Novel 2-hydrazino-pyrimidin-4(3H)-one derivatives as potential dihydrofolate reductase inhibitors

Article abstract of DOI:10.1002/jhet.216

(Chemical Equation Presented) Novel substituted 2-hydrazino-pyrimidin-4(3H) -one derivatives were synthesized and examined for their antifolate activity against DHFR from Pneumocystis carinii (pc), Toxoplasma gondii (tg), Mycobacterium avium (ma), and rat

Full text of DOI:10.1002/jhet.216

558
Novel 2-Hydrazino-pyrimidin-4(3H)-One Derivatives as Potential
Dihydrofolate Reductase Inhibitors
Vol 47
Mariam S. Degani,a* Seema Bag,a Ranjeet Bairwa,a Nilesh R. Tawari,a
and Sherry F. Queenerb
aInstitute of Chemical Technology, Deemed-to-be-University under Section 3 of the UGC Act
1956, Matunga (E), Mumbai 400019, India
bDepartment of Pharmacology and Toxicology, School of Medicine, Indiana University,
Indianapolis, Indiana 46202
*E-mail: msdegani@udct.org
Received November 5, 2008
DOI 10.1002/jhet.216
Published online 15 April 2010 in Wiley InterScience (www.interscience.wiley.com).
Novel substituted 2-hydrazino-pyrimidin-4(3H)-one derivatives were synthesized and examined for
their antifolate activity against DHFR from Pneumocystis carinii (pc), Toxoplasma gondii (tg), Myco-
bacterium avium (ma), and rat liver (rl). A novel, simple, and feasible methodology was developed for
the synthesis of the titled compounds. Amongst these, compound 8 6-phenyl-2-(2-(1-(thiophen-2-yl)
ethylidene)hydrazinyl) pyrimidin-4(3H)-one exhibited 17.74 lM activity against pcDHFR.
J. Heterocyclic Chem., 47, 558 (2010).
INTRODUCTION
virtual screening of ASINEX database using docking
algorithm Glide was undertaken [4]. Crystal structure
˚
pcDHFR PDB ID: 1KLK, 2.30 A resolution [5] was
Dihydrofolate reductase (DHFR), a crucial enzyme
required for the conversion of folic acid to dihydro and
tetrahydro folic acid (a cofactor involved in one carbon
transfer in purine and pyrimidine de-novo synthesis) has
been successfully explored as a target for the treatment
of various infective diseases. Opportunistic organisms
such as Pneumocystis carinii (pc), Toxoplasma gondii
(tg), and Mycobacterium avium (ma) cause life threaten-
ing infections in immunocompromised hosts. Majority
of the DHFR inhibitors explored have a 2,4-diamino
moiety on the aromatic/heteroaromatic ring as an impor-
tant pharmacophoric feature which forms a crucial H-
bonding interaction at the bottom of the active site in
both microbial and human DHFR [1]. The structural
requirements of potential DHFR inhibitors have been
summarized in a recent review article [2]. Only few
reports are found in literature for DHFR inhibitors lack-
ing 2,4-diamino moiety on the pyrimidine/triazine
nucleus.
used for the docking studies. Initially, all compounds
were docked using HTVS mode in Glide, top 10% hits
from this study were again docked using SP (Standard
precision mode). Finally, top 1% hits emerged from this
study were redocked using XP (Extra precision mode).
The scaffolds obtained from XP docking were used for
novel inhibitor design.
Interestingly, in these virtual screening studies some
of the new scaffolds lacking conventional 2,4-diamino
pharmacophore, were also identified as hits but have not
yet been reported as DHFR inhibitors. On the basis of
the structural features of the new scaffolds obtained
from virtual screening, 2-hydrazino-pyrimidin-4(3H)-one
as the basic nucleus was chosen as a potential part of
designed DHFR inhibitors.
The designed analogs were studied computationally to
get an insight into the binding pattern of these com-
pounds. When a 2-hydrazino-pyrimidin-4(3H)-one ana-
log was superimposed on trimethoprim, in the active
site of pcDHFR, conserved interactions were observed.
It was also observed that the –NH of the pyrimidinone
part forms hydrogen bonding with Ile123 in the active
site of pcDHFR. The docking studies revealed that pyri-
midinone part of the molecule is stabilized using van
der Waals interactions with residues like Ile123, Ile10,
Val11, Phe36, Glu32, Ile33, and Leu25. The bridge por-
tion of the designed analogs are shown to form
Gschwend et al. screened a library of 50,000 com-
pounds using the program DOCK to develop selective
inhibitors towards P. carinii [3]. Several novel classes of
compounds were identified as potential DHFR inhibitors,
providing new avenues for lead optimization. The most
potent compound (Threne Red Violet RH, Fig. 1) identi-
fied had IC50 of 6.9 lM towards the fungal enzyme.
This indicated that novel scaffolds could be designed
inhibiting the folate pathway efficiently. In this light,
C
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Novel 2-Hydrazino-pyrimidin-4(3H)-One Derivatives as Potential
Dihydrofolate Reductase Inhibitors
559
bersome. Therefore, designing an efficient protocol
using commercially available starting materials, involv-
ing easy workup procedure for the synthesis of these
compounds was taken into consideration.
In the present work, initially a two step process was
developed using conventional heating (Method 1). The
first step involves condensation of ethanolic solution of
substituted ketones with semicarbazide hydrochloride to
yield a substituted semicarbazone using absolute ethanol
as solvent.
Figure 1. Hit identified from the study of Gschwend et al.
favorable interactions with Ile123, Thr61, whereas the
distal part forms van der Waals interactions with Asn23,
Ser64, Pro66, Ile65, Phe69, Leu72, and Phe36 in the
active site of the enzyme. Pyrimidinone ring forms p-p
In step II, the ethanolic solution of semicarbazone
was treated with various b- ketoesters in presence of a
base to yield the desired analogs as shown in Scheme 1.
Various bases such as triethylamine, pyridine and am-
monium acetate were explored for this step. Triethyl-
amine was found to give good yields, in less time than
other bases.
˚
stacking interactions with Phe36 (4.470 A) at the bottom
of the active site.
Substituted pyrimidin-4(3H)-one compounds have
widespread biological activities [6]. However, to the
best of our knowledge these types of molecules are not
yet explored as DHFR inhibitors. Therefore, based on
virtual screening and new scaffold design, synthesis and
evaluation of 2-hydrazino-pyrimidin-4(3H)-one deriva-
tives against DHFR from various opportunistic microor-
ganisms were undertaken.
Microwave (MW) assisted synthesis is known to be
advantageous over conventional reaction reported in lit-
erature; with respect to time, yield and workup proce-
dures [9].
In this light, the above synthetic scheme was carried
out using microwave irradiation (Method 2). Although
steps I and II took many hours to complete under con-
ventional heating (Method 1) no more starting materials
could be detected after 10–20 min under microwave
irradiation.
RESULTS AND DISCUSSION
The reported methods for the synthesis of 2-hydra-
zino-pyrimidin-4(3H)-one derivatives involve acetic acid
catalyzed condensation reaction of aromatic aldehydes
with a cyclic intermediate of ethyl acetoacetate and
semicarbazide [6,7]. Formic acid catalyzed condensation
reaction of ketone with semicarbazide has also been
reported [8].
Encouraged by the results obtained using microwave
method, a one pot microwave assisted method was also
investigated.
In case of one pot microwave assisted reaction, an
ethanolic solution of b-ketoester, semicarbazide hydro-
chloride and substituted ketone was subjected to micro-
wave irradiation with intermittent addition of triethyl-
amine. Appropriate workup procedures followed by col-
umn purification led to the isolation of the desired
compound as shown in Scheme 2. Thus, a one step pro-
cess using microwave irradiation without isolating the
intermediate was developed (Method 3). Thereafter, all
However, reported methods for the synthesis of 2-
hydrazino-pyrimidin-4(3H)-one derivatives suffer from
several disadvantages such as use of commercially
unavailable cyclic intermediates as starting material,
multi-step reactions which in turn make the process
costly, lengthy, time consuming and also affect the yield
and quality of the final products. Moreover, the use of
acetic acid or formic acid [8], makes the workup cum-
Scheme 2. Microwave assisted one pot method for the synthesis of 2-
hydrazino-pyrimidin-4(3H)-ones.
Scheme 1. Method for the synthesis of 2-hydrazino-pyrimidin-
4(3H)-one derivatives. A, EtOH, reflux; b, TEA, EtOH, reflux.
Journal of Heterocyclic Chemistry
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M. S. Degani, S. Bag, R. Bairwa, N. R. Tawari, and S. F. Queener
Vol 47
Table 1
List of synthesized 2-hydrazino-pyrimidin-4(3H)-one derivatives.
No.
Structure
Mol. formula
No.
Structure
Mol. formula
1
C18H14F2N4O
5
C11H11BrN4OS
2
C23H16F2N4O
6
C16H13BrN4OS
3
C20H20N4O
7
C11H12N4OS
4
C23H26N4O
8
C16H14N4OS
the compounds were synthesized using one pot micro-
wave assisted method (Method 3).
continuous spectrophotometric assay measuring oxida-
tion at 340 nM of NADPH at 37ꢀC under conditions of
saturating substrate and cofactor as previously described
[10,11]. The results of this assay are given in Table 2,
along with previously reported data for reference com-
pounds [12].
The processes developed in this present work are fea-
sible, simple, cost-effective and time saving.
The course of the reaction was monitored by thin
layer chromatography (TLC) and the structures were
confirmed by spectral data. The MS of all the com-
The compound 5 showed 51.38 lM activity against
pcDHFR and 60.54 lM activity against maDHFR. The
Compound 8 also exhibited comparable potency as that
of trimethoprim against pcDHFR. The Compound 6
exhibited micromolar potency against pc DHFR. How-
ever, the synthesized molecules were not selective.
In summary based on virtual screening experiments,
2-hydrazino-pyrimidin-4(3H)-one was designed as novel
antifolate scaffold. An efficient, simple protocol was
1
pounds exhibited the molecular ion peak. H NMR spec-
tra of 2-hydrazino-pyrimidin-4(3H)-one showed the
presence of characteristic, D2O exchangeable –NH peaks
at d ranging from 7.0 to 8.0. All the other spectral data
was found to be satisfactory. The list of synthesized
compounds is given Table 1.
The synthesized compounds were evaluated for their
ability to inhibit DHFR from pc, tg, ma, and rl using a
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Novel 2-Hydrazino-pyrimidin-4(3H)-One Derivatives as Potential
Dihydrofolate Reductase Inhibitors
561
Table 2
Dihydrofolate reductase inhibition by synthesized compounds.
Activity IC50 (lM)
S. N.
pc
tg
ma
rl
1
2
3
4
5
6
7
8
138.102 (32)
10.313 (3)
12.515 (7)
126.036
13.294 (5)
88.833
19.130 (8)
17.740
12
138.102 (28)
10.313 (0)
12.515 (4)
12.401 (26)
51.375
138.102 (22)
10.313 (0)
12.515 (8)
12.401 (22)
60.544
138.102 (35)
10.313 (9)
12.515 (0)
20.208
13.294 (58)
58.674
19.130 (58)
14.766
180
95.949
126.981
93.153
173.499
14.209 (20)
2.80
14.209 (19)
0.30
0.00061
Trimethprima
Piritrexima
Trimetrexatea
0.013
0.042
0.0043
0.01
0.0033
0.003
0.0015
Inhibitory concentration (IC50, lM) against rlDHFR, pcDHFR, tgDHFR and maDHFR by target compounds. Triplicate assays were performed as
previously described [10,11].
Because of lack of solubility the exact IC50 could not be determined for some compounds; hence maximum soluble concentration was used to
determine % inhibition. Number in parentheses indicates percent inhibition obtained at that concentration. For e.g., 138.102 (32) indicates 32% in-
hibition at 138.102 lM concentration.
a Data taken from reference [12].
between 50 mL water and 50 mL EtOAc:hexanes (1:9) to
extract unreacted starting materials in organic layer. Aqueous
layer was stirred for 5 min with solid sodium bicarbonate (3 g)
leading to precipitation of solid semicarbazone which was then
filtered and washed with water (3 ꢁ 50 mL). The obtained
solid was recrystallized from 40 mL of MeOH. This gave pure
semicarbazone in free base form which was used for the cycli-
zation with b-ketoester.
Representative example. 2-(bis(4-fluorophenyl)methylene)
hydrazinecarboximidamide: To the ethanolic solution of bis(4-
fluorophenyl)methanone (3g, 13.7 mmol); semicarbazide
hydrochloride (1.51 g, 13.7 mmol) was added according to
step 1, to yield 2.87g (yield: 76.12%) of pure yellow colored
semicarbazone product ((2-(bis(4-fluorophenyl)methylene)
hydrazinecarboximidamide).
Step II: Synthesis of 2-hydrazino-pyrimidin-4(3H)-one
derivatives. The semicarbazone (6.16 mmol), the b-ketoester
derivative (6.16 mmol) and triethylamine (3.08 mmol) as a
catalyst were suspended in 30 mL absolute ethanol and the
mixture was refluxed on a sand bath with stirring for 18–22
hrs. TLC showed a product spot (Rf of 0.4–0.6 in the solvent
system EtOAc:Hexanes (7:3)). The reaction mixture was con-
centrated under vacuum and was partitioned between EtOAc
(25 mL) and water (25 mL). The organic layer was separated,
and the aqueous layer was extracted further with EtOAc (2 ꢁ
25 mL). The combined organic layers were washed with brine
(75 mL), dried (NaSO4), and concentrated in vacuo. Column
purification using flash chromatography (SiO2, 5 g, 15%
EtOAc/hexanes) of the crude product yielded pure 2-hydra-
zino-pyrimidin-4(3H)-one derivatives.
Representative example. 2-(2-(bis(4-fluorophenyl) methyl-
ene) hydrazinyl)-6-methylpyrimidin-4(3H)-one (1): The etha-
nolic solution of 2-(bis(4-fluorophenyl) methylene) hydrazine-
carboximidamide (1 g, 3.6 mmol) was treated with ethylace-
toacetate (0.47 g, 3.6 mmol) and triethyl amine (0.18 g, 1.8
mmol) according to step 2, to yield 0.521 g (yield: 42%) of 2-
(2-(bis(4-fluorophenyl)methylene)hydrazinyl)-6-methyl pyrimi-
din-4(3H)-one as buff colored solid.
developed for synthesis of these molecules. The synthe-
sized compounds were evaluated against DHFR of
opportunistic organisms. Some of the evaluated com-
pounds showed appreciable antifolate activity, thus vali-
dating our methodology. Therefore, these compounds
could act as good leads for novel antifolates. The results
would be used for design and synthesis of analogs with
improved potency and selectivity.
EXPERIMENTAL
Melting points (mp) were recorded on Thermomik Compbell
electronics, having oil-heating system and were uncorrected.
The microwave reactions were carried out using CEM Focused
Microwave System in monomode, Model Discover. Analytical
thin-layer chromatography (TLC) was carried out on precoated
plates SiO2 (silica gel 60, F 254, Merck). SiO2 (Silica gel 420,
Merck) was used for column chromatography using
R
R
CombiFlashV RETRIEVEV system. FTIR spectra were recorded
on ‘‘Buck scientific infrared spectroscopy M500 spectrophotom-
eter’’ using KBr pellets. All the NMR spectra were recorded on
FT-NMR JEOL, 60 MHz or JEOL AL 300 MHz spectrometer
with DMSO-d6 or CDCl3 as solvent using tetramethyl silane
(TMS) as internal reference: s ¼ singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, m ¼ mutiplet, bs ¼ broad singlet. The mass spec-
trum was recorded on a Waters Q/TOF Micromass spectrometer.
General procedure method 1 (method using conventional
reflux) Step I: synthesis of semicarbazone. Substituted ke-
tone (13.7 mmol) and semicarbazide hydrochloride (13.7
mmol) were stirred in 30 mL absolute ethanol in a round bot-
tom flask and the mixture was refluxed on a sand bath with
vigorous stirring for 14–18 hrs. After the reaction commenced,
ketones reacted with semicarbazide hydrochloride giving a
base spot on TLC (in solvent system EtOAc:Hexanes ¼ 9:1).
The reaction mixture was then concentrated under reduced
pressure and the obtained solid residue was partitioned
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M. S. Degani, S. Bag, R. Bairwa, N. R. Tawari, and S. F. Queener
Vol 47
115.33, 115.62, 116.91, 117.19, 127.80, 129.93, 130.03,
130.78, 130.90, 132.64, 151.93, 161.99, 163.99, 165.13,
165.32, 171.77; m/z [Mþ1]þ 341, [Mþ2]þ 342, [Mþ3]þ 343.
2-(2-(Bis(4-fluorophenyl)methylene)hydrazinyl)-6-phenylpyri-
midin-4(3H)-one (2) This compound was obtained as a yellow
colored solid in 20 % yield, mp: 235–237ꢀC; IR (KBr) major
Method 2: (method using microwave assisted reaction)
Step I: Synthesis of semicarbazone. A mixture of the ketone
(13.7 mmol) and semicarbazide hydrochloride (13.7 mmol)
suspended in 30 mL absolute ethanol. This reaction mixture
was subjected to microwave irradiation at a power of 60 W,
for 15 min (target temperature 100ꢀC). After the completion of
reaction the compounds were isolated and purified as described
in step I of method 1.
Representative example. 2-(2-(bis(4-fluorophenyl) methyl-
ene) hydrazinyl)-6-methylpyrimidin-4(3H)-one: To the ethanolic
solution of bis(4-fluorophenyl)methanone (3 g, 13.7 mmol); semi-
carbazide hydrochloride (1.51 g, 13.7 mmol) was added according
to step 1, to yield 3.2 g (yield: 85.13%) of pure yellow colored
bands at: 3473, 1654, 1607, 1498, 1383, 1223, 974, 844 cmꢂ1
;
1
H NMR: d 6.37 (s, 1H, Ar –H), 7.04–7.82 (m, 14H, Ar –H
and ex ANH), 9.70 (bs, 1H, ex ANH); 13C NMR: d 109.09,
114026, 115.51, 115.80, 117.25, 117.54, 126.87, 127.15,
128.69, 129.64, 129.75, 129.99, 130.52, 130.70, 130.82,
132.52, 136.79, 149.97, 151.72, 162.37, 163.40, 163.76,
165.31; m/z [Mþ1]þ403, [Mþ2]þ 404, [Mþ3]þ 405.
semicarbazone product
hydrazinecarboximidamide).
((2-(bis(4-fluorophenyl)methylene)
2-(2-(1,3-Diphenylpropylidene)hydrazinyl)-6-methylpyrimidin-
4(3H)-one (3) This compound was obtained as a buff colored
solid in 40.24 % yield, mp: 152–154ꢀC; IR (KBr) major
Step II: Synthesis of 2-hydrazino-pyrimidin-4(3H)-one
derivatives. The semicarbazone (3.6 mmol), the b-ketoester
derivative (3.6 mmol) and triethylamine (1.8 mmol) as a cata-
lyst were suspended in 30 mL absolute ethanol. This reaction
mixture was subjected to microwave irradiation at a power of
60 W, for 20 min (target temperature of 100ꢀC). After the
completion of reaction the compounds were isolated and puri-
fied as described in step II of method 1.
Representative example. 2-(2-(bis(4-fluorophenyl) methyl-
ene) hydrazinyl)-6-methylpyrimidin-4(3H)-one (1): The etha-
nolic solution of 2-(bis(4-fluorophenyl) methylene) hydrazine-
carboximidamide (1 g, 3.6 mmol) was treated with ethylace-
toacetate (0.47 g, 3.6 mmol) and triethyl amine (0.18 g, 1.8
mmol) according to step 2, to yield 0.583 g (yield: 47%) of 2-
(2-(bis(4-fluorophenyl)methylene)hydrazinyl)-6-methyl pyrimi-
din-4(3H)-one as buff colored solid.
bands at: 3468, 1648, 1492, 1378, 1119 cmꢂ1 1
; H NMR: d
2.09 (s, 3H, ACH3), 2.87 (t, 2H, ACH2), 3.12 (t, 2H,
ACH2), 5.73 (s, 1H, Ar-H), 7.26-7.72 (m, 11 H, Ar –H and
ex ANH), 9.69 (bs, 1H, ANH); 13C NMR: d 21.26, 29.41,
32.02, 103.42, 121.86, 126.27, 126.45, 126.64, 128.46,
128.65, 128.82, 128.88, 129.73, 129.88, 129.99, 136.37,
140.30, 162.11, 176.91; m/z [M]þ 333, [Mþ1]þ 334,
[Mþ2]þ 335.
2-(2-(1,3-Diphenylpropylidene)hydrazinyl)-6-methyl-5-propyl-
pyrimidin-4(3H)-one (4) This compound was obtained as a
1
buff colored solid in 10 % yield, mp: 213–214ꢀC; H NMR:
d 1.90 (s, 3H, ACH3), 2.18 (t, 3H, ACH3), 2.45 (m, 4H,
2ACH2), 2.78 (t, 2H, ACH2), 3.21 (t, 2H, ACH2), 7.20–8.00
(m, 9H, ArAH), 10.40 (bs, 1H, ex ANH), 11.40 (bs, 1H, ex
ANH).
Method 3: (One pot microwave assisted method). A mix-
ture of ketone (27.5 mmol), semicarbazide hydrochloride (27.5
mmol) and b-ketoester (27.5 mmol) were suspended in 30 mL
absolute ethanol. This reaction mixture was subjected to
microwave irradiation with power of 60 W, for 10 min (target
temperature 100ꢀC). After 10 min triethylamine (13.75 mmol)
was added in and reaction mixture was subjected to microwave
irradiation at the power range of 100 W, for 15–20 min (target
temperature 100ꢀC). Most of the starting material consumed
after this time, the reaction mixture was then concentrated
under reduced pressure and partitioned between water (50 mL)
and EtOAc (50 mL). The organic layer was separated, and the
aqueous layer was extracted further with EtOAc (2 ꢁ 25 mL).
The combined organic layers were washed with brine (75 mL),
dried (NaSO4), and concentrated in vacuo. Column purification
using flash chromatography (SiO2, 5 g, 15% EtOAc/hexanes)
of the crude product yielded pure 2-hydrazino-pyrimidin-
4(3H)-one derivatives.
2-(2-(1-(5-Bromothiophen-2-yl)ethylidene)hydrazinyl)-6-meth-
ylpyrimidin-4(3H)-one (5) This compound was obtained as a
light brown solid in 30 % yield, mp: 226–228ꢀC; IR (KBr)
1
major bands at: 3497, 1643, 1560, 1384, 1129, 828 cmꢂ1
;
H
NMR: d 2.17 (s, 3H, ACH3), 2.31 (s, 3H, ACH3), 5.70 (s, 1H,
ArAH), 6.99–7.26 (m, 4H, ArAH and ex ANH); 13C NMR: d
21.21, 21.92, 103.18, 113.64, 114.42, 127.24, 130.32, 144.08,
147.18, 152.32, 176.68; m/z [M]þ 327.
2-(2-(1-(5-Bromothiophen-2-yl)ethylidene)hydrazinyl)-6-phe-
nylpyrimidin-4(3H)-one (6) This compound was obtained as a
1
buff colored solid in 43% yield, mp: 225–226ꢀC; H NMR: d
2.12 (s, 3H, ACH3), 6.10 (s, 1H, ArAH), 6.96–6.97 (d, 1H,
ArAH), 7.091–7.099 (d, 1H, ArAH), 7.219–7.228 (d, 1H,
ArAH), 7.358–7.365 (d, 1H, ArAH), 7.477–7.489 (m, 1H,
ArAH), 8.016 (bs, 2H, ex ANH); m/z [M]þ 389, [Mþ2]þ 391.
6-methyl-2-(2-(1-(thiophen-2-yl)ethylidene) hydrazinyl) pyr-
imidin-4(3H)-one (7) This compound was obtained as a light
brown solid in 27 % yield, mp: 229–230ꢀC; IR (KBr) major
Representative example. 2-(2-(bis(4-fluorophenyl) methyl-
ene) hydrazinyl)-6-methyl pyrimidin -4(3H)-one (1): To the
ethanolic solution of bis(4-fluorophenyl)methanone (3 g, 13.7
mmol), aminoguanide hydrochloride (1.51 g, 13.7 mmol) and
ethylacetoacetate (1.41 g, 13.7 mmol) triethyl amine (0.69 g,
6.85 mmol) was added according to reaction described above
to yield 1.93 g (yield: 40.6%) of buff colored product.
bands at: 3497, 1664, 1633, 1575, 1425, 1384 cmꢂ1 1 H NMR:
;
d 2.17 (s, 3H, ACH3), 2.37 (s, 3H, ACH3), 5.69 (s, 1H, ArAH),
7.03–7.34 (m, 3H, ArAH), 9.24 (bs, 2H, ex ANH); 13C NMR: d
21.40, 22.20, 103.13, 127.27, 127.43, 128.46, 142.60, 147.78,
152.27, 152.36, 177.02; m/z [Mþ1]þ 249.
6-Phenyl-2-(2-(1-(thiophen-2-yl)ethylidene)hydrazinyl)pyri-
midin-4(3H)-one (8) This compound was obtained as yellow
1
2-(2-(Bis(4-fluorophenyl)methylene)hydrazinyl)-6-methylpyri-
midin-4(3H)-one (1) IR (KBr) major bands at: 3466, 1654,
colored solid in 20% yield, mp: 228–230ꢀC; H NMR: d 2.27
(s, 3H, ACH3), 6.30 (s, 1H, ArAH), 7.04–7.79 (m, 10H, ArAH
and exANH); 13C NMR: d 17.59, 101.31, 126.77, 126.87,
127.14, 127.23, 127.37, 127.44, 128.52, 128.64, 128.80, 130.44,
151.25, 152.10, 152.24, 167.55; m/z [Mþ1]þ 311.
1
1560, 1506, 1384, 1299, 1226, 1157 cmꢂ1
;
H NMR: d 1.99
(s, 3H, ACH3), 5.78 (s, 1H, Ar ACH), 7.01–7.67 (m, 8H, Ar
–H), 9.64 (bs, 2H, ex ANH); 13C NMR: d 23.01, 103.71,
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Novel 2-Hydrazino-pyrimidin-4(3H)-One Derivatives as Potential
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[5] Cody, V.; Galitsky, N.; Luft, J.; Pangborn, W.; Rosowsky,
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Acknowledgments. Seema Bag and Ranjeet Bairwa are thankful
to University Grand Commission (UGC), India and Nilesh R.
Tawari is thankful to Department of Biotechnology (DBT), India
for financial support.
´ ´ ´ ´
¨
[6] Szilagyi, L.; Illyes, T. Z.; Gyorgydeak, Z.; Szabo, G.;
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet