Site selectivity in reactions of hydrazonoyl halides with heterocycles containing amino and thione groups leading to fused heterocycles of potential antimicrobial activity

Article abstract of DOI:10.1134/S1068162014010075

Reaction of hydrazonoyl halides with 6-(benzylidenamino)-2-thioxo-2,3- dihydro-1H-pyrimidin-4-one and 2,3-diaminoquinazolin-4-one site-selectively afforded 3-substituted-7-(benzylidenamino)-1-phenyl-[1,2,4]triazolo[4,3-a]- pyrimidin-5(1H)-ones, [1,2,4,5]tetrazino[6,1-b]quinazolin-6(4H)-one, and 3-methyl-2-(4-substituted-phenylhydrazo)-[1,2,4]triazino[3,2-b] quinazolin-10-ones in good yields. The structures of the newly synthesized compounds were elucidated by chemical evidence and their IR, ¹H, ¹³C NMR, and MS spectra. Furthermore, some of the products were screened against different strains of bacteria and fungi.

Full text of DOI:10.1134/S1068162014010075

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2014, Vol. 40, No. 1, pp. 106–113. © Pleiades Publishing, Ltd., 2014.
Site Selectivity in Reactions of Hydrazonoyl Halides
with Heterocycles Containing Amino and Thione Groups Leading
to Fused Heterocycles of Potential Antimicrobial Activity1
2
M. E. A. Khalifaa, M. A. Amina, b, and M. A. N. Mosselhia, c,
aDepartment of Chemistry, Faculty of Science, Taif University, P.O. 888, Taif, Saudi Arabia
bDepartment of Chemistry, Faculty of Science, Suez Canal University, Ismailia, Egypt
cDepartment of Chemistry, Faculty of Science, Cairo University, 12613ꢀGiza, Egypt
Received April 25, 2013; in final form, June 20, 2013
Abstract
dinꢀ4ꢀone and 2,3ꢀdiaminoquinazolinꢀ4ꢀone siteꢀselectively afforded 3ꢀsubstitutedꢀ7ꢀ(benzylidenamino)ꢀ
1ꢀphenylꢀ[1,2,4]triazolo[4,3ꢀ ]ꢀpyrimidinꢀ5(1 )ꢀones, [1,2,4,5]tetrazino[6,1ꢀ ]quinazolinꢀ6(4 )ꢀone,
—Reaction of hydrazonoyl halides with 6ꢀ(benzylidenamino)ꢀ2ꢀthioxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrimiꢀ
a
H
b
H
and 3ꢀmethylꢀ2ꢀ(4ꢀsubstitutedꢀphenylhydrazo)ꢀ[1,2,4]triazino[3,2ꢀb]quinazolinꢀ10ꢀones in good yields.
The structures of the newly synthesized compounds were elucidated by chemical evidence and their IR, 1H,
13C NMR, and MS spectra. Furthermore, some of the products were screened against different strains of bacꢀ
teria and fungi
.
Keywords: hydrazonoyl halide, siteꢀselectivity, quinazoline, pyrimidine, antimicrobial activity
DOI: 10.1134/S1068162014010075
2 1
INTRODUCTION
access to various fused quinazoline and pyrimidine deꢀ
rivatives. Fused quinazolines are reported to be bioacꢀ
tive: there are cytotoxic compounds with potential anꢀ
titumoral activity [17] and various therapeutic agents,
such as anticancer agents [18] and anticonvulsants
[19]. Triazinoquinazoline derivatives are reported to
be good DNAꢀbinding fluorophores [20–23].
The regioselectivity in the reactions of hydrazonoyl
halides has been widely employed in the synthesis of hetꢀ
erocyclic derivatives [1–10]. Also the reactions of hydraꢀ
zonoyl halides with aminoazoles, aminoazines, and variꢀ
ous types of heterocyclic thiones provided convenient
strategies for synthesis of fused heterocycles [11–16].
From this point of view and in continuation of part of our
program aimed at developing new convenient approachꢀ
es for synthesis of fused heterocycles via utility of hydraꢀ
Furthermore, it is reported that pyrimidines are of
chemical and pharmacological interest [24] and comꢀ
pounds containing the pyrimidine ring system have
been shown to possess antibacterial [25], antifungal
[26], antimalarial [27], anticonvulsant [28], and antiꢀ
tumor [29] activities.
zonoyl halides (
containing amino and/or thione groups, we wish to reꢀ
port the results of our study of the reactions of 6ꢀ(benꢀ
zylidenamino)ꢀ2ꢀthioxoꢀ2,3ꢀdihydroꢀ1 ꢀpyrimidinꢀ4ꢀ
one (II) or 2,3ꢀdiaminoquinazolinꢀ4ꢀone (IX) with hyꢀ
drazonoyl halides ( ). Our objective of such a study is to
I) as starting materials and heterocycles
H
RESULTS AND DISCUSSION
I
Synthesis. The starting hydrazonoyl chlorides (
[3, 30, 31] and 6ꢀ(benzylidenamino)ꢀ2ꢀthioxoꢀ2,3ꢀ
dihydroꢀ1 ꢀpyrimidinꢀ4ꢀone (II) [32] and 2,3ꢀdiꢀ
I)
shed some light on the site selectivity in such reactions as
they can in principle lead to the formation of 3ꢀsubstitutꢀ
edꢀ7ꢀ(benzylidenamino)ꢀ1ꢀphenylꢀ[1,2,4]triazolo[4,3ꢀ
H
aminoquinazolinꢀ4ꢀone (IX) [33] were prepared by
literature methods. The reaction of (II) with each of
the hydrazonoyl chlorides (Ia–j) in refluxing mixture
of dioxane and dimethylformamide and in the presꢀ
ence of triethylamine afforded in each case a single
product as indicated by TLC analysis of the crude
product, whose mass spectrum and elemental analysis
proved it to contain no sulfur. This finding excludes the
possible formation of 6ꢀ(3ꢀsubstitutedꢀ1ꢀarylꢀ5ꢀphenylꢀ
a
]pyrimidinꢀ5(1
H
)ꢀones (
V
), 1,3ꢀdiphenylꢀ1
Hꢀ
[1,2,4,5]tetrazino[6,1ꢀ
b
]quinazolinꢀ6(4
H
)ꢀone (XI),
and 3ꢀmethylꢀ2ꢀ(4ꢀsubstitutedꢀphenylhydrazono)ꢀ1,2ꢀ
dihydroꢀ[1,2,4]triazino[3,2ꢀ]quinazolinꢀ10ꢀone derivaꢀ
tives (XIVb–d) (Schemes 1, 2). The studied reactions
were found to be site selective and provide new general
1
The article is published in the original.
Corresponding author: phone: 00966ꢀ5ꢀ4377ꢀ2635; eꢀmail:
mosselhi2008@hotmail.com.
2
lHꢀ1,2,4ꢀtriazolꢀ4(5H)ꢀylꢀ2,3ꢀdihydroꢀ2ꢀthioxoꢀpyꢀ
106

SITE SELECTIVITY IN REACTIONS OF HYDRAZONOYL HALIDES
O
107
O
Cl
Dioxane/DMF
Et N/Δ
HN
HN
+
Ar NH
N
3
NNHAr
R
C
CHC6H5
N
CHC6H5
N
C
R
S
N
S
N
H
I
II
III
O
N
S
O
R
HN
R
C
HN
C
N
CHC6H5
N
H N
N
N Ar
CH
S
N
N
Ar
H
C6H5
IV
VI
–H S
2
I, V
R
Ar
O
N
a
b
c
d
C6H5
C6H5
C6H5
C6H4–CH ꢀ4
R
C
N
CH3CO
CH3CO
CH3CO
N
CHC6H5
N
N
3
C6H4–Clꢀ4
Ar
V
e
f
g
C2H5
C2H5
C2H5
O
O
O
CO
CO
CO
C6H5
C6H4–CH ꢀ4
C6H4–Clꢀ4
PhCHO
DMF
Δ
Va , R = Ar = Ph
3
O
N
h
i
C6H5NHCO C6H5
C6H5NHCO C6H4–CH ꢀ4
Ph
C
3
j
C6H5NHCO C6H4–Clꢀ4
N
N
NH2
VIII
N
Ph
O
Cl
HN
NNHPh
Ia
Dioxane/Et N,
Ph
C
S
N
H
NH2
Δ
3
VII
Scheme 1. Synthesis of 3ꢀsubstitutedꢀ7ꢀ(benzylidenamino)ꢀ1ꢀarylꢀ[1,2,4]triazoloꢀ
[4,3ꢀ ]ꢀpyrimidinꢀ5(1 )ꢀones (Va – j ).
a
H
rimidinꢀ4(1
H
)ꢀone (VI) (Scheme 1). The structure of assigned to Hꢀ6 of the pyrimidine ring residue and a
singlet signal in the region of 7.93 assigned to
N7=CH. 13C NMR spectrum of (Va ) showed signals at
118 (C6), [(ArꢀC, 120.5, 125.3–131.1, 149.1 (N1–
δ
the product was identified as 3ꢀsubstitutedꢀ7ꢀ(benꢀ
zylidenamino)ꢀ1ꢀarylꢀ[1,2,4]triazolo[4,3ꢀ ]ꢀpyrimiꢀ
) (Scheme 1). This assignment is
a
δ
dinꢀ5(1H)ꢀones (V
C)], 155.2 (C3), 158.5 (C7), 162.2 (C5=O), 163.1
(N4=C), 164.2 (N7=C). 13C NMR spectrum of (Va ),
revealed the signals of the carbonyl carbon of the pyriꢀ
based on their elemental and spectral (IR, MS, and 1H
13
and C NMR) analyses (see Experimental). Comꢀ
pound (Va ) is taken as a typical example, its 1H NMR
midinone ring residue at
δ
162.2. Such chemical shift
spectrum showed a singlet signal in the region of
δ
6.7 value is similar to that of annulated pyrimidines with
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2014

108
KHALIFA et al.
O
N
O
N
H
N
Cl
C
NH2
NH2
Dioxane/Et N
3
N
C
C6H5
N
NNHC6H5
+
C6H5
Δ
NNHC6H5
Ia
NH2
IX
X
H
N
O
C6H5
–NH
3
N
N
N
N
C6H5
XI
O
O
O
H
N
NH2
NH2
CꢀR
C
O
Cl
C
Dioxane/Et N
3
N
+
N
Δ
NNHC6H4ꢀXꢀ4
H3C
C
N
NNHC6H4ꢀXꢀ4
Ib–d
N
NH2
IX
(a)
XII
–H O
2
(a)
–NH
3
(b)
O
N
H
N
H
N
O
N
N
COCH3
NNHC6H4ꢀXꢀ4
CH3
N
N
N
N
N
XIV
C6H4Xꢀ4
XIII
b
, X = H;
Scheme 2. Synthesis of 1,3ꢀdiphenylꢀ[1,2,4,5]tetrazino[6,1ꢀ
and 3ꢀmethylꢀ2ꢀ(4ꢀsubstitutedphenylhydrazo)ꢀ[1,2,4]triazino[3,2ꢀ
c
, X = CH3;
]quinazolinꢀ6(4
]quinazolinꢀ10ꢀones (XIVb–d).
d, X = Cl
b
H)ꢀone (XI)
b
N3 pyrrole type [7]. IR spectra of (Va ) revealed abꢀ with concurrent elimination of hydrogen sulfide gas to
sorption bands at 1605 cm–1 (CO at Cꢀ5). The assignꢀ
ment of the formation of (Va ) was further manifested
by alternate synthesis. Thus, treatment of 6ꢀaminoꢀ2ꢀ
give (V) as end products (Scheme 1). All attempts to
isolate the intermediates (III) and (IV) failed since
they were consumed as soon as they were formed unꢀ
der the employed reaction conditions. On the other
hand, refluxing equimolar quantities of hydrazonoyl
thioxouracil (6ꢀaminoꢀ4ꢀoxopyrimidineꢀ2ꢀthione) (VII
with hydrazonoyl chloride (Ia) in dioxane in the presꢀ
ence of triethylamine under reflux led to evolution of
methanethiol and the formation of product (VIII
)
chloride (Ia) with 2,3ꢀdiaminoquinazolinꢀ4ꢀone (IX
)
in dioxane in the presence of triethylamine gave a sinꢀ
gle product, as indicated by TLC analysis of the crude
product. The structure of the product was identified as
)
[11]. The reaction of the latter with benzaldehyde in
refluxing DMF afforded a product that proved to be
identical in all respects (mp, mixed mp, and IR) with
compound (Va ) (Scheme 1). The direct formation of
1,3ꢀdiphenylꢀ[1,2,4,5]tetrazino[6,1ꢀ
one (XI), which may be formed via the intermediate (
b]quinazolinꢀ6(4H)ꢀ
X)
(Scheme 2). By the same manner, when the reaction
of each of hydrazonoyl halides (Ib–d) with (IX) in a
products (
hydrazonoyl chloride
V
) from the reaction of compound (II) with
I
indicates that the intermediate
thiohydrazonate esters (III) underwent Smiles rearꢀ mixture of dioxane and dimethylformamide in the
rangement [34] to give the corresponding thiohyꢀ presence of triethylamine also gave a single product as
drazides (IV), which in situ underwent cyclization indicated by TLC analysis of the crude product. The
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 40
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SITE SELECTIVITY IN REACTIONS OF HYDRAZONOYL HALIDES
Antibacterial and antifungal activities of the synthesized compounds (Va – c , e , f , h ) (XI), and (XIVb–d
IZD*, mm/mg compound tested
109
)
Compound No.
Gram negative bacteria Gram positive bacteria
fungi
EC
SA
AF
CA
Control: DMSO
0.0
30
0.0
29
0.0
–
0.0
–
Tetracycline
(antibacterial agent)
Amphotericin B
–
–
16
19
(antifungal agent)
(
(
(
(
(
(
(
(
Va
)
15
16
12
16
13
14
13
14
14
12
12
15
16
13
15
13
0
0
0
0
0
0
0
0
10
12
13
13
10
12
13
10
Vb
)
Vc)
Ve)
Vf
Vh
XI
XIVd
)
)
)
)
* IZD, inhibition zone diameter; IZD = 2–10 mm beyond control, low activity; IZD = 11–24 mm beyond control, moderate activity;
IZD = 25–35 mm beyond control, high activity.
structures of such products were identified as 3ꢀmethylꢀ phylococcus aureus (SA) and antifungal activity,
2ꢀ(4ꢀsubstitutedꢀphenylhydrazo)ꢀ[1,2,4]triazino[3,2ꢀ against Aspergillus flavus (AF) and Candida albicans
b]quinazolinꢀ10ꢀones (XIVb–d), and not the correꢀ (CA). The reference antibiotics tetracycline and amꢀ
sponding [1,2,4,5]tetrazino[6,1ꢀb]quinazolinꢀ6(4H)ꢀ photericin B were used as references to evaluate the
one (XIII). The reaction of (Ib–d) with (IX) proceeds potency of the tested compounds under the same conꢀ
through nucleophilic substitution followed by cycloꢀ ditions. The test results are depicted in table. The solꢀ
condensation. Confirmatory evidence for the strucꢀ vent used was dimethylsulfoxide. Concentration of the
ture assignment for compounds (XI) and (XIVb–d
was provided by spectroscopic data (IR, MS and compounds exhibited moderate activity against the
two bacterial species and all compounds, except (Va ),
Vf), and (XIVd), showed moderate activity against
one fungal species, Candida albicans
)
sample is 100 μg/mL. The test results revealed that all
1H and 13C NMR). The 1H NMR of product (XI) reꢀ
vealed only aromatic protons at 7.20–8.10 and NH
proton at 11.50, which is D2O exchangeable, and no
(
δ
.
δ
NH2 protons found. These spectral data are conveꢀ
nient with the proposed structure of 1,3ꢀdiphenylꢀ
EXPERIMENTAL
[1,2,4,5]tetrazino[6,1ꢀ
b
]quinazolinꢀ6(4
H
)ꢀone (XI
)
which may be formed via the intermediate (
X
). IR Specꢀ
All melting points were determined on an electroꢀ
thermal Gallenkamp apparatus and are reported unꢀ
corrected. Solvents were generally distilled and dried
by standard literature procedures prior to use. The IR
spectra were measured on a PyeꢀUnicam SP300 inꢀ
strument in potassium bromide discs. The 1H and 13C
NMR spectra were recorded on a Varian Mercury
tra of products (XIVb–d) showed only CO absorption
band of quinazoline moiety at 1660–1675 cm–1, while
their 1H NMR revealed characteristic peaks of 3ꢀCH3
at
nal at
indicate collectively that such compounds (XIVb–d
exist predominantly in the structures of 3ꢀmethylꢀ2ꢀ
(4ꢀsubstitutedꢀphenylhydrazo)ꢀ[1,2,4]triazino[3,2ꢀ
δ
2.9–3.01 and their 13C NMR showed only CO sigꢀ
162.5–163.0. The spectral data presented here
δ
)
1
VXRꢀ300 spectrometer (300 MHz for H NMR and
13
75 MHz for C NMR) and the chemical shifts were
b
]quinazolinꢀ10ꢀones.
related to that of the solvent DMSOꢀ
spectra were recorded on a GCMSꢀQ1000ꢀEX Shiꢀ
madzu and GCMS 5988ꢀA HP spectrometers, the
d6. The mass
Antimicrobial activity. The compounds were tested
in vitro against gram negative anaerobic bacteria
Escherichia coli (EC) and gram positive bacteria Staꢀ ionizing voltage was 70 eV. Elemental analyses were
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 40
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2014

110
KHALIFA et al.
carried out by the Microanalytical Center of Cairo 67.91; H, 4.61; N, 18.86. Found: C, 67.8; H, 4.5; N,
University, Giza, Egypt. The starting compounds, hyꢀ 18.5%.
drazonoyl chlorides ( ) [3, 30, 31], 6ꢀ(benzylidenamiꢀ
no)ꢀ2ꢀthioxoꢀ2,3ꢀdihydroꢀ1 ꢀpyrimidinꢀ4ꢀone (II
I
3ꢀAcetylꢀ7ꢀ(benzylidenamino)ꢀ1ꢀ(4ꢀchloropheꢀ
nyl)ꢀ[1,2,4]triazoloꢀ[4,3ꢀ ]ꢀpyrimidinꢀ5(1 )ꢀone
(Vd). Yield, 68%; yellow crystals, mp 230 C (ethaꢀ
nol/dioxane); IR (KBr) ν, cm–1 = 1665, 1610 (2CO),
1565 (N7=C); 1H NMR
: 2.5 (s, 3 H, CH3), 6.5 (s, 1 H,
H6), 7.15–7.40 (m, 5 H, ArꢀH), 7.50 (d, 2 H, aromatic
protons, = 8.0 Hz), 7.75 (d, 2 H, aromatic protons,
= 8.0 Hz), 7.95 (s, 1 H, N7=C–H); MS, (%) 392
+ + 1, 15), 391( +, 20), 306 (10), 260 (19), 240 (10),
190 (10), 90 (20), 77 (100). Anal Calcd. for
H
)
a
H
[32], and 2,3ꢀdiaminoquinazolinꢀ4ꢀone (IX) [33]
were prepared as previously reported.
°
Synthesis of 3ꢀsubstitutedꢀ7ꢀ(benzylidenamino)ꢀ1ꢀ
δ
phenylꢀ[1,2,4]triazoloꢀ[4,3ꢀ
(V). General procedure. To a mixture of equimolar
amounts of 6ꢀ(benzylidenamino)ꢀ2ꢀthioxoꢀ2,3ꢀdihyꢀ
droꢀ1 ꢀpyrimidinꢀ4ꢀone (II) and an appropriate hyꢀ
drazonoyl chloride ( ) (5 mmol ) in dioxane (30 mL) and
dimethylformamide (20 mL) triethylamine (0.7 mL,
5 mmol) was added. The reaction mixture was refluxed
till all of the starting materials have disappeared (8–12) h,
as monitored by TLC. After cooling, the reaction solvent
was evaporated and 10 mL methanol was added. The solꢀ
id formed was collected and recrystallized from
a]ꢀpyrimidinꢀ5(1H)ꢀones
J
J
m/z
H
(M
M
I
.
C20H14ClN5O2 (391.81): C, 61.31; H, 3.60; N, 17.87.
Found: C, 61.0; H, 3.2; N, 17.5%.
3ꢀEthylꢀ7ꢀ(benzylidenamino)ꢀ1ꢀphenylꢀ[1,2,4]triꢀ
azoloꢀ[4,3ꢀa]ꢀpyrimidinꢀ5(1H)ꢀone 3ꢀcarboxylate (Ve).
Yield, 70%, pale yellow crystals, mp 220–223°C
(ethanol/dioxane); IR (KBr) ν, cm–1 = 1751, 1676
EtOH/dioxane (v : v, 1 : 1) to give the products (V).
1
(2CO), 1575 (N7=C); H NMR
δ: 1.3 (t,
J
= 7Hz,
The compounds prepared, together with their
physical constants, are given below.
3 H, CH3), 4.47 (q,
H6), 7.2–7.6 (m, 10 H, ArꢀH), 8.0 (s, 1 H, N7=C–H);
13C NMR
: 12.2, 21.0, 118.3, 120.5, 125.5–131.6,
149.1, 155.2 (N=C), 158.5, 162.2 (CO), 163.1
(N=C), 164.2 (N7=C), 198.1 (CO). MS, (%):
371 (
+, 10), 306 (9), 282 (17), 190 (11), 91 (15), 77
(100). Anal Calcd. for C24H17N5O (371.14): C, 67.91;
J = 7 Hz, 2 H, CH2), 6.4 (s, 1 H,
7ꢀ(Benzylidenamino)ꢀ1,3ꢀdiphenylꢀ[1,2,4]triazoloꢀ
δ
[4,3ꢀ
crystals, mp 180–182
, cm–1 = 1605 (CO), 1545 (N7=C); 1H NMR
(s, 1 H, H6), 7.007.85 (m, 15 H, ArꢀH), 7.93 (s, 1 H,
a
]ꢀpyrimidinꢀ5(1
H
)ꢀone (Va). Yield, 65%; yellow
C (ethanol/dioxane); IR (KBr)
: 6.7
°
m/z
ν
δ
M
.
13
N7=C–H); C NMR
149.1, 155.2 (N=C), 158.5, 162.2 (CO), 163.1
(N=C), 164.2 (N7=C). MS, (%): 391 (
+, 20),
306 (9), 262 (17), 242 (11), 190 (11), 91 (20), 77 (100).
Anal. Calcd. for C24H17N5O (391.14): C, 73.64; H, 4.38;
N, 17.89. Found: C, 73.5; H, 4.25; N, 17.58%.
δ
: 118.0, 120.5, 125.3–131.1,
H, 4.61; N, 18.86. Found: C, 68.0; H, 4.4; N, 18.7%.
3ꢀEthylꢀ7ꢀ(benzylidenamino)ꢀ1ꢀ(4ꢀmethylphenyl)ꢀ
m
/z
M
[1,2,4]triazoloꢀ[4,3ꢀ
boxylate (Vf). Yield, 72%; pale yellow crystals,
mp 203–204 C (ethanol/dioxane); IR (KBr)
, cm–1:
1750, 1666 (2CO), 1565 (N7=C); 1H NMR
: 1.25 (t,
= 7 Hz, 3 H, CH3), 4.50 (q, = 7 Hz, 2H, CH2), 6.50
(s, 1 H, Cꢀ6), 7.20–7.50 (m, 5H, ArꢀH), 7.61 (d, 2 H,
aromatic protons, = 8.0 Hz), 7.72 (d, 2 H, aromatic
a]ꢀpyrimidinꢀ5(1H)ꢀone 3ꢀcarꢀ
°
ν
δ
3ꢀAcetylꢀ7ꢀ(benzylidenamino)ꢀ1ꢀphenylꢀ[1,2,4]triꢀ
J
J
azoloꢀ[4,3ꢀ
pale yellow crystals, mp 205
(KBr)
, cm–1 = 1664, 1610 (2CO), 1568 (N7=C);
1H NMR
: 2.6 (s, 3 H, CH3), 6.8 (s, 1 H, H6), 7.10–
7.80 (m, 10H, ArꢀH), 7.95 (s, 1 H, N7=C–H);
13C NMR (DMSOꢀd6
: 24.4, 116.0, 128.1–131.1,
146.3, 154.0 (N=C), 158.5, 162.0 (CO), 163.2 (N=C),
163.7 (N7=C), 180.5 (Me–CO). MS, (%): 391
+, 15), 306 (10), 260 (19), 240 (10), 190 (10),
90 (20), 77 (100). Anal Calcd. for C20H15N5O2 (391.14):
a
]ꢀpyrimidinꢀ5(1
H
°
)ꢀone (Vb). Yield, 62%;
C (ethanol/dioxane); IR
J
ν
protons,
J
= 8.0 Hz), 8.0 (s, 1 H, N7=C–H);
: 12.2, 22.1, 24.5, 116.2, 120.5, 125.5–
δ
13C NMR
δ
131.6, 149.1, 155.2 (N=C), 158.5, 162.2 (CO), 163.1
(N=C), 164.2 (N7=C), 198.0 (CO). MS, (%) 385
+, 100), 306 (9), 282 (30), 195 (22), 91 (18), 77
(80). Anal Calcd. for C22H19N5O2 (385.15): C, 68.56;
)
δ
m/z
(M
m/z
.
(M
H, 4.97; N, 18.17. Found: C, 68.2; H, 4.8; N, 18.0%.
.
3ꢀEthylꢀ7ꢀ(benzylidenamino)ꢀ1ꢀ(4ꢀchlorophenyl)ꢀ
C, 67.22; H, 4.23; N, 19.60. Found: C, 67.0; H, 4.2; N,
19.2%.
[1,2,4]triazoloꢀ[4,3ꢀ
boxylate (Vg). Yield, 70%, pale yellow crystals,
mp 235–236
C (ethanol/dioxane); IR (KBr) ν, cm–1 =
1750, 1674 (2CO), 1570 (N7=C) cm–1; H NMR
1.3 (t, = 7 Hz, 3H, CH3), 4.45 (q, = 7 Hz, 2 H,
CH2), 6.4 (s, 1 H, H6), 7.11–7.54 (m, 5 H, ArꢀH),
7.60 (d, 2 H, aromatic protons, = 8.0 Hz), 7.70 (d, 2 H,
aromatic protons, = 8.0 Hz), 7.95 (s, 1 H, N7=C–H);
MS, (%) 405 (
+, 50), 305 (20), 280 (33), 190
(15), 91 (25), 77 (100). Anal Calcd. for C21H16ClN5O2
(405.1): C, 62.15; H, 3.97; N, 17.26. Found: C, 62.0;
H, 4.0; N, 17.5%.
a]ꢀpyrimidinꢀ5(1H)ꢀones 3ꢀcarꢀ
3ꢀAcetylꢀ7ꢀ(benzylidenamino)ꢀ1ꢀ(4ꢀmethylphenyl)ꢀ
°
[1,2,4]triazoloꢀ[4,3ꢀ
Yield, 60%; pale yellow crystals, mp 196
oxane); IR (KBr)
, cm–1 = 1660, 1600 (2CO), 1550
: 2.3 (s, 3 H, CH3), 2.6 (s, 3 H,
CH3), 6.6 (s, 1 H, H6), 7.2–7.5 (m, 5 H, ArꢀH), 7.55 (d,
2 H, aromatic protons, = 8.0 Hz), 7.8 (d, 2 H, aromatic
protons, = 8.0 Hz), 8.0 (s, 1 H, N7=C–H); MS,
(%) 371 (
+, 25), 305 (15), 280 (19), 190 (14), 91 (20),
77 (100). Anal Calcd. for C21H17N5O2 (371.14): C,
a
]ꢀpyrimidinꢀ5(1
H
)ꢀone (Vc).
C (ethanol/diꢀ
1
δ:
°
J
J
ν
1
(N7=C); H NMR
δ
J
J
J
m/z
M
J
m/z
.
M
.
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2014

SITE SELECTIVITY IN REACTIONS OF HYDRAZONOYL HALIDES
111
7ꢀ(Benzylidenamino)ꢀ3,1ꢀdiphenylꢀ[1,2,4]triazoꢀ
loꢀ[4,3ꢀ ]ꢀpyrimidinꢀ5(1 )ꢀoneꢀ3ꢀcarboxamide (Vh).
Yield, 66%, pale yellow crystals, mp 240–242 C (ethꢀ
anol/dioxane); IR (KBr) ν, cm–1 = 1664, 1632 (2CO),
1541 (N7=C); 1H NMR
: 6.53 (s, 1 H, Cꢀ6), 7.14–
7.87 (m, 15 H, ArꢀH), 8.16 (s, 1 H, N7=C–H), 10.35
(s, 1 H, NH); 13C NMR (DMSOꢀd6
: 116.3, 122.6–
133.8, 146.1, 154.2 (N=C), 158.5, 160.0 (CO), 162.2
(CO), 163.0 (N=C), 164.5 (N7=C); MS, (%) 434
+, 44), 254 (30), 167 (15), 91 (25), 77 (100). Anal
General procedure. To a mixture of the appropriate
hydrazonoyl chloride (Ib–d (5 mmol) and 2,3ꢀdiamiꢀ
a
H
)
°
noquinazolinꢀ4ꢀone (IX) (0.88 g, 5 mmol) in dioxane
(40 mL) triethylamine (0.7 mL, 5 mmol) was added.
The mixture was then stirred under reflux for 10 h
(monitored by TLC). During this period, the reactants
dissolved and the crude product began to precipitate.
After cooling, the solid formed was collected by filtraꢀ
tion, dried and finally crystallized from EtOH/dioxꢀ
ane (v : v, 1 : 1) to give 1,3ꢀdiphenylꢀ[1,2,4,5]tetraziꢀ
δ
)
δ
m/z
(M
.
no[6,1ꢀ
sponding 3ꢀmethylꢀ2ꢀ(4ꢀsubstitutedꢀphenylhydrazoꢀ
[1,2,4]triazinoꢀ[3,2ꢀ ]quinazolinꢀ10ꢀones (XIVb–d).
b]quinazolinꢀ6(4H)ꢀone (XI) and the correꢀ
Calcd. for C25H18N6O2 (434.15): C, 69.11; H, 4.18; N,
19.34. Found: C, 69.5; H, 4.0; N, 19.5%.
b
7ꢀBenzylidenaminoꢀ3ꢀpheny1ꢀ(4ꢀmethylphenyl)ꢀ
The compounds prepared, together with their
physical constants, are listed below.
[1,2,4]ꢀtriazoloꢀ[4,3ꢀ
amide (Vi). Yield, 65%, pale yellow crystals, mp 211–
213
C (ethanol/dioxane); IR (KBr) ν, cm–1 = 1660,
1630 (2CO), 1550 (N7=C); 1H NMR
: 2.3 (s, 3 H,
CH3), 6.50 (s, 1 H, H6), 7.30–7.67 (m, 10 H, ArꢀH),
7.75 (d, 2 H, aromatic protons, = 8.0 Hz), 7.85 (d, 2 H,
aromatic protons, = 8.0 Hz), 8.16 (s, 1 H, N7=C–H),
10.40 (s, 1 H, NH); 13C NMR
: 22.5, 116.8, 122.6–
131.8, 140.0, 146.1, 154.5 (N=C), 158.0, 161.0 (CO),
162.5 (CO), 163.0 (N=C), 164.0 (N7=C); MS,
(%) 448 (
+, 30), 366 (19), 338 (15), 254 (30), 167
(15), 110 (4), 94 (25),82 (10), 77 (100). Anal Calcd.
a]ꢀpyrimidinꢀ5(1H)ꢀone 3ꢀcarboxꢀ
1,3ꢀDiphenylꢀ[1,2,4,5]tetrazino[6,1ꢀb]quinazoꢀ
°
linꢀ6(4H)ꢀone (XI). Yield, 75%, yellow crystals, mp
δ
>300
1688 (CO); 1H NMR
7.60 (d, 2 H, aromatic protons,
2 H, aromatic protons, = 8.0 Hz), 11.50 (s, 1 H,
: 122.0–133.5, 145.1, 146.5, 155.0,
162.5, 163.1 (CO). MS, (%) 353 (
+, 50), 276
(20), 264 (11), 190 (11), 89 (20), 77 (60). Anal Calcd.
°
C; (dioxane); IR (KBr) ν, cm–1 = 3131 (NH),
δ: 7.20–7.50 (m, 10 H, ArꢀH),
J
J
= 8.0 Hz), 8.10 (d,
J
J
δ
13
NH); C NMR
δ
m/z
M
m/z
.
M
for C21H15N5O (353.13): C, 71.38; H, 4.28; N, 19.82.
Found: C, 71.4; H, 4.1; N, 19.5%.
3ꢀMethylꢀ2ꢀphenyhydrazoꢀ[1,2,4]triazino[3,2ꢀ
.
for C26H20N6O2 (448.16): C, 69.63; H, 4.49; N, 18.74.
Found: C, 69.4; H, 4.5; N, 19.0%.
b]quinazolinꢀ10ꢀone (XIVb). Yield, 69%, orange crysꢀ
7ꢀBenzylidenaminoꢀ3ꢀpheny1ꢀ(4ꢀchlorophenyl)
tals, mp >300°
(NH), 1675 (CO); H NMR
C; (dioxane); IR (KBr) ν, cm–1 = 3130
[1,2,4]triazoloꢀ[4,3ꢀ
amide (Vj). Yield, 55%, pale yellow crystals, mp 230–
232
C (ethanol/dioxane); IR (KBr) ν, cm–1 = 1664,
1630 (2CO), 1545 (N7=C); 1H NMR
: 6.50 (s, 1 H,
H6), 7.15–7.60 (m, 10 H, ArꢀH), 7.75 (d, 2 H, aroꢀ
matic protons, = 8.0 Hz), 7.85 (d, 2 H, aromatic
protons, = 8.0 Hz), 8.10 (s, 1 H, N7=C–H), 10.50
(s, 1 H, NH); MS,
(%) 469 (M+ +1, 25), 468 (M+
40), 391 (20), 386 (15), 354 (30), 167 (15), 110 (4), 94
(25), 82 (10), 77 (100). Anal Calcd. for C25H17ClN6O2
a]ꢀpyrimidinꢀ5(1H)ꢀone 3ꢀcarboxꢀ
1
δ: 2.9 (s, 3 H, CH3),
6.95–7.45 (m, 5 H, ArꢀH), 7.60 (d, 2 H, aromatic proꢀ
tons, = 8.0 Hz), 7.85 (d, 2 H, aromatic protons,
= 8.0 Hz), 10.20 (s, 1 H, NH), 11.30 (s, 1 H, NH); 13C
NMR : 20.5, 120.0–130.5, 140.1, 145.0, 154.3,
161.0, 162.5 (CO). MS, (%) 318 (
+, 30), 227
(20), 203 (11), 190 (11), 105 (15), 91 (20), 77 (100).
Anal Calcd. for C17H14N6O (318.12): C, 64.14; H,
°
J
J
δ
δ
J
m/z
M
J
m/z
,
.
4.43; N, 26.40. Found: C, 64.0; H, 4.2; N, 26.8%.
.
3ꢀMethylꢀ2ꢀ(4ꢀmethylphenylhydrazo)ꢀ[1,2,4]triaziꢀ
(468.11): C, 64.04; H, 3.65; N, 17.92. Found: C, 64.3;
H, 3.4; N, 17.7%.
no[3,2ꢀ
crystals, mp >300
(NH), 1675 (CO); 1H NMR
(s, 3 H, CH3), 7.15 (d, 2 H, aromatic protons,
Hz), 7.35 (d, 2 H, aromatic protons, = 8.0 Hz), 7.50
(d, 2 H, aromatic protons, = 8.0 Hz), 7.65 (d, 2 H, arꢀ
omatic protons, = 8.0 Hz), 10.35 (s, 1 H, NH), 11.20
b
]quinazolinꢀ10ꢀone (XIVc). Yield, 60%, orange
C (dioxane); IR (KBr) ν, cm–1 = 3130
: 2.4 (s, 3 H, CH3), 3.01
= 8.0
°
Alternate synthesis of Va. To a solution of 7ꢀaminoꢀ
δ
1,3ꢀdiphenyl[1,2,4]triazolo[4,3ꢀa]pyrimidinꢀ5(1H)ꢀone
J
(VIII) [11] (1.51 g, 0.005 mol) in DMF (20 mL), an
J
equivalent amount of benzaldehyde (0.005 mol) and
few drops of acetic acid were added. The reaction mixꢀ
ture was heated under reflux for 4 h and then left to
cool. The solid product formed after pouring into ice
water was filtered and crystallized from the ethanol–diꢀ
J
J
13
(s, 1 H, NH); C NMR
140.1, 145.0, 154.3, 161.0, 163.0 (CO). MS,
+, 25), 255 (20), 241 (11), 190 (11), 105 (15), 91
)ꢀone (Va ), (20), 77 (100). Anal Calcd. for C18H16N6O (332.14):
δ
: 21.0, 22.5, 120.0–131.0,
m/z
(%)
oxane mixture to give 7ꢀ(benzylidenamino)ꢀ1,3ꢀdipheꢀ 332 (
nylꢀ[1,2,4]triazoloꢀ[4,3ꢀ ]ꢀpyrimidinꢀ5(1
M
a
H
.
which is identical in all respects (mp, mixed mp, and IR)
with that formed from reaction between (Ia) and (II).
C, 65.05; H, 4.85; N, 25.29. Found: C, 65.4; H, 4.6;
N, 25.5%.
3ꢀMethylꢀ2ꢀ(4ꢀchlorophenylhydrazo)ꢀ[1,2,4]triꢀ
Synthesis of 1,3ꢀdiphenylꢀ[1,2,4,5]tetrazino[6,1ꢀ
azino[3,2ꢀ
orange crystals, mp >300
cm–1 = 3150 (NH), 1660 (CO); 1H NMR
b
]quinazolinꢀ10ꢀone (XIVd). Yield, 64%,
C; (dioxane); IR (KBr) ν,
: 2.90 (s, 3 H,
b
]quinazolinꢀ6(4
stitutedphenylhydrazoꢀ[1,2,4]triazino[3,2ꢀb]quinazolinꢀ
10ꢀones (XIVbd).
H)ꢀone (XI) and 3ꢀmethylꢀ2ꢀ(4ꢀsubꢀ
°
δ
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 40
No. 1
2014

112
KHALIFA et al.
CH3), 7.20 (d, 2 H, aromatic protons,
J
= 8.0 Hz),
ACKNOWLEDGMENTS
7.35 (d, 2 H, aromatic protons,
aromatic protons, = 8.0 Hz), 7.70 (d, 2 H, aromatic
protons, = 8.0 Hz), 10.50 (s, 1 H, NH), 11.40 (s,
1 H, NH); MS, (%) 353 (
++1, 5), 352 ( +, 10),
275 (25), 240 (11), 140 (15), 112 (20), 77 (100). Anal
Calcd. for C17H13ClN6O (352.1): C, 57.88; H, 3.71;
N, 23.82. Found: C, 57.7; H, 3.5; N, 23.9%.
J = 8.0 Hz), 7.55 (d, 2 H,
The authors thank Taif University, Taif, Saudi Arabia
for the financial support under project number 1888ꢀ
433ꢀ1.
J
J
m
/z
M
M
.
REFERENCES
1. Abbass, I.M., Abdallah, M.A., Mosselhi, M.A.N.,
Mohammed, S.Z., and Shawali, A.S., J. Chem. Res.
1994, vol. S, pp. 308–309.
,
Antimicrobial assay. Cultures of two bacterial speꢀ
cies, namely, Escherichia coli (EC) and Staphylococꢀ
cus aureus (SA), as well as two fungal species, namely,
Aspergillus flavus (AF) and Candida albicans (CA),
were used to investigate the antimicrobial activity of
ten products, (Va–c, e, f, h), (XI), and (XIVb–d). The
antibacterial and antifungal activity assays were carꢀ
ried out in the Microbiology Division of Microanalytꢀ
ical Center of Cairo university, using the diffusion
plate method [35–37]. The latter technique was carꢀ
ried out by pouring a spore suspension of the fungal
species (1 cm3 of sterile water contains approximately
108 conidia) or spreading bacterial suspension over a
solidified malt agar medium. The layer was allowed
to set for 30 min. A solution of the test compounds
(1.0 g = cm3) in DMSO was placed onto sterile 5ꢀmm
filter paper discs and allowed to dry, then the discs
were placed on the center of the malt agar plate and inꢀ
cubated at the optimum incubation temperature, 28
2. Albar, H.A., Abdalha, M.A., Mosselhi, M.A.N., and
Shawali, A.S., Heteroatom Chem., 1996, vol. 7,
pp. 225–228.
3. Shawali, A.S., Mosselhi, M.A.N, and Tawfik, N.M.A.,
J. Org. Chem., 2001, vol. 66, pp. 4055–4057.
4. Shawali, A.S., Abdalha, M.A., Mosselhi, M.A.N., and
Farghaly, T.A.A., Heteroatom Chem., 2002, vol. 13,
pp. 136–140.
5. Shawali, A.S. and Samy, N.A., Open Bioactive Comp. J.
2009, vol. 2, pp. 8–16.
,
6. Abdel Hafez, N.A., Farghaly, T.A., AlꢀOmar, M.A., and
Abdalla, M.M., Eur. J. Med. Chem., 2010, vol. 45,
pp. 4838–4844.
7. Farghaly, T.A., Abbas, I.M., Abdalla, M.M., and Mahꢀ
goub, R.O.A., Arkivoc, 2012, vol. vi., pp. 57–70.
8. Farghaly, T.A, Gomha, S.M., Abbas, E.M.H., and
Abdalla, M.M., Arch. Pharm. Chem. Life Sci., 2012,
vol. 345, pp. 117–122.
9. Abdelhamid, A.O., Fahmi, A.A., and Halim, K.N.M.,
Eur. J. Chem., 2011, vol. 2, pp. 317–323.
2°C. The bactericide tetracycline and the fungicide
10. Shawali, A.S. and Edrees, M.M., Arkivoc, 2006,
amphotericin B were used as standards under the same
conditions. Measurements were performed after 72 h
incubation for fungi and 24 h, for bacteria. The results
are summarized in the table.
vol. IX, pp. 292–365.
11. Mosselhi, M.A.N., Monatsh. Chem. (Chem. Month.)
,
2002, vol. 133, pp. 1297–1304.
12. Shawali, A.S., Mosselhi, M.A.N., and Farghaly T.A.,
Sulfur Silicon Relat. Elem., 2005, vol. 180, pp. 2391–
2402.
CONCLUSION
13. Shawali, A.S., Mosselhi, M.A.N, and Hussein, A.M.,
J. Sulfur Chem., 2006, vol. 27, pp. 329–339.
In this report, it was found that the siteꢀselecꢀ
14. Shawali, A.S., Abdallah, M.A., Mosselhi, M.A.N, and
tivity of the reaction of hydrazonoyl halides (
with 6ꢀ(benzylidenamino)ꢀ2ꢀthioxoꢀ2,3ꢀdihydroꢀ
ꢀpyrimidinꢀ4ꢀone (II) or 2,3ꢀdiaminoquinazoꢀ
I)
Elewa, M.S., J. Heterocycl. Chem., 2007, vol. 44, pp. 1–4.
15. Shawali, A.S., Mosselhi, M.A.N, Abdallah, M.A, and
1
H
Elewa, M.S., J. Chem. Res., 2008, vol. 2, pp. 67–69.
linꢀ4ꢀone (IX), in dioxane (and dimethylformamide)
in the presence of triethylamine afforded good results
for fused heterocycles. Thus, the spectral analyses of
such fused heterocycles revealed the structures of 3ꢀsubꢀ
stitutedꢀ7ꢀ(benzylidenamino)ꢀ1ꢀphenylꢀ[1,2,4]triazolo
16. Shawali, A.S. and Farghaly, T.A., Arkivoc, 2008, vol. i,
pp. 18–64.
17. Galarcei, G.D., Foncea, R.E., Edwards, A.M., Pesꢀ
soamahana, H., Mahana, C.D.P., and Ebenspergeri R.A.,
Biol. Res., 2008, vol. 41, pp. 43–50.
[4,3ꢀa]ꢀpyrimidinꢀ5(1
no[6,1ꢀ
H
)ꢀones (
V
), [1,2,4,5]tetraziꢀ 18. Dolzhenko, A.V., Foo, M.C., Tan, B.J.,
Dolzhenko, A.V., Chiu, G.N.C., and Chui, W.K., Heteꢀ
b
]quinazolinꢀ6(4H)ꢀone (XI), and 3ꢀmethylꢀ2ꢀ
rocycles, 2009, vol. 78, pp. 1761–1775.
(4ꢀsubstitutedphenylhydrazo)ꢀ[1,2,4]triazino[3,2ꢀb]
quinazolinꢀ10ꢀones (XIVb–d), respectively. The antiꢀ
bacterial and antifungal activity screening of some
of the prepared compounds revealed moderate acꢀ
tivity against the two bacterial species and all comꢀ
pounds showed moderate activity against one fungal
species, Candida albicans (CA).
19. Vostrova, L.N., Voronina, T.A., Karaseva, T.L.,
Gernega, S.A., Ivanov, E.I., Kirichenko, A.M., and
Totrova, Yu.M., Pharma. Chem. J., 1986, vol. 20,
pp. 404–406.
20. Hawkins, M.E., Pfleiderer, W., Jungmann, O., and
Balis, F.M., Anal. Biochem., 2001, vol. 298, pp. 231–
240.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 40
No. 1
2014

SITE SELECTIVITY IN REACTIONS OF HYDRAZONOYL HALIDES
113
21. Nakamura, M.Y., Fukunaga, Y., Sasa, K., Ohtoshi, Y., 29. Ghorab, M.M., Ragab, F.A., Heiba, H.I., Youssef, H.A.,
Kanaori, K., Hayashi, H., Nakano, H., and Yamana, K.,
Nucleic Acids Res., 2005, vol. 33, pp. 5887–5895.
and ElꢀGazzar, M.G., Bioorg. Med. Chem. Lett., 2010,
vol. 20, pp. 6316–6320.
30. Shawali, A.S., Abdallah, M.A., and Zayed, M.M.,
J. Heterocycl. Chem., 2002, vol. 39, pp. 45–49.
31. Shawali, A.S., Hassaneen, H.M., Shetta, A.F, Osman, A.,
22. Luo, H.ꢀY., Zhang, X.ꢀB., Hea, C.ꢀL., Shen, G.ꢀL.,
and Yu, R.ꢀQ., Spectrochimica Acta Part A, 2008,
vol. 70, pp. 337–342.
Heterocycles, 1982, vol. 19, pp. 57–62.
23. Mosselhi, M.A.N. and Break, L.M., Nucl. Nucl.
Nucleic Acids, 2011, vol. 30, pp. 681–695.
32. Mohamed, N.R., ElꢀSaidi, M.M.T., Ali, Y.M., and
Elnagdi, M.H., Bioorg. Med. Chem., 2007, vol. 15,
pp. 6227–6235.
33. Bowie, R.A., Edwards, P.N., Nicholson, S., Taylor, P.J.,
and Thomson, D.A., J. Chem. Soc. Perkin Trans., 1979,
vol. 2, pp. 1708–1714.
34. Elliott, A.J., Callaghan, P.D., Gibson, M.S., and Nemꢀ
eth, S.T., Can. J. Chem., 1975, vol. 53, pp. 1484–1488.
35. Bauer, A.W., Kirby, W.M., Sherris, C., and Turck, M.,
24. Ghorab, M.M., Heiba, H.I., Amina. Hassan, A.A.,
Abd ElꢀAziz, A.B., and ElꢀGazzar, M.G., J. Am. Sci.,
2011, vol. 7, pp. 1063–1073.
25. Deshmukh, M.B., Salunkhe, S.M., Patil, D.R., and
Anbhule, P.V., Eur. J. Med. Chem., 2009, vol. 44,
pp. 2651–2654.
26. Atul, R.G., Kiran, S.T., Fazal, S., Mukund, V.D., and
Kumar, V.S., Tetrahedron, 2008, vol. 64, pp. 10214–
10223.
Am. J. Clin. Phath., 1966, vol. 45, pp. 493–496.
36. Pfaller, M.A., Burmeister, L., Bartlett, M.A., and
Rinaldi, M.G., J. Clin. Microbiol., 1988, vol. 26,
pp. 1437–1441.
37. Matar, M.J., OstroskyꢀZeichner, L., Paetznick, V.L.,
Rodriguez, J.R., Chen, E., and Rex J.H., Antimicrob.
Agents Chemother., 2003, vol. 47, pp. 1647–1651.
27. Azas, N., Rathelot, P., Djekou, S., Delmas, F., Gellis, A.,
DiꢀGiorgio, C., Vanelle, P., and TimonꢀDavid, P., Il
Farmaco, 2003, vol. 58, pp. 1263–1270.
28. Said, S.A., Amr A.E., Sabry N.M., and Abdalla M.M.,
Eur. J. Med. Chem., 2009, vol. 44, pp. 4787–4792.
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