2).
CONCLUSION
Novel quinoline, cyanoacetamide, acrylonitrile, coumarin,
and pyrazole derivatives incorporating the triazolepyrimidine
Table 1
Antibacterial activity of compounds.a,b,c
Gram positive bacteria
Gram negative bacteria
Staphylococcus aureus
Bacillus subtilis
Pseudomonas aeruginosa
Escherichia coli
Compounds
(RCMB 000106)d
(RCMB 000107)
(RCMB 000102)
(RCMB 000103)
1
2
3
10.30 0.52
11.10 0.32
NA
8.85 0.45
9.10 0.60
NA
NA
NA
NA
NA
NA
NA
4
5
9
10
11
12
13
14
18
19
20
22
25
26
28
31
12.90 0.10
14.40 0.28
23.20 0.60
25.30 0.82
24.10 0.52
17.50 0.70
19.10 0.60
18.20 0.40
22.50 0.30
14.20 0.80
20.20 0.50
21.60 0.70
26.50 0.72
16.40 0.80
26.90 0.45
29.50 0.30
29.70 0.21
27.50 0.34
28.60 0.07
30.50 0.62
28 0.30
10.40 0.20
12.80 0.50
22.50 0.80
24.20 0.50
23.60 0.70
16.30 0.50
18.50 0.20
17.40 0.10
21.80 0.60
13.10 0.60
19.70 0.30
20.60 0.50
25.40 0.40
15.10 0.90
25.60 0.55
30.10 0.90
29.50 0.80
26.20 0.42
28.90 0.70
34.25 0.85
30 0.50
NA
NA
7.10 0.52
7.80 0.74
14.10 0.30
15.60 0.15
15.20 0.20
NA
10.30 0.70
NA
13.50 0.60
NA
11.40 0.80
12.70 0.90
16.80 0.10
NA
17.60 0.85
22.40 0.60
23.60 0.50
18.80 0.95
20.20 0.30
35.40 0.55
27 0.46
14.50 0.40
16.70 0.40
15.80 0.50
NA
10.40 0.50
NA
13.70 0.20
NA
11.50 0.70
12.80 0.40
17.80 0.35
NA
18.50 0.75
22.80 0.75
24.30 0.40
19.70 0.25
20.80 0.50
29.45 0.20
26 0.30
32
33
34
Penicillin G
Streptomycin
RCMB, Regional Center for Mycology and Biotechnology Culture Collection.; NA, no activity.
aMean zone of inhibition in mm standard deviation beyond well diameter (6 mm) produced on a range of environmental and clinically pathogenic
microorganisms using (10 mg/mL) concentration of tested samples. The concentration used for the standard antibiotic was (30 μg/mL).
bThe test was done using the diffusion agar technique. Well diameter: 6.0 mm (100 μL was tested).
cData are expressed in the form of mean SD.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Novel Bioactive Triazolopyrimidines
Table 2
Antifungal activity of compounds.a,b,c
Fungi
Aspergillus fumigatus
Geotrichum candidum
Candida albicans
Syncephalastrum racemosum
Compounds
(RCMB 002003)
(RCMB 052006)
(RCMB 005002)
(RCMB 005003)
1
2
3
NA
NA
NA
NA
7.70 0.60
NA
NA
NA
NA
NA
NA
NA
4
5
9
10
11
12
13
14
8.10 0.05
9.50 0.60
18.40 0.50
20.20 0.60
19.50 0.45
10.90 0.50
14.60 0.40
13.70 0.20
17.30 0.40
14.20 0.80
NA
8.50 0.80
9.80 0.50
18.20 0.30
20.40 0.50
19.25 0.60
9.80 0.30
12.80 0.60
11.50 0.40
16.50 0.40
13.10 0.60
NA
7.10 0.40
8.60 0.50
10.70 0.40
12.50 0.80
11.20 0.85
NA
NA
NA
9.40 0.30
NA
NA
NA
NA
10.10 0.50
11.60 0.30
11.10 0.35
NA
NA
NA
8.60 0.70
NA
18
19
20
NA
22
25
26
28
31
32
33
34
16.40 0.20
21.40 0.35
9.20 0.50
22.10 0.40
25.30 0.20
25.60 0.32
23.60 0.45
24.20 0.08
30 0.08
15.40 0.80
21.30 0.90
NA
22.60 0.75
25.20 0.40
25.40 0.70
22.10 0.90
24.50 0.40
29 0.40
NA
13.10 0.60
NA
14.30 0.25
19.60 0.60
20.20 0.50
16.70 0.50
18.30 0.20
28 0.05
20 0.30
NA
12.30 0.40
NA
13.50 0.65
18.50 0.30
20.40 0.20
15.60 0.80
17.10 0.50
24 0.10
22 0.08
Itraconazole
Clotrimazole
28 0.20
25 0.50
RCMB, Regional Center for Mycology and Biotechnology Culture Collection; NA, no activity.
aMean zone of inhibition in mm standard deviation beyond well diameter (6 mm) produced on a range of environmental and clinically pathogenic
microorganisms using (10 mg/mL) concentration of tested samples. The concentration used for the standard antibiotic was (30 μg/mL).
bThe test was done using the diffusion agar technique. Well diameter: 6.0 mm (100 μL was tested).
cData are expressed in the form of mean SD.
Figure 1. Structure–activity relationship of the more potent antimicrobial compounds. [Color figure can be viewed in the online issue, which is available
at wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. A. Abu-Hashem and M. A. Gouda
Vol 000
moiety have been synthesized and their microbial activity
evaluated. The results clearly showed that most of the com-
pounds had mild to moderate activity, and that coupling of
tiazolopyrimidine moiety to arylidine, pyrazole through a
carboxamide linkage improves the antimicrobial activity.
1675 (CO), 1620(C¼N), 1558(C¼C); 1H NMR (DMSO-d6): δ
(ppm)= 4.66 (s, 1H, C6―H), 6. 34 (br, 2H, NH2, D2O exchange-
able), 7.49–7.91 (m, 5H, phenyl), 11.65 (br, 1H, NH, D2O
exchangeable); 13CNMR (DMSO-d6): δ (ppm): 83.1 (C6, pyrimi-
dine), 128.1, 128.6, 128.8, 131.2 (6C, ArC), 150.8 (C3, triazole
ring); 158.5 (C7, pyrimidine), 160.4 (C8a, pyrimidine); 162.5 (C5,
pyrimidine); MS (EI, 70eV): m/z (%) = 229 (M+ + 2, 11.6) 227
(M+, 20.2), 203 (27.9), 125 (100), 103 (18.5), 91 (51.1), 77 (37.0),
63 (74.4); Anal. Calcd. for C11H9N5O (227.22): C, 58.14; H,
3.99; N, 30.82%; Found: C, 58.10; H, 3.95; N, 30.75%.
EXPERIMENTAL
General procedure for synthesis of (E)-10-(arylidene)-6-
Chemistry.
All melting points are in degree centigrade
(aryl)-3-phenyl-[1,2,4]triazolo[4′,3′:1,2]-pyrimido[4,5-b]quinoline-
(uncorrected) and were determined on Gallenkamp electric
melting point apparatus. TLC analysis was carried out on silica
gel 60 F254 precoated aluminum sheets. The IR spectra were
recorded (KBr) on a Perkin–Elmer 1430 spectrometer (λ, cmꢀ1) in
the National Research Center, Egypt. 1HNMR/13CNMR spectra
were measured on JEOL-ECA 500 and JEOL JNM-LA-400 FT
NMR Spectrometers at 500 and 125 MHz, respectively, using
tetramethylsilane (TMS) as an internal reference and DMSO-d6 as
solvent at the Microanalytical Center in National Research Center,
Egypt. The mass spectra (EI) were recorded on GCMS-QP 1000
EX (Shimadzu) at the National Research Center, Egypt. Elemental
analyses (C, H, and N) were carried out at the Microanalytical
Center in National Research Center, Egypt. The elemental
analyses were found to agree favorably with the calculated values.
Biological activities were carried in the Regional Center for
Mycology and Biotechnology, Al-Azhar University, Nasr City,
Cairo, Egypt.
5 (1H, 4H, 6H, 7H, 8H, 9H, 11H)-one (9–11).
A mixture of
7-amino-3-phenyl-[1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-one (5)
(2.27 g, 10 mmol), (2E, 6E)-2,6-dibenzylidenecyclohexanone
(6) (2.74 g, 10 mmol), (2E, 6E)-2,6-bis(4-chlorobenzylidene)
cyclohexanone (7) (3.42 g, 10 mmol), (2E, 6E)-2,6-bis (4-
methoxylbenzylidene) cyclohexanone (8) (3.34 g, 10 mmol),
was refluxed in dimethylformamide (45 mL) for 5–7 h. The
reaction mixture was cooled, then poured onto ice cold
water, the formed precipitate was filtered off, washed with
ethanol, and crystallized from the appropriate solvent to
afford 9–11.
(E)-10-(benzylidene)-6-(phenyl)-3-phenyl-[1,2,4]triazolo[4’,3’:1,2]-
pyrimido[4,5-b]quinoline-5 (1H, 4H, 6H, 7H, 8H, 9H, 11H)-one
(9). Yield 60%; mp 285–287°C; yellow powder; reaction time
6 h, crystallized from EtOH/DMF; IR (KBr): (ν/cmꢀ1) = 3380 (br,
2NH), 3050 (CH aryl), 1680 (CO), 1632 (C¼N; 1H NMR
(DMSO-d6): δ (ppm): 1.60–1.62(m, 2H, CH2), 2.20–2.25 (t, 2H,
CH2), 2.72–2.88 (t, 2H, CH2), 5.50 (s, 1H, pyridine ring), 7.00–
7.85 (m, 15H, ArH), 8.20 (s, 1H, methylenic proton), 10.40 and
12.10 (2brs,2H, 2NH, D2O exchangeable); MS (EI, 70 eV): m/z
(%) = 483 (M+, 30.4), 358 (55.7), 443 (22.4), 342 (38.5), 301
(26.4), 278 (22.0), 243(10.2), 168 (26.1), 125 (100), 89(23), 84
(35.2), 54(61.1); Anal. Calcd. for C31H25N5O (483.56); C, 77.00;
H, 5.21; N, 14.48%; Found: C, 77.10; H, 5.24; N, 14.56%.
Synthesis of N′-(6-amino-1, 2, 3, 4-tetrahydro-4-oxopyrimidin-2-yl)
benzohydrazide (4).
To a solution of compound 1, (1.43g,
10mmol) or 2 (1.57 g, 10mmol) in DMF (30 mL) and ethanol
(25 mL) respectively, benzohydrazide (3) (1.36g, 10mmol) was
added. The reaction mixture was heated under reflux for 9 h, and
then allowed to cool, poured onto ice/water, and the formed solid
product was collected by filtration and crystallized from
ethanol/benzene to give compound 4.
(E)-10-(4-chlorobenzylidene)-6-(4-chlorophenyl)-3-phenyl-
[1,2,4]triazolo [4′,3′:1,2]-pyrimido[4,5-b]quinoline-5 (1H, 4H,
Yield 73% (78%); yellow crystals; mp > 325 °C; IR (KBr):
(ν/cmꢀ1) = 3360 (br, NH, NH2), 3035 (CH―Ar), 1690, 1680
(2CO), 1622 (C¼N); 1555 (C¼C); 1H NMR (DMSO-d6): δ
(ppm):4.66 (s, 1H, C5-H), 6. 35 (br, NH2, D2O exchangeable)
7.48–7.90 (m, 5H, ArH): 11.51, 11.61 (br, 2NH, D2O exchange-
able), 12.10 (br, NH, D2O exchangeable); 13CNMR (DMSO-d6):
(δ ppm): 82.5 (C5, pyrimidine), 127.5, 128.7, 132.1, 132.4 (6C,
Ar―C), 158.6 (C6, pyrimidine), 161.2 (C4, pyrimidine), 164.5 (C2
pyrimidine), 165.1(CONH); MS (EI, 70 eV): m/z (%) = 247
(M++2, 2.1), 245 (M+, 6.3), 242 (74.4), 241 (18.5), 229 (12.6),
196 (34.4), 184 (25.3), 156 (24.2), 125 (17.9), 110 (15.7), 97
(7.4), 68 (15.7), 67 (45.3), 59(11.6). Anal. Calcd. for C11H11N5O2
(245.24): Calcd.: C, 53.87; H, 4.52; N, 28.56%. Found: C, 53.80;
H, 4.52; N, 28.56%.
6H, 7H, 8H, 9H, 11H)-one (10). Yield 65%; mp 315–317 °C;
yellow powder; reaction time 5 h crystallized from EtOH/benzene;
IR (KBr): (ν/cmꢀ1) = 3381 (br, 2 NH), 3052 (CH aryl), 1682
(CO), 1634 (C¼N); 1H NMR (DMSO-d6): δ (ppm): 1.64–1.67
(m, 2H, CH2), 2.27–2.37 (t, 2H, CH2), 2.74–2.86 (t, 2H, CH2),
5.43 (s, 1H, pyridine ring), 7.16–7.68 (m, 11H, Ar―H), 8.22 (s,
1H, CH¼), 11.00 and 12.30 (2brs, 2H, 2NH, D2O exchangeable);
MS (EI, 70eV): m/z (%) = 556 (M++4, 2.3), 554 (M++2, 6.2) 552
(M+, 11.4), 474 (11.7), 369 (5.5), 339 (7.2), 177 (8.9), 125 (49.7),
107 (55.8), 90 (100), 79 (54.4); Anal. Calcd. for C31H23Cl2N5O
(552.4); C, 67.40; H, 4.20; N, 12.68%; Found: C, 67.45; H, 4.15;
N, 12.63%.
Synthesis of 7-amino-3-phenyl-[1, 2, 4]triazolo[4,3-a]
(E)-10-(4-Methoxylbenzylidene)-6-(4-methoxylphenyl)-3-phenyl-
pyrimidin-5 (1H)-one (5). A solution of compound 4 (2.45 g,
10mmol) in ethanol (50mL) containing sodium ethoxide
(prepared by dissolving sodium metal) (0.23g, 10mmol in
ethanol) was heated under reflux for 9 h; the reaction mixture was
cooled, and the deposited precipitate was filtered off and washed
with ethanol. The formed salt was dissolved in water (50 mL) and
acidified with 10% HCl; the formed precipitate was filtered, dried,
and crystallized from methanol to afford 5.
[1,2,4]triazolo [4′,3′:1,2]-pyrimido[4,5-b]quinoline-5 (1H, 4H, 6H,
7H, 8H, 9H, 11H)-one (11). Yield 59%; mp 303–305 °C; yellow
powder; reaction time 5 h, crystallized from EtOH/DMF; IR (KBr):
(ν/cmꢀ1) = 3385 (br, 2NH), 3040 (CH aryl), 2910 (CH alkyl), 1681
1
(CO), 1635 (C¼N); H NMR (DMSO-d6): δ (ppm):1.63–1.66 (m,
2H, CH2), 2.26–2.36 (t, 2H, CH2), 2.73–2.85 (t, 2H, CH2), 3.88 (br,
6H, 2 methoxy groups), 5.42 (s, 1H, pyridine ring), 7.15–7.69 (m,
11H, ArH), 8.24 (s, 1H, CH¼), 11.20 and 12.40 (2brs,2H, 2NH,
D2O exchangeable; MS (EI, 70 eV): m/z (%) = 543 (M+, 2.5), 538
(15.7), 465 (71.6), 463 (85.2), 449 (73.3), 386 (15.8), 341(18.2),
Yield 75%; mp > 325 °C; Yellowish crystals; IR (KBr):
(ν/cmꢀ1) = 3312, 3352 (br, 2NH, NH2), 3038 (CH aryl),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Novel Bioactive Triazolopyrimidines
239 (17.5), 175 (20.8), 151(29.1), 139 (44.1), 125(100), 115(20.0), 93
(25.0), 77 (20.1), 55 (21.6); Anal. Calcd. for C33H29N5O3 (543.6); C,
72.91; H, 5.38; N, 12.88%; Found: C, 72.88; H, 5.35; N, 12.80%.
General procedure for synthesis of (E)-10-(arylidene)-6-
precipitate reaction after cooling was filtered off, dried, and
recrystallized from the proper solvent to afford compounds
(18–20).
9-Chloro-3-phenyl[1,2,4]triazolo [4′,3′:1,2]-pyrimido[4,5-b]
(aryl)-3-phenyl-[1,2,4]triazolo[4′,3′:1,2] Pyrimido[4,5-b]quinoline-
quinoline-5,6(1H, 4H,11H) dione (18). Yield 70%; mp > 325 °C;
brown powder; Reaction time 20 h, recrystallization from methanol;
IR (KBr): (ν/cm-1) = 3345 (br, 2NH), 1715, 1665 (2CO), 1628
5 (1H, 4H, 7H, 8H, 9H)-one (12–14) and 9–11. A suspension of
7-amino-3-phenyl-[1,2,4]triazolo[4,3-a]pyrimidin-5 (1H)-one (5)
(2.27 g, 10mmol) and (2E, 6E)-2,6-dibenzylidenecyclohexanone
(6) (2.74 g, 10 mM), (2E, 6E)-2,6-bis(4-chlorobenzylidene)
cyclohexanone (7) (3.42 g, 10 mM) or 2E, 6E)-2,6-bis (4-
methoxylbenzylidene) cyclohexanone (8) (3.34 g, 10 mmol) in
dimethylformamide (45mL) was refluxed for 45 h. The reaction
mixture was cooled; the deposited precipitate was filtered off,
washed with ethanol and dried, and crystallized from DMF to
give 12–14 in a good yield. The filtrate was poured onto ice
cold water, the formed precipitate was filtered off, and crystallized
from appropriate solvent to afford 9–11.
1
(C¼N); H NMR (DMSO-d6): δ (ppm): 7.01–7.85 (m, 8H, ArH),
11.70, 12.35 (2brs, 2H, 2NH, D2O exchangeable); MS (EI, 70 eV):
m/z (%) = m/z 365 (M+ + 2, 4.7), 363 (M+, 14.2), 336 (39.3), 322
(28.9), 286 (10.7), 250 (14.0), 188 (32.1), 167 (46.4), 124 (100), 98
(17.3), 63 (50); Anal. Calcd. for C18H10ClN5O2 (363.7); C, 59.43;
H, 2.77; N, 19.25%; Found: C, 59.40; H, 2.70; N, 19.15%.
3-Phenyl[1,2,4]triazolo-[4′,3′:1,2]pyrimido[4,5-b]quinoline-5
(1H, 4H) one(19).
Yield, 60%; mp > 325 °C; white powder;
reaction time 14 h, recrystallization from dioxane; IR (KBr):
1
(ν/cmꢀ1) = 3340 (br, 2NH), 1680 (CO), 1630 (C¼N); H NMR
(E)-10-benzylidene–3,6-diphenyl-[1,2,4]triazolo-[4′,3′:1,2]
pyrimido[4,5-b]quino-line-5 (1H, 4H, 7H, 8H, 9H)-one
(DMSO-d6): δ (ppm): 7.30–7.91 (m, 9H, ArH); 8.55 (s, 1H,
C5―H, pyridine ring), 11.60, (br., NH, D2O exchangeable); Anal.
Calcd. for C18H11N5O (313.3); C, 69.00; H, 3.54; N, 22.35%;
Found: C, 69.10; H, 3.50; N, 22.31%.
(12).
Yield 65%; mp >325 °C; yellow powder; IR (KBr):
(ν/cmꢀ1) = 3355 (brs, NH), 3030 (CH aryl), 1687 (CO), 1634
(C=N); 1H NMR (DMSO-d6): δ (ppm): δ1.63–1.66 (m, 2H, CH2),
2.28–2.31 (t, 2H, CH2), 2.76–2.98 (t, 2H, CH2), 7.01–7.873 (m,
15H, ArH), 8.21 (s, 1H, CH¼) and 11.55 (br.,1H, NH, D2O
exchangeable); MS (EI, 70 eV): m/z (%)= 481 (M+, 21.1), 477
(100), 464 (36.8), 450 (64.2), 405 (22.1), 366 (21.1), 342 (15.7),
302 (18.9), 220 (31.6), 125 (77.9), 115(7.3), 53(4.3); Anal. Calcd.
for C31H23N5O (481.55); C, 77.32; H, 4.81; N, 14.54%; Found:
C, 77.38; H, 4.74; N, 14.45%.
3-Phenyl[1,2,4]triazolo-[4′,3′:1,2]pyrimido[4,5-b]quinoline-5
(1H, 4H, 7H, 8H, 9H,10H)-one (20). Yield, 68%; mp 270–272 °C;
white powder; reaction time 12 h, recrystallization from DMF; IR
(KBr): (ν/cmꢀ1) = 3349 (br, NH), 1682 (CO), 1632 (C¼N); 1H
NMR (DMSO-d6): δ (ppm): 1.70–1.74 (m, 2H, CH2 of quinolone
ring), 1.75–1.79 (m, 2H, CH2 of quinolone ring), 2.70 (t, 2H,
quinolone ring), 3.02 (t, 2H, quinolone ring), 7.37–7.43 (m, 5H,
phenyl), 8.35 (s, 1H, pyridine ring), 11.70, (br., 1H, NH, D2O
exchangeable). MS (EI, 70 eV): m/z (%) = m/z 365(M+, 11.4), 307
(100), 280 (81.8), 253 (31.8), 244 (45.5), 216 (36.4), 167 (22.7), 128
(54.5), 115 (95.4), 63 (36.4); Anal. Calcd. for C18H15N5O (317.3);
C, 68.13; H, 4.76; N, 22.07%; Found: C, 68.06; H, 4.70; N, 22.01%.
Synthesis of 2-cyano-N-(5-oxo-3-phenyl-1,5-dihydro-[1,2,4]
triazolo[4,3-a]pyrim-idin-7-yl)acetamide (22). To a solution
of 5 (2.27 g, 10 mmol) in dimethylformamide (30 mL), ethyl
cyanoacetate (1.13 g, 10 mmol) was added. The reaction mixture
was heated under reflux for 7 h. The formed solid product upon
pouring onto ice/water was collected by filtration and
crystallized from benzene to give 22.
Yield 73%; mp 268–270 C; yellow crystals; IR (KBr):
(ν/cmꢀ1) = 3330, 3225 (2 NH), 3045 (CH aryl), 2915 (CH
aliphatic), 2260 (CN), 1695, 1680 (2CO), 1630 (C¼N), 1545
(C¼C); 1H NMR (DMSO-d6): δ (ppm): δ 4.10 (s, 2H, CH2), 6.88
(s, 1H, pyrimidine ring), 7.50–7.58 (m, 5H, ArH), 8.22 (br,1H,
NH, D2O exchangeable), 11.50 (br.,1H, NH, D2O exchangeable);
MS (EI, 70eV): m/z (%) = 294 (100) Anal. Calcd. for
C14H10N6O2 (294.27); C, 57.14; H, 3.43; N, 28.56%; Found C,
57.20; H, 3.35; N, 28.50%.
(E)-10-(4-chlorobenzylidene)-6-(4-chlorophenyl)-3-phenyl-
[1,2,4]triazolo [4’,3’: 1,2] Pyrimido[4,5-b]quinoline-5 (1H, 4H,
7H, 8H, 9H)-one (13).
Yield 66%; mp >325°C; yellow
powder; IR (KBr): (ν/cmꢀ1) = 3375 (brs, NH), 3035 (CH aryl),
1688 (CO), 1630 (C¼N); 1H NMR (DMSO-d6): δ (ppm):
1.65–1.68 (m, 2H, CH2), 2.28–2.31 (t, 2H, CH2) 2.74–2.96 (t, 2H,
CH2), 7.14–7.66 (m, 13H, ArH), 8.20 (s, 1H, CH¼), 11.50 (br.,
1H, NH, D2O exchangeable); MS (EI, 70 eV): m/z (%) = 464
(M++4, 5.2), 462 (M++2, 15.3) 560 (M+, 20.0), 549 (28.6), 448
(25.7), 390(5.7), 342 (22.8), 279 (20.0), 165 (25.6), 125 (100),
113 (45.2), 102 (45.2), 83 (20.7), 50 (48). Anal. Calcd. for
C31H21Cl2N5O (550.4); C, 67.64; H, 3.85; N, 12.72%; Found: C,
67.60; H, 3.81; N, 12.79%.
(E)-10-(4-methoxybenzylidene)-6-(4-methoxyphenyl)-3-phenyl-
[1,2,4]triazolo-[4′,3′:1,2]-pyrim-ido[4,5-b]quinoline-5 (1H, 4H,
7H, 8H, 9H)-one (14).
Yield 63%; mp > 325 °C; yellow
powder; IR (KBr): (ν/cmꢀ1) = 3350 (brs, NH), 3035 (CH aryl),
2905 (CH alkyl), 1688 (CO), 1641 (C¼N); 1H NMR (DMSO-d6):
δ (ppm): 1.66–1.71 (m, 2H, CH2), 2.28–2.31 (t, 2H, CH2)
2.75–2.96 (t, 2H, CH2), 3.79 (brs, 6H, OCH3) 7.17–7.71(m, 13H,
ArH), 8.24 (s, 1H, CH¼), 11.65 (br.,1H, NH, D2O exchangeable);
Anal. Calcd. for C33H27N5O3 (541.6); C, 73.18; H, 5.02; N, 12.93;
%; Found: C, 73.15; H, 5.10; N, 12.90%.
General procedure for synthesis of [1,2,4]triazolo
[4′,3′:1,2]-pyrimido[4,5-b]quinolone derivatives 25–26.
To
a solution of (22) (2.94 g, 10 mmol) in 1,4-dioxane (30 mL)
containing piperidine (1.00 mL) either benzaldehyde (23)
(1.06 g, 10 mmol) or salicylaldehyde (24) (1.22 g, 10 mmol)
was added. The reaction mixture, in each case, was heated
under reflux for 6–8 h. The formed precipitate upon pouring
onto ice-water mixture containing few drops of hydrochloric
acid was collected by filtration to give (25) and (26),
respectively.
The yield of compounds 9 (13%), 10, (15%), and 11 (14%),
respectively.
General procedure for synthesis of [1,2,4]triazolo [4′,3′:1,2]-
pyrimido[4,5-b]quinoline derivatives (18–20).
To a solution of
5 (2.27 g, 10 mmol) glacial acetic acid (40 mL), 2,4-dichlorobenzoic
acid (15) (1.89 g, 10 mmol), 2-fluorobenzaldehyde (16)
(1.24 g, 10 mmol) or 2-chlorocyclohex-1-enecarbaldehyde
(17) (1.46 g, 10 mmol) was added. The reaction mixture was
stirred and heated under reflux for 12–20 h. The formed
(2E)-2-cyano-N-(1,5-dihydro-5-oxo-3-phenyl-[1,2,4]triazolo
[4,3-a]pyrimidin-7-yl)-3-phenylacrylamide (25). Yield 78%; mp
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. A. Abu-Hashem and M. A. Gouda
Vol 000
186–188 °C; yellow powder; Reaction time 8 h, crystallization
from DMF; IR (KBr): (ν/cmꢀ1) = 3335, 3230 (2NH), 3055 (CH
aryl), 2920 (CH aliph), 2265 (CN), 1698, 1686 (2CO), 1628
exchangeable), 11.64, 12.10 (brs, 2NH, D2O exchangeable); MS
(EI, 70eV): m/z (%) = 412(M+, 57.8), 366 (52.6), 326 (42.2), 248
(18.4), 215 (21.1), 167 (23.7), 125 (100), 75 (31.5); Anal. Calcd.
for C21H16N8O2 (412); C, 64.23; H, 4.16; N, 23.83%; Found: C,
64.15; H, 4.10; N, 23.91%.
3-Amino-N-(1,5-dihydro-5-oxo-3-phenyl [1,2,4]triazolo[4,3-
a]pyrimidin-7-yl)-1,5-diphenyl-1H-pyrazole-4-carboxamide
1
(C¼N), 1540 (C¼C); H NMR (DMSO-d6): δ (ppm): δ 6.85 (s,
1H, pyrimidine ring), 7.35–7.85 (m, 10H, ArH), 8.05 (br.,1H,
NH, D2O exchangeable), 8.18 (s, 1H, CH¼) 11.52 (br.,1H, NH,
D2O exchangeable); MS (EI, 70 eV): m/z (%) = m/z 382(M+,
31.8), 380(M+, ꢀ2, 100), 337 (13.6), 55 (18.2); Anal. Calcd. for
C21H14N6O2 (382.37); C, 65.96; H, 3.69; N, 21.98%; Found: C,
65.91; H, 3.62; N, 21.90%.
(32).
Yield 66%, m.p. 238–240°C; white crystals; IR (KBr):
(ν/cm–1) = 3412–3208 (brs, NH2, NH), 3048 (CH aryl), 1692,
1686 (2CO), 1634 (C¼N), 1564 (C¼C; 1H NMR (DMSO-d6):
δ (ppm): 6.50 (br., 2H, NH2, D2O exchangeable), 6.94 (s, 1H,
pyrimidine ring), 7.15–7.85 (m, 15H, ArH), 8.09 (br.,1H, NH,
D2O exchangeable), 11.61 (br., 1H, NH, D2O exchangeable);
MS (EI, 70 eV): m/z (%) = 488 (M+, 4.1), 448 (35.5), 423
(6.3), 369 (6.6), 344 (31.2), 264 (79.1), 235 (44.4), 213 (100),
185 (14.5), 164(62.5), 139 (31.3), 121 (93.7), 105 (83.3), 84
(10.4), 56(8.3); Anal. Calcd. for C27H20N8O2 (488.50); C,
68.98; H, 4.34; N, 20.11%; Found: C, 68.90; H, 4.48; N,
20.03%.
N-(1,5-dihydro-5-oxo-3-phenyl-[1,2,4]triazolo[4,3-a]pyrimidin-
7-yl)-2-imino-2H-chromene-3-carboxamide (26). Yield 60%;
mp 250–252 °C; orange powder; reaction time 6 h,
recrystallization from dioxan; IR (KBr): (ν/cmꢀ1) = 3430–3240
(brs, NH), 3050 (CH aryl), 2930(CH alphatic), 1700, 1680
(3CO), 1632 (C¼N), 1565 (C¼C); 1H NMR (DMSO-d6): δ
(ppm): 6.92 (s, 1H, pyrimidine ring), 7.35–7.68 (m, 10H, ArH),
7.83 (br 1H, NH, D2O exchangeable), 8.14 (br.,1H, NH, D2O
exchangeable), 11.61 (br.,1H, NH, D2O exchangeable); MS (EI,
70 eV): m/z (%) = 399 (M+, 68.7), 352 (69.7), 291 (31.2), 253
(18.7), 214(16.7), 166(25.0), 125 (100), 89(56.2); Anal. Calcd.
for C21H13N5O4 (398.37); C, 63.31; H, 3.54; N, 21.10%; Found:
C, 63.15; H, 3.60; N, 21.02%.
(E)-7-(4-benzylidene-5-imino-4,5-dihydro-1H-pyrazol-3-ylamino)-
3-phenyl [1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-one (33). Yield
15%; mp 198–200 °C; white crystals; IR (KBr): (ν/cmꢀ1) = 3420–
3210 (brs, 2NH), 3040 (CH aryl), 1685 (CO), 1633 (C¼N), 1550
(C¼C); 1H NMR (DMSO-d6): δ (ppm): 6.82 (br., NH, D2O
exchangeable), 7.32–7.84 (m, 10H, two phenyl), 8.08 (s, 1H,
pyrimidine ring), 8.20 (s, 1H, CH¼), 9.10, 10.25, 11.68 (brs,
3NH, D2O exchangeable); Anal. Calcd. for C21H16N8O (396.40);
C, 63.63; H, 4.07; N, 28.27%; Found: C, 63.60; H, 4.02; N,
28.20%.
Synthesis of (E)-2-cyano-N-(5-oxo-3-phenyl-1,5-dihydro-[1,2,4]
triazolo[4,3-a]pyrimidin-7-yl)-3-phenylbut-2-enamide (28). To a
mixture of 22 (2.94 g, 10 mmol) and acetophenone (27) (1.20 g,
10 mmol), ammonium acetate (0.50 g) was added, and the
reaction mixture was heated in an oil bath 140 °C for 50 min.
Then, ethanol (65 mL) was added, and the reaction mixture was
boiled for 15 min. The reaction mixture was poured onto ice/water,
and the formed product was crystallized from methanol to
give 28.
(E)-7-(4-benzylidene-5-imino-1-phenyl-4,5-dihydro-1H-pyrazol-
3-ylamino)-3-phenyl-[1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-one
(34).
Yield 13%; mp 234–236 °C; white crystals; IR (KBr):
(ν/cmꢀ1) = 3410–3230 (brs, 2NH), 3030 (CH aryl), 2920 (CH
alkyl), 1682 (CO), 1630 (C¼N), 1555 (C¼C); 1H NMR
(DMSO-d6): δ (ppm): 6.80 (s, 1H, pyrimidine ring)), 7.10–7.89
(m, 15H, ArH), 8.09 (br., NH, D2O exchangeable), 8.19 (s,
1H, CH¼), 10.20, 11.65 (brs, 2NH, D2O exchangeable); MS
(EI, 70eV): m/z (%) = 472 (M+, 100), 435 (95.6), 404 (78.3),
341 (52.2), 310 (60.8), 277 (26.1), 202 (34.8), 164 (47.8), 146
(52.2), 125 (86.9), 99 (56.5), 65 (69.5); Anal. Calcd. for
C27H20N8O (472.50); C, 68.63; H, 4.27; N, 23.72%; Found: C,
68.63; H, 4.27; N, 23.72 5%.
Yield (70%); mp 212–214 °C; yellow powder; IR (KBr):
(ν/cmꢀ1) = 3436–3231 (brs, NH), 3058 (CH aryl), 2922 (CH alkyl),
2262 (CN), 1699,1684 (2CO), 1629 (C¼N), 1535 (C¼C); 1H NMR
(DMSO-d6): δ (ppm): 2.25 (s, 3H, CH3), 6.90 (s, 1H, pyrimidine
ring), 7.15–7.84 (m, 10H, ArH), 8.09 (br.,1H, NH, D2O exchange-
able), 11.54 (br., 1H, NH, D2O exchangeable); MS (EI, 70 eV): m/z
(%) = 396 (M+, 55.5), 395 (100, M+ ꢀ 1), 365 (90.9), 315 (40.9),
308(13.6), 276 (10.2), 249 (0.7), 91 (27.3) Anal. Calcd. for
C22H16N6O2 (396.40); C, 66.66; H, 4.07; N, 21.20%; Found: C,
66.60; H, 4.15; N, 21.28%.
General procedure for synthesis of [1,2,4]triazolo [4′,3′:1,2]-
In vitro antimicrobial activity.
The tested compounds
pyrimido[4,5-b]quinolone derivatives 31–34. To a solution of
compound 25 (3.82 g, 10mmol) in 1, 4-dioxane (30 mL) and
either hydrazine hydrate (29) (0.50g, 10mmol), or phenyl
hydrazine (30) (1.08 g, 10 mmol) was added. The reaction
mixture, in each case, was heated under reflux for 5 h and 6 h. The
solid products formed, were collected by filtration, and
crystallized from dimethylformamide and MeOH mixture to give
31 and 32 respectively. The mother liquor were poured onto
ice/water mixture containing few drops of hydrochloric acid. The
solid products formed, were collected by filtration, and
crystallized from dimethylformamide to give 33 and 34.
were evaluated by the agar diffusion technique [32] using a
2 mg/mL solution in DMSO. The test organisms were four
bacterial strains: S. aureus and B. subtilis (as Gram positive
bacteria) and P. aeruginosa, E. coli, and Salmonella typhi (as
Gram negative bacteria). and two fungi: A. fumigatus, G.
candidum, C. albicans, and S. racemosum. A control using
DMSO without the test compound was included for each
organism. Penicillin G and Streptomycin were purchased from
the Egyptian market and used in a concentration 10 mg/mL as
reference drugs for antibacterial activity, whereas, Itraconazole
and Clotrimazole were used as reference drugs for antifungal
activity The bacteria and fungi were tested on nutrient agar
and potato dextrose agar media, respectively. Three plates were
used for each compound as replicates. The plates were
incubated for 24 h and seven days for bacteria and fungi,
respectively. After the incubation period, the diameter of
inhibition zone was measured as an indicator for the activity of
the compounds.
3-Amino-N-(1,5-dihydro-5-oxo-3-phenyl-[1,2,4]triazolo[4,3-
a]pyrimidin-7-yl)-5-phenyl-1H-pyrazole-4-carboxamide (31). Yield
60%; mp 218–220 °C; yellow crystals;; IR (KBr): (ν/cmꢀ1
)
= 3415–3205 (brs, NH2, NH), 3042 (CH aryl), 1690, 1684 (2CO),
1
1632 (C¼N), 1560 (C¼C); H NMR (DMSO-d6): δ (ppm): 6.48
(br., 2H, NH2, D2O exchangeable), 6.95 (s, 1H, pyrimidine
ring),7.40–7.85 (m, 10H, ArH), 8.10 (br., NH, D2O
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Novel Bioactive Triazolopyrimidines
[14] El-Sayed, O. A.; El-Bieh, F. M.; Al-Bassam, B. A. Boll Chim
Farm 2002, 141, 461–465.
Acknowledgments. We deeply appreciate the Regional Center
for Mycology and Biotechnology, Al-Azhar University, Nasr City,
Cairo, Egypt, for carrying out the biological activity tests.
The presented work was supported by the Department of
Photochemistry (Heterocyclic unit); Chemical Industries Research
Division, National Research Centre in Cairo, Egypt.
[15] El-Sayed, O. A.; Al-Turki, T. M.; Al-Daffiri, H. M.;
Al-Bassam, B. A.; Hussein, M. E. Boll Chim Farm 2004, 143, 227.
[16] Murray, R. D. H.; Mendez, J.; Brown, S. A. The Natural
Coumarins: Occurrence, Chemistry and Biochemistry; John Wiley: New
York, 1982, pp 28.
[17] Soine, T. O. J. Pharm. Sci. 1964, 53, 231.
[18] O’Kennedy, R. D. Coumarins E Biology; Applications and
Mode of Action John Wiley: Chichester, 1997, pp 125.
[19] Tewari, A. K.; Mishra, A. Bioorg Med Chem 2001, 9, 715.
[20] Janus, S. L.; Magdif, A. Z.; Erik, B. P.; Claus, N. Monatsh
Chem 1999, 130, 1167.
[21] Pimerova, E. V.; Voronina, E. V. Pharm Chem J 2001, 35, 602.
[22] Bouabdallah, I.; Barret, L. A.; Zyad, A.; Ramadan, A.; Zidane,
M. I A Nat Prod Res 2006, 20, 1024.
REFERENCES AND NOTES
[1] Broom, D.; Shim, J. L.; Anderson, G. L. J Org Chem 1976,
41, 1095.
[2] Chen, Q.; Zhu, X. L.; Jiang, L. L.; Liu, Z. M.; Yang, G. F. Eur
J Med Chem 2008, 43, 595.
[3] Degraw, J. I.; Kisliuk, R. L.; Gaumont, Y.; Baugh, C. M.
J Med Chem 1974, 17, 470.
[4] Deyanov, B.; Niyazov, R. K.; Nazmetdivov, F. Y.; Syropyatov,
B. Y.; Kolla, V. E.; Konshin, M. E. J. Pharm Chem 1991, 25, 248.
[5] Navarro, J. A. R.; Salas, J. M.; Romero, M. A.; Vilaplana, R.;
Faure, R. J Med Chem 1998, 41, 332.
[6] Magan, R.; Marin, C.; Salas, J. M.; Perez, M. B.; Rosales, M.
J Mem Inst Oswaldo Cruz 2004, 99, 651.
[7] Traxler, P. M.; Furet, P.; Mett, H.; Buchdunger, E.; Meyer, T.;
Lydon, N. J. J Med Chem 1996, 39, 2285.
[8] Sato, Y.; Shimoji, Y.; Fujita, H.; Nishino, H.; Mizuno, H.;
Kobayashi, S.; Kumakura, S. J Med Chem 1980, 23,927, 927.
[9] Fischer, G. Adv Heterocycl Chem 2008, 95, 143.
[10] Salas, J. M.; Romero, M. A.; Sánchez, M. P.; Quirós, M. A.
Coord Chem Rev 1999, 193, 1119.
[23] Park, H. J.; Lee, K.; Park, S. J.; Ahn, B.; Lee, J. C.; Cho, H. Y.;
Lee, K. I. Bioorg Med Chem Lett 2005, 15, 3307.
[24] Chu, C. K.; Cutler, J. J Heterocycl Chem 1986, 23, 289.
[25] Michon, V.; Du Penhoat, C. H.; Tombret, F.; Gillardin, J. M.;
Lepagez, F.; Berthon, L. Eur J Med Chem 1995, 30, 147.
[26] Abu-Hashem, A. A.; Youssef, M. M.; Hussein, H. A. R.
J Chinese Chem Soc 2011, 58, 41.
[27] Abu-Hashem, A. A.; Aly, A. S. Activity Arch Pharm Res
2012, 35, 437.
[28] Hussein, H. A. R.; Abu-Zied, K. M.; Abu-Hashem, A. A.
Egypt J Chem 2010, 53, 527.
[29] Abu-Hashem, A. A.; Gouda, M. A.; Badria, F. A. Eur J Med
Chem 2010, 45, 1976.
[30] Guiney, D.; Gibson, C. L.; Suckling, C. J Org Biomol Chem
2003, 1, 664.
[11] El-Gendy, M. M. A.; Shaaban, M.; Shaaban, K. A.;
El-Bondkly, M.; Laatsch, A. H. J Antibiotics 2008, 61, 149.
[12] Joshi, A. A.; Viswanathan, C. L. Med Chem 2006, 5, 105.
[13] Dlugosz, A.; Dus, D. Farmaco 1996, 51, 364.
[31] Khalil, M. A.; Sayed, S. M.; Raslan, M. A. Am J Org Chem
2012, 2(6), 161.
[32] Cruickshank, R.; Duguid, J. P.; Marion, B. P.; Swain, R. H. A.
Medicinal Microbiology, II; Churchill Livingstone: London, 1975, pp 196.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet