Promising Antimicrobial Agents: Synthetic Approaches to Novel Tricyclic and Tetracyclic Pyrimidinones with Antimicrobial Properties

Article abstract of DOI:10.1002/jhet.446

(Chemical Equation Presented) New tricyclic pyrimidinone derivatives were obtained from the corresponding thiazolopyrimidinone or hydrazino systems. The annelation of tricyclic hydrazino compound with 1,2,4-triazole and tetrazole moieties gave novel tetracyclic condensed pyrimidinones. The investigation of the antimicrobial properties of tricyclic and tetracyclic pyrimidinones, by agar-well diffusion assay, was carried out against six pathogenic bacteria (Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella spp, and Salmonella typhyrium) and four pathogenic fungi (Aspergillus flavus, Aspergillus niger, Aspergillus fumigatus, and Trichderma horozianum). Most of the compounds tested exhibited some degree of antimicrobial activity against microorganisms. Among these compounds, 4-benzylidenhydrazino- 8-cyano-7-(furan-2-yl)thiazolo[3,2-a:4,5-d′]dipyrimidin-9-one (12) showed the most favorable antibacterial activity, while compound 17 showed the highest effect on fungi. Interestingly, tetrazole derivative 19 displayed a remarkable effect on fungi much more than the corresponding 3-substituted triazole derivatives on the one hand, whereas the lowest effect on bacteria on the other.

Full text of DOI:10.1002/jhet.446

1162
Promising Antimicrobial Agents: Synthetic Approaches to Novel
Tricyclic and Tetracyclic Pyrimidinones with Antimicrobial
Properties
Vol 47
Hatem M. Gaber,a* Mark C. Bagley,b Sherif M. Sherif,c
and Usama M. Abdul-Raoufd
aNational Organization for Drug Control and Research (NODCAR), P.O. Box 29, Cairo, Egypt
bSchool of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT,
United Kingdom
cDepartment of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
dBotany and Microbiology Department, Faculty of Science, Al-Azhar University, Assuit Branch,
Assuit 71534, Egypt
*E-mail: hatem.gaber@yahoo.com
Received November 10, 2009
DOI 10.1002/jhet.446
Published online 26 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
New tricyclic pyrimidinone derivatives were obtained from the corresponding thiazolopyrimidinone
or hydrazino systems. The annelation of tricyclic hydrazino compound with 1,2,4-triazole and tetrazole
moieties gave novel tetracyclic condensed pyrimidinones. The investigation of the antimicrobial proper-
ties of tricyclic and tetracyclic pyrimidinones, by agar-well diffusion assay, was carried out against six
pathogenic bacteria (Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia
coli, Klebsiella spp, and Salmonella typhyrium) and four pathogenic fungi (Aspergillus flavus, Aspergil-
lus niger, Aspergillus fumigatus, and Trichderma horozianum). Most of the compounds tested exhibited
some degree of antimicrobial activity against microorganisms. Among these compounds, 4-benzyliden-
hydrazino-8-cyano-7-(furan-2-yl)thiazolo[3,2-a:4,5-d0]dipyrimidin-9-one (12) showed the most favorable
antibacterial activity, while compound 17 showed the highest effect on fungi. Interestingly, tetrazole de-
rivative 19 displayed a remarkable effect on fungi much more than the corresponding 3-substituted tria-
zole derivatives on the one hand, whereas the lowest effect on bacteria on the other.
J. Heterocyclic Chem., 47, 1162 (2010).
INTRODUCTION
[3,6], whereas some derivatives of dihydropyrimidine
(DHPM) have interesting biological properties such as
antimicrobial [7], antiviral [8], and anticancer [9] activ-
ities and moreover are found to be useful in the treat-
ment of benign prostatic hyperplasia [10]. More
recently, these partly reduced DHPMs have emerged as
anti-inflammatory agents [11]. Very recently, S-alkylpyr-
imidines possessing antifungal and antibacterial activ-
ities have been also reported in the literature [12]. Some
time ago, a series of chloropyrimidines were identified
as a new class of antimicrobial agents [13]. Also,
Pyrimidine and its derivatives are ubiquitous in na-
ture. As such, the pyrimidine subunit has found wide-
spread applications in therapeutically active compounds.
Most importantly, pyrimidine bases are fundamental
constituents of the building blocks of DNA and RNA
and hence play a significant role in biochemical vital
processes for human beings and animals [1,2]. Various
analogs of thiopyrimidinones display antibacterial, anti-
fungal, antiviral [3–5], and antileishmanial activities
C
V
2010 HeteroCorporation

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Promising Antimicrobial Agents: Synthetic Approaches to Novel Tricyclic
and Tetracyclic Pyrimidinones with Antimicrobial Properties
1163
numerous nucleosides containing 1-substituted pyrimi-
dines have found utility as anticancer and antiviral che-
motherapeutic agents [8,14,15]. It should be kept in
mind that thiazoles have occupied a unique place and
have remarkably contributed to biological and medicinal
chemistry [16–18]. Such medicines as sulfathiazole,
phthalylsulfathiazole and related compounds are widely
used in medical practice [19]. The thiazole ring unit is a
useful structural component of natural compounds, e.g.,
Vitamin B1 (thiamine), penicillin, and carboxylase
[19,20]. The 2-aminothiazole ring system has been
employed in the preparation of a number of important
drugs required for treatment of hypertension [21],
inflammation [22], bacterial [23], and HIV infections
[24]. Furthermore, aminothiazoles are well known for
their antifungal [25], antimicrobial [26–28], antiviral
[29], anti-inflammatory, and antioxidant [30] applica-
tions and also have been utilized for the treatment of
both breast and prostate cancer [31,32], as a novel class
of adenosine receptor antagonists [33,34] and in the de-
velopment of cyclin-dependent kinase (CDK) inhibitors
[35]. Moreover, some of the thiazole analogues are used
as fungicides, inhibiting in vivo the growth of Xantho-
monas and as an ingredient of herbicides or an schisto-
somicidal and anthelmintic drugs [36]. Literature survey
reveals that triazole-containing substances are also well
known for their diverse pharmaceutical activities includ-
ing antimicrobial [37], insecticidal [38], antitumor
[37,39], and anticonvulsant [40] effects, and moreover,
triazolopyrimidines have recently been identified as
adenosine A3 receptor antagonists [41]. Interestingly, the
fused tetrazoles have been found to exhibit similar bio-
logical properties to those of their corresponding triazole
analogs [42].
in each case, the formation of only one isolable product
as evidenced by TLC analysis. The structure of the iso-
lated products was considered to be 5-one structure 3
rather than the related isomeric 7-one structure 2 based
on the fact that the N-3 nitrogen atom of the pyrimidine
ring in 2-thiouracil analogues has higher nucleophilic
character when compared with N-1 atom, and hence, N-
3 nitrogen is more reactive towards electrophiles than
the N-1 position, which is part of a push-pull system
with the cyano group in the 5-position of the pyrimidine
ring. Therefore, the N-3 and not the N-1 always partici-
pates in the cyclization processes as clearily indicated
from literature reports [4,47–52]. The IR and 13C NMR
spectra provide further evidence for the proposed struc-
ture by comparison of these spectra with those of similar
annelated pyrimidinones. The IR spectra of the products
isolated from the studied reactions showed among its
peaks those for carbonyl carbon of the pyrimidinone
ring at m 1692 and 1690 cmꢀ1, respectively. This high
frequency absorption is in favor of structure
3
[47,51,52]. Literature reports [47,53] have shown that
the chemical shift for the carbonyl carbon in pyrimidin-
4-one derivatives is markedly affected by the nature of
the adjacent nitrogen (N-3) (pyrrole type in our structure
3 and pyridine type as in structure 2). For instance, the
13C NMR spectrum of compound 3a, as a typical exam-
ple, displayed the signal of the carbonyl carbon residue
at d 160.8 ppm. Such an upfield chemical shift value is
in agreement with pyrimidin-5-one 3 rather than with
pyrimidin-7-one 2, for which carbonyl stretching fre-
quencies would be expected to appear in the region
m 1640–1660 cmꢀ1, and the cyclic carbonyl groups
would be expected to resonate in the lower field region
(dC ꢁ 170 ppm) as reported by Shawali et al. [47]. Con-
sequently, it is reasonable to conclude that the studied
reactions are completely regioselective and the structure
of the isolated products is pyrimidin-5-one 3; the alter-
native cyclization mode to the respective 7-one 2 is
therefore discarded. Condensation of 3-amino-2-cyano-
thiazolopyrimidines 3a,b with triethyl orthoformate gave
the corresponding imino ethers 4a,b while with dime-
thylformamide dimethylacetal (DMFDMA), the ami-
dines 4c,d were obtained (Scheme 1).
Closure of a second pyrimidine ring of the thiazolodi-
pyrimidine ring system was carried out by heating N-
ethoxymethylene derivative 4a at reflux in an alcoholic
solution of hydrazine hydrate (Scheme 2) to yield a
reaction product of molecular formula C13H7N7O2S,
which corresponded to the addition of the hydrazine to
4a and the loss of one molecule of ethanol. The IR
spectrum of the reaction product was characterized by
the absence of one absorption for the cyano group
and the presence of an absorption band in the region
m 3382–3200 cmꢀ1 due to the hydrazino moiety in
On the basis of the above data and continuing our
studies on condensed heterocycles as a part of a chemo-
therapeutic research program [43–45], it was envisaged
that the combined effect of all the above pharmaco-
phores could result in interesting chemotherapeutic ac-
tivity. Therefore, the goal of the present work was to
synthesize substances containing a fused pyrimidine-thi-
azole scaffold as part of a tricyclic framework 8, 10–12
and tetracyclic compounds of the same tricyclic struc-
ture with a heterocycle anellated to the pyrimidine ring
13, 16–19 and to screen for their antibacterial and anti-
fungal activities.
RESULTS AND DISCUSSION
Treatment of the 2-thioxopyrimidines 1a,b [4,46] with
bromomalononitrile, in ethanol containing potassium hy-
droxide, provided bicyclic products. Principally, there
are three possible cyclization sites, i.e., either at N-3 or
N-1 or partial cyclization at both, depending on the
mode of cyclization. In practice, these reactions led to,
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Vol 47
Scheme 1. Synthetic pathway of thiazolopyrimidines 3, 4.
ment [54–56] of the initial cyclization product 5a. The
13C NMR spectrum of the isolated product was also in
accordance with the proposed structure (see Experimen-
tal section). The pathway of this reaction, as illustrated
in Scheme 2, may involve, first, the anticipated forma-
tion of imino compound 5a followed by subsequent
covalent hydration under the applied reaction conditions
to afford the 2-hydroxy intermediate 6a. Then, the py-
rimidine ring opens and forms the formyl intermediate
7a, which undergoes spontaneous heteroannelation with
the more nucleophilic imino group to give the rear-
ranged hydrazino compound 8a (Scheme 2). A similar
treatment of amidine 4d with hydrazine hydrate resulted
in the formation of the Dimroth rearrangement product
8b. Intermediacy of 5b, 6b, and 7b are most likely. It is
worth mentioning that the latter products of the reaction
of 4a,d with hydrazine hydrate were recovered com-
pletely unchanged when subjected to conditions leading
to hydrolysis of the imino group to carbonyl function,
thus supporting the Dimroth rearrangement of 5a,b to
8a,b (Scheme 2).
addition to a single cyano group at m 2219 cmꢀ1 and
1
carbonyl function at m 1697 cmꢀ1. The H NMR spec-
trum of that product indicated the disappearance of the
resonance signals from protons of the ethyl unit and the
appearance of signals from the hydrazino moiety and a
pyrimidine methine in their proper positions, besides the
expected furyl resonances. Accordingly, this compound
could be formulated as the tricyclic hydrazino derivative
8a, formed most likely via a Dimroth-type rearrange-
Nevertheless, a proof of structure 8 was accomplished
by using an alternative synthetic route involving the
cycliztion of aminonitrile 3a with formic acid to give
the dione 10 through the intermediate formation of car-
boxamide 9. A further reaction of 10 with phosphorus
Scheme 2. Synthetic pathway of thiazolodipyrimidines 8, 10, 11.
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and Tetracyclic Pyrimidinones with Antimicrobial Properties
1165
Scheme 3. Synthetic pathway of tetracyclic pyrimidinones 13, 16–19.
oxychloride produced the respective chloro derivative
11, hydrazinolysis of which led to the hydrazino com-
pound 8a (61% yield), whose spectral characteristics
were completely coincident with the previously isolated
sample (Scheme 2).
attempt to obtain the pyrazolyl derivative 15. To our
surprise, this reaction did not give the desired 15 and
instead the Schiff’s base 12 was isolated as indicated
from TLC analysis, mp, mixed mp, and IR data of the
reaction product. This result can be explained by assum-
ing the formation of Michael adduct 14 as a first step.
Subsequent ethyl cyanoacetate elimination leads eventu-
ally to the final benzylidene derivative 12, what is in
agreement with a previous literature report [37].
Treatment of 8a with benzaldehyde, in boiling abso-
lute ethanol in the presence of piperidine furnished the
corresponding acyclic condensation product 12. Oxida-
tive cyclodehydrogenation of Schiff’s base 12 by boiling
in nitrobenzene or by treatment with ethanolic iron(III)
chloride solution led to, in every case, a single product
for which the tetracyclic-condensed structure 13 was
established on the basis of its analytical and spectro-
scopic data. The absence of the methine proton of the
Another new tetracyclic pyrimidinone derivative 16
was synthesized from the hydrazino compound 8a by
reaction with one carbon inserting agents. Thus, interac-
tion of 8a with phenyl isothiocyanate in ethanolic so-
dium ethoxide solution gave the target 16 (Scheme 3).
This reaction is assumed to proceed most likely with in
situ evolution of aniline. In support of this hypothesis,
the desired 16 was also obtained by an independent
route involving the reaction of 8a with carbon disulfide
at reflux in pyridine, leading to a reaction product that
was identical to 16 obtained by the prescribed method
according to TLC analysis, mp, mixed mp, and IR data.
The hydrazino derivative 8a proved to be a useful
precursor for the synthesis of other tetracyclic pyrimidi-
nones. Thus, reaction of 8a with an excess of ethyl
chloroformate, at reflux in pyridine, led to the triazolone
1
hydrazone 12 in the H NMR spectrum of 13 confirmed
the structure. It is interesting to note that the same prod-
uct 13 could be also obtained directly from cyclocon-
densation of the hydrazino derivative 8a with benzoic
acid in boiling phosphorus oxychloride. This fact was
supported by heating compound 8a at reflux in an
excess of benzoyl chloride, wherein compound 13 was
also isolated.
It is remarkable to report here that an unexpected
reaction took place on reacting 8a with ethyl benzylide-
necyanoacetate in the presence of piperidine in an
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Table 1
Mean diameter of inhibition zone (mm) as a criterion of antibacterial activity for selected tricyclic and tetracyclic derivatives.
Test bacterial isolate
Compd.
S. aureus
Klep. spp
S. typhy.
B. cereus
E. coli
P. aeruginosa
8a
10
11
12
13
16
17
18
2.9 6 0.2
1.9 6 0.2
1.7 6 0.1
1.4 6 0.2
1.7 6 0.2
1.6 6 0.2
1.4 6 0.1
1.5 6 0.2
1.7 6 0.2
1.4 6 0.1
1.7 6 0.2
1.7 6 0.2
1.4 6 0.2
1.6 6 0.2
1.5 6 0.2
1.6 6 0.2
1.8 6 0.2
1.6 6 0.2
1.5 6 0.2
1.3 6 0.1
1.4 6 0.2
0.0
1.7 6 0.2
1.4 6 0.2
1.4 6 0.1
1.9 6 0.2
1.8 6 0.2
1.8 6 0.2
2.1 6 0.2
1.8 6 0.2
1.5 6 0.2
1.2 6 0.1
0.0
1.7 6 0.2
1.5 6 0.2
1.5 6 0.2
0.0
0.0
0.0
1.3 6 0.2
1.3 6 0.2
0.0
1.4 6 0.2
1.7 6 0.2
0.0
0.0
0.0
0.0
0.0
2
0.0
1.7 6 0.2
0.0
0.0
0.0
0.0
19
Standarda
0.0
1.3 6 0.2
1.4 6 0.2
1.2 6 0.2
a Standard for bacteria: Oxacillin 1 mg/mL.
analogue 17, while with diethyl malonate, the ethyl ester
18 was isolated in acceptable yield. Elucidation of struc-
ture for the latter products was established on the basis
of elemental and spectroscopic analyses in each case
(see Experimental section).
activity relative to the corresponding tricyclic products.
However, the antifungal activity of tetracyclic triazole
derivative 17 was found to be the highest. This was fol-
lowed by the tetrazole derivative 19, which displayed a
remarkable effect on fungi much more than the other 3-
substituted triazole derivatives (compounds 13, 16, and
18). Despite promising in vitro antifungal activity of 19,
only poor activity was found against test bacterial iso-
lates (Staphylococcus aureus, Klebsiella spp, and Bacil-
lus cereus).
As an extension to this synthetic route, treatment of
compound 8a with sodium nitrite resulted in the forma-
tion of a similar product with annelated tetrazole ring
19, formed most likely via diazotization, by the action
of in situ generated nitrous acid on 8a, followed by self-
condensation. A similar diazotization of hydrazinopyri-
midines with sodium nitrite has been reported previously
[42,49,54].
CONCLUSION
Antimicrobial evaluation. As shown by the results
in Tables 1 and 2, the majority of the new tricyclic and
tetracyclic compounds tested displayed in vitro antibac-
terial and antifungal activities. In general, the chemical
structure of the whole molecule, comprising the nature
of the heterocyclic system as well as the type of the
substituted function present in the heterocyclic ring
structure, has a pronounced effect on antimicrobial ac-
tivity. In particular, it has been found that antimicrobial
activity was highly dependent on the type of substituent
at the 4-position of pyrimidine ring in the tricyclic core
(compounds 8a and 10–12, respectively). The most toxic
compound to the test bacterial isolates was that contain-
ing a benzylidenhydrazino moiety at position 4 of py-
rimidine ring in the tricyclic ring system (compound 12)
as compared with the other 4-substituted analogues
(compounds 8a, 10, and 11). Replacement of the benzy-
lidenhydrazino moiety by a chlorine atom diminished
slightly the activity of 11; however, 4-chloro analog 11
exhibited more pronounced antibacterial activity than
the corresponding 4-hydrazino 8a or 4-oxo 10 deriva-
tives. Fusion of 3-substituted 1,2,4-triazoles with the
parent thiazolodipyrimidine structure (compounds 13
and 16–18) led in general to a decrease in antibacterial
New heterocyclic motifs were obtained from the reac-
tion of aminonitriles 3a,b and hydrazino compound 8a
with several commercially available reactants. All the
tricyclic and tetracyclic compounds described in this
work retain a thiazolodipyrimidinone core, while a
fourth fused heterocyclic nucleus (triazole or tetrazole)
Table 2
Mean diameter of inhibition zone (mm) as a criterion of antifungal
activity for selected tricyclic and tetracyclic derivatives.
Test fungal isolate
Compd.
A. niger A. flavus A. fumigatus T. horozianum
8a
10
11
12
13
16
17
18
19
2.6 6 0.2 2.4 6 0.2 1.7 6 0.2
2.5 6 0.2 2.8 6 0.4 0.0
2.4 6 0.2 2.2 6 0.2 1.6 6 0.2
2
2.4 6 0.4
2.4 6 0.4
2.2 6 0.2
2.5 6 0.2
2.5 6 0.2
2.9 6 0.4
1.8 6 0.2
2.5 6 0.2
2.4 6 0.2
2
3 6 0.4
0.0
0.0
2.1 6 0.2 2.6 6 0.4
2.5 6 0.2 2.5 6 0.2 1.6 6 0.2
3.1 6 0.2 3.2 6 0.2 2.8 6 0.4
2.5 6 0.2 2.6 6 0.2
0.0
2.4 6 0.2 2.5 6 0.2 1.8 6 0.2
Standarda 2.6 6 0.2 2.8 6 0.1 2.8 6 0.1
a Standard for fungi: Mycostatine 1 mg/mL.
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J ¼ 3.5 Hz, thiophene H-3), 8.04 (d, 1H, J ¼ 4.9 Hz, thio-
phene H-5), 8.72 (s, 2H, NH2, D2O-exchangeable); Anal.
Calcd. for C12H5N5OS2 (299.337): C, 48.15; H, 1.68; N,
23.40; S, 21.42. Found: C, 47.87; H, 1.53; N, 23.31; S, 21.15.
General procedure for the preparation of 7-substituted-
3-(ethoxymethylene)amino-5-oxo-5H-thiazolo[3,2-a]pyrimi-
dine-2,6-dicarbonitriles (4a,b). A mixture of either 3a or 3b
(0.005 mol) and triethyl orthoformate (10 mL) was heated at
reflux for 10 h. After distillation of the ortho ester, the viscous
mass was treated with ether or petroleum ether (3 mL). The
precipitated crystals of products 4a,b were collected by filtra-
tion and recrystallized from the proper solvents to give the im-
ino ethers 4a (0.85 g; 50%) and 4b (0.59 g; 33%),
respectively.
3-(Ethoxymethylene)amino-7-(2-furyl)-5-oxo-5H-thiazolo[3,2-
a]pyrimidine-2,6-dicarbonitrile (4a). This compound was
obtained as a pale brown solid (EtOH/H2O), mp 214ꢂC; IR
(m/cmꢀ1): 2225, 2216 (2CN), 1700 (CO), 1621 (C¼N); 1H
NMR (d ppm): 1.41 (t, 3H, J ¼ 7.3 Hz, CH3 ethoxy), 4.43 (q,
2H, J ¼ 7.3 Hz, OCH2), 6.68 (dd, 1H, J ¼ 1.6, 3.8 Hz, furan
H-4), 7.35 (d, 1H, J ¼ 3.8 Hz, furan H-3), 7.85 (d, 1H, J ¼
1.6 Hz, furan H-5), 8.36 (s, 1H, methylenic CH); MS: m/z (%)
¼ 339 (Mþ, 18%); Anal. Calcd. for C15H9N5O3S (339.334):
C, 53.09; H, 2.67; N, 20.64; S, 9.45. Found: C, 52.93; H, 2.51;
N, 20.37; S, 9.30.
was constructed by cyclocondensation reactions of tricy-
clic hydrazino compound 8a with various chemical
reagents. The biological potential of all the fused pyri-
midinone derivatives was further investigated by screen-
ing for their antimicrobial activity. The test compounds
displayed different levels of antibacterial and antifungal
activities, with the assays carried out on six pathogenic
bacteria and four pathogenic fungi. The most potent
compounds against test bacterial and fungal isolates
were 4-benzylidenhydrazino compound 12 and dione de-
rivative 17, respectively. Further studies on structure–ac-
tivity relationships (SAR) combined with molecular
modeling approaches of these condensed heterocyclic
derivatives are currently underway, and the results of
this research will be reported in due course. We believe
that research in this direction should be encouraged in
order to broaden the applicability of these new heterocy-
clic frameworks to serving as leads for designing novel
chemotherapeutic agents.
EXPERIMENTAL
3-(Ethoxymethylene)amino-5-oxo-7-(2-thienyl)-5H-thia-
zolo[3,2-a]pyrimidine-2,6-dicarbonitrile (4b). This com-
pound was obtained as a golden yellow solid (EtOH), mp
201–202ꢂC; IR (m/cmꢀ1): 2221, 2215 (2CN), 1704 (CO), 1621
(C¼¼N); 1H NMR (d ppm): 1.39 (t, 3H, J ¼ 7.4 Hz, ethoxy
CH3), 4.45 (q, 2H, J ¼ 7.4 Hz, OCH2), 7.24 (dd, 1H, J ¼ 3.7,
4.8 Hz, thiophene H-4), 7.95 (d, 1H, J ¼ 3.7 Hz, thiophene H-
3), 8.10 (d, 1H, J ¼ 4.8 Hz, thiophene H-5), 8.36 (s, 1H,
methylenic CH); Anal. Calcd. for C15H9N5O2S2 (355.390): C,
50.69; H, 2.55; N, 19.71; S, 18.04. Found: C, 50.47; H, 2.43;
N, 19.49; S, 17.86.
General procedure for the preparation of 7-substituted-
3-(dimethylaminomethylenamino)-5-oxo-5H-thiazolo[3,2-a]py-
rimidine-2,6-dicarbonitriles (4c,d). To a solution of either 3a
or 3b (0.005 mol), in dry xylene (30 mL), DMFDMA (0.006
mol) was added and the reaction content was then heated
under reflux for 6 h. The reaction mixture was cooled and tri-
turated with petroleum ether (40–60). The solid product
obtained was filtered off, dried and recrystallized from the
appropriate solvents to give the amidines 4c (0.52 g; 31%) and
4d (0.82 g; 46%), respectively.
3-(Dimethylaminomethylenamino)-7-(2-furyl)-5-oxo-5H-thia-
zolo[3,2-a]pyrimidine-2,6-dicarbonitrile (4c). This compound
was obtained as an orange solid (EtOH), mp 239–241ꢂC; IR
(m/cmꢀ1): 2225, 2214 (2CN), 1700 (CO), 1618 (C¼¼N); 1H
NMR (d ppm): 3.05, 3.14 (2s, 6H, NMe2), 6.85–7.17 (m, 2H,
furan H-3,4), 7.83 (d, 1H, J ¼ 1.9 Hz, furan H-5), 8.23 (s, 1H,
methylenic CH); Anal. Calcd. for C15H10N6O2S (338.340): C,
53.25; H, 2.98; N, 24.84; S, 9.48. Found: C, 52.99; H, 2.81;
N, 24.57; S, 9.20.
3-(Dimethylaminomethylenamino)-5-oxo-7-(2-thienyl)-5H-
thiazolo[3,2-a]pyrimidine-2,6-dicarbonitrile (4d). This com-
pound was obtained as a brown solid (1,4-dioxane), mp 232–
233ꢂC; IR (m/cmꢀ1): 2220, 2212 (2CN), 1695 (CO), 1617
(C¼¼N); 1H NMR (d ppm): 2.89, 2.99 (2s, 6H, NMe2), 7.30
(dd, 1H, J ¼ 3.9, 5.2 Hz, thiophene H-4), 7.81 (d, 1H, J ¼ 3.9
Melting points are uncorrected. IR spectra were recorded
(KBr) on a Pye Unicam SP-1000 spectrophotometer. NMR
spectra were obtained on a Varian Gemini 300 MHz spectrom-
eter in DMSO-d6 as solvent and TMS as internal reference.
Chemical shifts are expressed in d ppm. EI mass spectra were
recorded on a Shimadzu GC MS-QP 1000 EI mass spectrome-
ter at 70 eV. Compounds 1a,b were prepared according to
known methods [4,46].
General procedure for the preparation of 7-substituted-
3-amino-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2,6-dicarboni-
triles (3a,b). To a warm ethanolic potassium hydroxide solu-
tion [prepared by dissolving potassium hydroxide (0.005 mol)
in ethanol (30 mL)] of either pyrimidinethione 1a or 1b (0.005
mol), bromomalononitrile (0.005 mol) was added portionwise
with stirring. The reaction content was then left overnight at
room temperature, whereby the solid product so precipitated
upon dilution with water was filtered off, dried, and recrystal-
lized from the appropriate solvents to give the title compounds
3a (0.64 g; 45%) and 3b (0.61 g; 41%), respectively.
3-Amino-7-(2-furyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-
2,6-dicarbonitrile (3a). This compound was obtained as a
yellow solid (DMF/H2O), mp 267–268ꢂC; IR (m/cmꢀ1): 3380,
1
3272 (NH2), 2221, 2202 (2CN), 1692 (CO); H NMR (d ppm):
6.74 (dd, 1H, J ¼ 1.6, 3.7 Hz, furan H-4), 7.31 (d, 1H, J ¼
3.7 Hz, furan H-3), 7.90 (d, 1H, J ¼ 1.6 Hz, furan H-5), 8.48
(s, 2H, NH2, D2O-exchangeable); 13C NMR (d ppm): 79.9,
98.5 (C-2, C-6), 111.2, 112.1 (furan C-3,4), 116.8 (CN), 118.0
(CN), 144.2 (furan C-5), 155.0 (furan C-2), 158.5, 159.0 (C-
8a, C-3), 160.8 (CO), 167.9 (C-7); Anal. Calcd. for
C12H5N5O2S (283.270): C, 50.88; H, 1.78; N, 24.72; S, 11.32.
Found: C, 50.59; H, 1.60; N, 24.51; S, 11.09.
3-Amino-5-oxo-7-(2-thienyl)-5H-thiazolo[3,2-a]pyrimidine-
2,6-dicarbonitrile (3b). This compoundꢂwas obtained as a yel-
lowish white solid (DMF), mp 251-252 C; IR (m/cmꢀ1): 3374,
1
3260 (NH2), 2218, 2202 (2CN), 1690 (CO); H NMR (d ppm):
7.05 (dd, 1H, J ¼ 3.5, 4.9 Hz, thiophene H-4), 7.89 (d, 1H,
Journal of Heterocyclic Chemistry
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H. M. Gaber, M. C. Bagley, S. M. Sherif, and U. M. Abdul-Raouf
Vol 47
Hz, thiophene H-3), 7.97 (d, 1H, J ¼ 5.2 Hz, thiophene H-5),
8.12 (s, 1H, methylenic CH); Anal. Calcd. for C15H10N6OS2
(354.417): C, 50.83; H, 2.84; N, 23.71; S, 18.09; Found: C,
50.55; H, 2.72; N, 23.46; S, 17.91.
General procedure for the preparation of 7-substituted-
8-cyano-4-hydrazinothiazolo[3,2-a:4,5-d0]dipyrimidin-9-ones
(8a,b). Method A for compounds 8a,b. A mixture of either
4a or 4d (0.005 mol), hydrazine hydrate (0.05 mol, 2.5 mL)
and absolute ethanol (12 mL) was refluxed for 5 h. The precip-
itates formed after cooling overnight were collected by filtra-
tion, washed with cold alcohol, and recrystallized from the
proper solvents to give the hydrazino compounds 8a (0.89 g;
55%) and 8b (0.55 g; 32%), respectively.
8-Cyano-7-(2-furyl)-4-hydrazinothiazolo[3,2-a:4,5-d0]dipyrimidin-
9-one (8a). This compound was obtained as a light brown solid
(EtOH), mp 246–247ꢂC; IR (m/cmꢀ1): 3382–3200 (NH, NH2),
2219 (CN), 1697 (CO); 1H NMR (d ppm): 4.76 (s, br, 2H,
NH2, D2O-exchangeable), 6.69 (dd, 1H, J ¼ 1.6, 3.7 Hz, furan
H-4), 7.25 (d, 1H, J ¼ 3.7 Hz, furan H-3), 7.81 (d, 1H, J ¼
1.6 Hz, furan H-5), 7.95 (s, 1H, pyrimidine H-2), 10.15 (s, br,
1H, NH, D2O-exchangeable); 13C NMR (d ppm): 95.3, 99.0,
111.5, 112.2 (furan C-3,4), 117.1 (CN), 143.5 (furan C-5),
155.2 (furan C-2), 157.4, 158.0, 158.5, 159.6, 161.4 (CO),
167.8 (C-7); Anal. Calcd. for C13H7N7O2S (325.311): C,
48.00; H, 2.17; N, 30.14; S, 9.86. Found: C, 47.73; H, 1.99;
N, 29.88; S, 9.72.
the precipitate was filtered off, dried, and recrystallized from ace-
tone to give the chloro compound 11 as a dark brown solid (0.51
1
g; 77%), mp > 300ꢂC; IR (m/cmꢀ1): 2223 (CN), 1699 (CO); H
NMR (d ppm): 6.72 (dd, 1H, J ¼ 1.8, 3.9 Hz, furan H-4), 7.31 (d,
1H, J ¼ 3.9 Hz, furan H-3), 7.84 (d, 1H, J ¼ 1.8 Hz, furan H-5),
8.45 (s, 1H, pyrimidine H-2); Anal. Calcd. for C13H4ClN5O2S
(329.726): C, 47.35; H, 1.22; Cl, 10.75; N, 21.24; S, 9.72. Found:
C, 47.09; H, 1.10; Cl, 10.62; N, 20.98; S, 9.56.
4-Benzylidenhydrazino-8-cyano-7-(2-furyl)thiazolo[3,2-a:4,5-
d0]dipyrimidin-9-one (12). Method A. Compound 8a (0.005
mol) was dissolved in absolute ethanol (20 mL), then benzalde-
hyde (0.006 mol) and piperidine (0.5 mL) were added. The reac-
tion mixture was heated at reflux for 1.5 h. On cooling, the de-
posited solid product was filtered off and dried. Recrystallization
from EtOH gave yellow crystals of the title compound 12 (0.83
g; 40%), mp 261–262ꢂC; IR (m/cmꢀ1): 3330 (NH), 3080 (arom.
1
CH), 2223 (CN), 1698 (CO), 1626 (C¼¼N); H NMR (d ppm):
6.71–6.76 (m, 1H, furan H-4), 7.42–7.76 (m, 6H, furan H-3,
Ph), 7.86 (d, 1H, J ¼ 2.0 Hz, furan H-5), 7.95 (s, 1H, pyrimi-
dine H-2), 8.49 (s, 1H, CH¼¼N), 11.92 (s, 1H, NH, D2O-
exchangeable); Anal. Calcd. for C20H11N7O2S (413.419): C,
58.11; H, 2.68; N, 23.72; S, 7.76. Found: C, 57.86; H, 2.52; N,
23.50; S, 7.49.
Method B. To a solution of 8a (0.002 mol) and few drops of
piperidine (0.5 mL) in ethanol (10 mL), ethyl benzylidenecya-
noacetate (0.002 mol) was added. The reaction content was
heated under reflux for 3 h. After cooling, the obtained crystal-
line product was collected by filtration, washed several times
with water, and dried. Recrystallization from EtOH gave, upon
air drying, a yellow product (0.44 g; 53%) identical in all aspects
(mp, mixed mp, and IR data) to that described in method A.
9-Cyano-10-(2-furyl)-3-phenylpyrimido[20,10:2,3]thiazolo[5,4-
e][1,2,4]triazolo[4,3-c]pyrimidin-8-one (13). Method A. Com-
pound 12 (0.002 mol) was heated at reflux in nitrobenzene (10
mL) for 1 h. The final mixture was concentrated and the product
deposited after cooling was recrystallized from dilute acetic acid
to give the 3-phenyl derivative 13 as a brown solid (0.59 g;
72%), mp > 300ꢂC; IR (m/cmꢀ1): 3064 (arom. CH), 2220 (CN),
8-Cyano-4-hydrazino-7-(2-thienyl)thiazolo[3,2-a:4,5-d0]dipyrimidin-
9-one (8b). This compound was obtained as canary yellow crys-
tals (MeOH), mp 261ꢂC; IR (m/cmꢀ1): 3370–3208 (NH, NH2),
2219 (CN), 1702 (CO); 1H NMR (d ppm): 4.95 (s, br, 2H,
NH2, D2O-exchangeable), 7.16 (dd, 1H, J ¼ 4.3, 4.8 Hz, thio-
phene H-4), 7.88–7.92 (m, 2H, thiophene H-3, pyrimidine H-
2), 8.06 (d, 1H, J ¼ 4.8 Hz, thiophene H-5), 10.54 (s, br, 1H,
NH, D2O-exchangeable); MS: m/z (%) ¼ 341 (Mþ, 26%);
Anal. Calcd. for C13H7N7OS2 (341.378): C, 45.74; H, 2.07; N,
28.72; S, 18.79. Found: C, 45.60; H, 1.92; N, 28.46; S, 18.51.
Method B for compound 8a. Chloro compound 11 (0.002
mol) was mixed with hydrazine hydrate (0.006 mol), in abso-
lute ethanol (20 mL). The mixture was stirred under reflux for
3 h. The precipitate formed during reflux was collected by fil-
tration and found, after recrystallization from EtOH, identical
in all respects to that obtained from method A (61% yield).
8-Cyano-7-(2-furyl)-4,9-dioxo-3,4-dihydro-9H-thiazolo[3,2-
a:4,5-d0]dipyrimidine (10). Compound 3a (0.003 mol) was
heated under reflux in formic acid (10 mL) for 7 h. The reac-
tion mixture was then diluted with cold water and allowed to
stand overnight. The resulting precipitate was filtered off,
washed with ethanol (20 mL), dried, and recrystallized from
DMF/EtOH (2:1) as reddish brown crystals (0.52 g; 56%), mp
256–257ꢂC; IR (m/cmꢀ1): 3157 (NH), 2221 (CN), 1697, 1670
1
1697 (CO); H NMR (d ppm): 6.75 (dd, 1H, J ¼ 1.7, 3.8 Hz,
furan H-4), 7.34–7.79 (m, 6H, furan H-3, Ph), 7.89 (d, 1H, J ¼
1.7 Hz, furan H-5), 8.30 (s, 1H, pyrimidine H-5); Anal. Calcd.
for C20H9N7O2S (411.404): C, 58.39; H, 2.21; N, 23.83; S, 7.79.
Found: C, 58.21; H, 2.08; N, 23.56; S, 7.80.
Method B. To a solution of 12 (0.0025 mol) in ethanol (50
mL), ethanolic iron(III) chloride solution [prepared by dissolv-
ing iron(III) chloride (0.005 mol) in ethanol (10 mL)] was added
portionwise while stirring. The reaction content was then boiled
for 15 min and left at room temperature overnight. The solid
product that separated out was collected by filtration and recrys-
tallized from dilute acetic acid to give a tetracyclic product
(0.65 g; 63%) that was found to be identical in all aspects (mp,
mixed mp, and IR data) to the product prepared by method A.
Method C. A mixture of 8a (0.002 mol) and benzoic acid
(0.004 mol) was refluxed with phosphorus oxychloride (10 mL)
for 30 min. Excess phosphorus oxychloride was distilled off under
reduced pressure. The residue was triturated with dilute sodium
hydroxide solution to remove the unreacted material. The solid
residue was recrystallized from dilute acetic acid to give a solid
product (0.49 g; 59%). Again, this product was identified as 13.
Method D. A mixture of 8a (0.002 mol) and benzoyl chlo-
ride (10 mL) was refluxed for 4 h. The excess of benzoyl chlo-
ride was extracted with benzene and the residue was
1
(2CO); H NMR (d ppm): 6.64 (dd, 1H, J ¼ 1.7, 4.0 Hz, furan
H-4), 7.33 (d, 1H, J ¼ 4.0 Hz, furan H-3), 7.76 (d, 1H, J ¼
1.7 Hz, furan H-5), 8.01 (s, 1H, pyrimidine H-2), 12.52 (s, br,
1H, NH, D2O-exchangeable); Anal. Calcd. for C13H5N5O3S
(311.280): C, 50.16; H, 1.62; N, 22.50; S, 10.30. Found: C,
49.87; H, 1.54; N, 22.42; S, 10.13.
4-Chloro-8-cyano7-(2-furyl)thiazolo[3,2-a:4,5-d0]dipyrimidin-
9-one (11). A suspension of compound 10 (0.002 mol) in phos-
phorus oxychloride (30 mL) was refluxed with stirring for 5 h
and then left aside to cool to room temperature overnight
under stirring. Excess reagent was removed under reduced
pressure. The residue was poured to ice/water with stirring and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Promising Antimicrobial Agents: Synthetic Approaches to Novel Tricyclic
and Tetracyclic Pyrimidinones with Antimicrobial Properties
1169
recrystallized from dilute acetic acid to give a solid product
(0.51 g; 62%). The material proved to be 13.
Anal. Calcd. for C18H11N7O4S (421.395): C, 51.30; H, 2.63;
N, 23.27; S, 7.61. Found: C, 51.06; H, 2.49; N, 22.99; S, 7.50.
9-Cyano-10-(2-furyl)pyrimido[20,10:2,3]thiazolo[5,4-e]tet-
razolo[1,5-c]pyrimidin-8-one (19). Compound 8a (0.003
mol) was dissolved in glacial acetic acid (15 mL) containing
concentrated hydrochloric acid (1.5 mL), a small amount of in-
soluble material was filtered off, then the liquid was cooled in
ice bath at 0–5ꢂC. The mixture was stirred at this temperature
and treated gradually with a cold saturated solution of sodium
nitrite [1g of sodium nitrite (0.015 mol) in water (10 mL)]
over a period of 15 min. The mixture was kept in ice bath at
0–5ꢂC with continuous stirring for further 2 h, then it was left
to stand overnight at room temperature and diluted with water,
whereon precipitation took place. The solid thus formed was
isolated by filtration, washed abundantly with cold water,
recrystallized from aqueous DMF, and air dried to give the
fused tetrazole derivative 19 as a yellow solid (0.58 g; 60%),
9-Cyano-10-(2-furyl)-3-thioxo-2,3-dihydropyrimido[20,10:2,
3]thiazolo[5,4-e][1,2,4]triazolo[4,3-c]pyrimidin-8-one (16).
Method A. To a solution of 8a (0.002 mol) in ethanolic so-
dium ethoxide [prepared by dissolving sodium metal (0.002
mol) in absolute ethanol (25 mL)], phenyl isothiocyanate
(0.002 mol) was added dropwise. The mixture was refluxed
with stirring for 10 h and then left to cool to room temperature
overnight under stirring. The reaction mixture was then poured
onto iced water and neutralized with dilute hydrochloric acid.
The resulting precipitate was collected by filtration, washed
several times with water and recrystallized from DMF to give
pale brown crystals of the thione derivative 16 (0.55 g; 75%),
mp 285–288ꢂC; IR (m/cmꢀ1): 3305–3110 (NH), 2225 (CN),
1
1700 (CO), 1395 (C¼¼S); H NMR (d ppm): 6.64 (dd, 1H, J ¼
1.6, 3.7 Hz, furan H-4), 7.26 (d, 1H, J ¼ 3.7 Hz, furan H-3),
7.80 (d, 1H, J ¼ 1.6 Hz, furan H-5), 8.40 (s, 1H, pyrimidine
H-5), 9.55 (s, 1H, NH, D2O-exchangeable); Anal. Calcd. for
C14H5N7O2S2 (367.372): C, 45.77; H, 1.37; N, 26.69; S,
17.46. Found: C, 45.60; H, 1.27; N, 26.39; S, 17.36.
1
mp 221–222ꢂC; IR (m/cmꢀ1): 2218 (CN), 1701 (CO); H NMR
(d ppm): 6.75 (dd, 1H, J ¼ 1.8, 4.0 Hz, furan H-4), 7.30 (d,
1H, J ¼ 4.0 Hz, furan H-3), 7.84 (d, 1H, J ¼ 1.8 Hz, furan H-
5), 9.80 (s, 1H, pyrimidine H-5); MS: m/z (%) ¼ 336 (Mþ,
22%); Anal. Calcd. for C13H4N8O2S (336.288): C, 46.43; H,
1.20; N, 33.32; S, 9.53. Found: C, 46.25; H, 1.12; N, 33.07; S,
9.41.
Method B. A mixture of compound 8a (0.002 mol) and car-
bon disulfide (0.02 mol) in dry pyridine (10 mL) was heated
under reflux for 6 h. The precipitated crystals were filtered off,
dried, and recrystallized from DMF to produce the thione de-
rivative 16 (0.47 g; 64%). Mixed melting points with a sample
of 16 prepared from phenyl isothiocyanate according to
method A showed no depression. The spectral data of com-
pound 16 obtained from both sources were superimposable.
9-Cyano-10-(2-furyl)-3,8-dioxo-2,3-dihydro-8H-pyrimido[20,10:2,
3]thiazolo[5,4-e][1,2,4]triazolo[4,3-c]pyrimidine (17). To a mixture
of dry pyridine (10 mL) and 8a (0.0012 mol) was carefully
added ethyl chloroformate (1 mL, 0.01 mol) and the mixture
was refluxed for 48 h. After cooling, the reaction mixture was
poured onto iced water containing a few drops of hydrochloric
acid. The solid that separated out was filtered off, washed with
water several times, dried, and then recrystallized from EtOH
to give the dione derivative 17 as a yellow solid (0.38 g;
89%), mp > 300ꢂC; IR (m/cmꢀ1): 3300 (NH), 2221 (CN),
Antimicrobial activity. The preliminary antimicrobial activ-
ity of the synthesized tricyclic and tetracyclic derivatives was
evaluated in vitro by means of the agar-well diffusion assay.
The assay was carried out according to the method of Hufford
et al. [57] with some modifications. A total of 10 test microor-
ganisms were used for the current antimicrobial activity stud-
ies: two gram positive bacteria (Staphylococcus aureus and
Bacillus cereus), four gram negative bacteria (Pseudomonas
aeruginosa, Escherichia coli, Salmonella typhyrium, and Kleb-
siella spp), and four fungi (Aspergillus flavus, Aspergillus
fumigatus, Aspergillus niger, and Trichoderma horozianum).
The culture media used were Nutrient agar for bacteria and
Czapek’s agar (Difco) for fungi. Twenty-five milliliters of the
specified molten agar (45ꢂC) was aseptically mixed with either
100 lL of a bacterial suspension or 1 mL of a fungal suspen-
sion and poured into 15 mm sterile Petri dishes. For the prepa-
ration of the inocula colonies of bacteria were suspended in
nutrient broth incubated overnight and fungi were suspended
in sterile saline solution (NaCl, 0.85%), respectively. Once the
agar was hardened, 9-mm wells were bored using a sterile
cork borer. One hundred milliliters of the DMF extract (2 lm)
were placed into the wells and the plates were incubated for
24 h at 37ꢂC for the bacteria and 24–72 h at 28ꢂC for the
fungi. The antimicrobial activity was measured as the diameter
(mm) of clear zone of growth inhibition. Solvent controls
(DMF) were included in every experiment as negative con-
trols. DMF was used for dissolving the crude extracts and
gave negative results, confirming that it did not influence on
antimicrobial activity observed for the compounds tested.
1
1702, 1680 (2CO); H NMR (d ppm): 6.88–7.15 (m, 2H, furan
H-3,4), 7.78 (d, 1H, J ¼ 2.0 Hz, furan H-5), 8.11 (s, 1H, py-
rimidine H-5), 10.92 (s, br, 1H, NH, D2O-exchangeable); MS:
m/z (%) ¼ 351 (Mþ, 16%); Anal. Calcd. for C14H5N7O3S
(351.305): C, 47.87; H, 1.43; N, 27.91; S, 9.13. Found: C,
47.58; H, 1.33; N, 27.74; S, 8.96.
Ethyl {9-cyano-10-(2-furyl)-8-oxo-8H-pyrimido[20,10:2,3]-
thiazolo[5,4-e][1,2,4]triazolo[4,3-c]pyrimidin-3-yl}acetate
(18). A suspension of compound 8a (0.002 mol) in diethyl
malonate (10 mL) was gently heated under reflux for 10 h.
The reaction mixture was triturated with ethanol (15 mL) and
then allowed to cool. The formed precipitate was collected by
filtration and purified by recrystallization from 1,4-dioxane to
give light brown crystals of the ethyl ester 18 (0.58 g; 69%),
mp 209–210ꢂC; IR (m/cmꢀ1): 2960, 2835 (aliph. CH), 2223
1
(CN), 1730, 1698 (2CO); H NMR (d ppm): 1.25 (t, 3H, J ¼
Acknowledgments. H. M. Gaber would like to express his grati-
tude and thanks for the Research Fellowship grant in School of
Chemistry, Cardiff University, UK, and for all facilities provided
to this fellowship. Financial support from Cardiff University, the
Engineering and Physical Sciences Research Council (EPSRC)
and the Biotechnology and Biological Sciences Research Council
(BBSRC), in collaboration with the University of Wales College
of Medicine, UK, is gratefully acknowledged.
7.2 Hz, ester Me), 4.20 (q, 2H, J ¼ 7.2 Hz, ester CH2), 5.11
(s, 2H, CH2CO), 6.90–7.19 (m, 2H, furan H-3,4), 7.75 (d, 1H,
J ¼ 1.9 Hz, furan H-5), 8.70 (s, 1H, pyrimidine H-5); 13C
NMR (d ppm): 14.0 (ester Me), 34.5 (CH2), 60.7 (ester CH2),
98.7 (C-9), 111.4, 112.5 (furan C-3,4), 118.3 (CN), 133.1,
138.5, 143.8 (furan C-5), 148.0, 155.6 (furan C-2), 156.3,
158.4, 160.1, 161.6 (ring CO), 166.9, 168.0 (ester CO, C-10);
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1170
H. M. Gaber, M. C. Bagley, S. M. Sherif, and U. M. Abdul-Raouf
Vol 47
[27] Rudolph, J.; Theis, H.; Hanke, R.; Endermann, R.; Johann-
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[28] Pandeya, S. N.; Sriram, D.; Nath, G.; DeClercq, E. Eur J
Pharm Sci 1999, 9, 25.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet