Synthesis and prediction of bioactivity of new nitroimidazole derivatives

Article abstract of DOI:10.1002/jhet.5570420521

Syntheses of 1-propyl derivatives of 2-methyl-5-nitroimidazole (11-17), containing various azanaphthalene systems attached at 3-position of the propyl group have been described. Due to structural similarity of the derivatives 11-17 with metronidazole, an

Full text of DOI:10.1002/jhet.5570420521

Jul-Aug 2005
Synthesis and Prediction of Bioactivity of
New Nitroimidazole Derivatives
883
Piotr Kowalski*, Krystyna Nowak and Barbara Szpakiewicz
Cracow University of Technology, Institute of Organic Chemistry and Technology,
ul.Warszawska 24, 31-155 Kraków, Poland
e-mail: kowapi@usk.pk.edu.pl
Received October 10, 2004
Syntheses of 1-propyl derivatives of 2-methyl-5-nitroimidazole (11-17), containing various azanaphtha-
lene systems attached at 3-position of the propyl group have been described. Due to structural similarity of
the derivatives 11-17 with metronidazole, an antibacterial and antiprotozoal drug, pharmacological proper-
ties of the target compounds were predicted using the PASS program. Polar surface area (PSA) parameter
was also applied for estimation of the physical properties of 11-17 as drug-like candidates.
J. Heterocyclic Chem., 42, 883 (2005).
Introduction.
Syntheses.
Imidazole and its derivatives, including nitroimidazole,
are the compounds that raise continuous interest as biolog-
ically active substances [1-4]. The simplest derivative, 2-
nitroimidazole (azomycin), is a natural antibiotic with
antitrichomonal activity [5]. Antiprotozoal acivity, in par-
ticular towards trichomonas and amoebas is shown by N-
substituted derivatives of imidazole containing nitro group
in 2- or 5-position. The most known derivative, 2-(2-
methyl-5-nitroimidazolyl)ethanol (Metronidazole,
Flagyl , MetroCream , Noritrate , Protostat ), is a syn-
thetic derivative of azomycin. Metronidazole is an antibac-
terial and antiprotozoal drug, which also has a radiosensi-
tising effect on hypoxic tumor cells. Metronidazole is used
in the treatment of various infections, such as amoebiasis,
giardiasis, trichomoniasis and leishmaniasis [6,7].
The synthesis of the compounds 11-17 is shown in
Scheme 1.
1-(3-Chloropropyl)-2-methyl-5-nitroimidazole (3) was
obtained by alkylation of 2-methyl-5-nitroimidazole (1)
Scheme 1




This work is a continuation of our research on synthesis
of azaheterocyclic compounds and studies of their bioac-
tivity [8-11]. Synthesis of the new metronidazole analogs
(11-17), where the hydroxyethyl group of metronidazole
was replaced by a propyl group containing diversified
azanaphthalene systems at the chain end, is described. As
the azanaphthalene system is present in many therapeutic
substances, it can be expected that the new derivatives of
2
-methyl-5-nitroimidazole will also show biological activ-
ity. The potential bioactivity of 11-17 has been evaluated
using the PASS program (Prediction of Activity Spectra
for Substances) [12-16], while their bioavailability, which
is an important feature of bioactive compounds, has been
determined on the basis of their physical properties.
Results and Discussion.

8
84
P. Kowalski, K. Nowak and B. Szpakiewicz
Vol. 42
with 1-bromo-3-chloropropane (2). Next, 3 was condensed
with quinolin-2(1H)-one (4), isoquinolin-1(2H)-one (5),
quinazolin-4(3H)-one (6), quinoxalin-2(1H)-one (7),
phthalazin-1(2H)-one (8), 1,8-naphthyridin-2(1H)-one (9),
and pyrido[2,3-b]pyrazin-6(5H)-one (10). Both the alkyla-
tion and the condensation reactions were carried out under
the same conditions (i.e., at room temperature, in
dimethylformamide (DMF) solution and in the presence of
K CO ). In all cases, after 48 h of reaction time, N-substi-
the case of 14b the formation of 14a was detected. Hence,
these data indicate that the formation of 14a in the reaction
of 3 with 7 may result both from direct N-alkylation of the
amide form of 7 and from rearrangement of the thermody-
namically less stable O-isomer (14b). The formation of the
more stable isomer 14a is consistent with quantum chemi-
cal calculations. The heat of formation (∆H ) of 14b, cal-
f
culated using AM1 parameterization of MOPAC 6 pro-
gram, equals 78.9 kcal/mol, which is by 3.9 kcal/mol
2
3
tuted derivatives (11a-17a) of the heterocyclic amides
were obtained with 8% to 82% yields (Table 1).
Low yield of the reaction of 3 with quinolin-2(1H)-one
higher than the ∆H of 14a. Figure 1 presents the heat of
f
formation and some details (i.e., torsionals angles) of the
final geometry of 14a and 14b.
(
4) resulted from low conversion of lactame 4 (50% of
unreacted quinolin-2(1H)-one (4) was recovered), and for-
mation of the O-substituted isomer (11b), which was iso-
lated from the product mixture in 15% yield. Similarly, the
condensation of 3 with quinoxalin-2(1H)-one (7) led to a
mixture of N-substituted (14a) and O-substituted (14b)
derivatives. The presence of the N- and O-isomers was
confirmed by chromatographic analysis of the product
mixtures; these isomers show distinctly different R coef-
F
ficients. Moreover, no characteristic C=O vibrations are
observed in the IR spectra of 11b and 14b; only the bands
corresponding to C-O-C vibrations are present (Table 1).
1
4a; ∆H = 75.0 kcal/mol
14b; ∆H = 78.9 kcal/mol
f
1 2 3 4
f
C -N -C -C = -83.33
N -C -O -C = 3.47
1
2
3
4
Table 1
N2-C3-C4-C5 = -179.01
C -C -C -N = -52.88
C2-O3-C4-C5 = 178.33
O -C -C -C = 73.15
3
4
5
6
3
4
5
6
Yields of the compounds 11-17 obtained after 48 h condensation
of 3 with 4-10, and their characteristic IR bands.
C -C -N -C = -60.24
C -C -C -N = -178.55
4
5
6
7
4 5 6 7
C -N -C -N = -175.53
C -C -N -C = 98.47
5 6 7 8
5
6
7
9
C -N -C -N = -178.68
Location of stretching vibrations, cm-1
6
7
8
9
Compound
No.
Yield
(%)
ν C=O
ν C-O-C
Figure 1. Heats of formation and selected torsional angles of the final
geometry of 14a and 14b, calculated using AM1 parameterization of
MOPAC 6 program.
1
1a
8
1648
-
-
1
1b
15
52
85
35
23
82
78
45
1244 (asym.), 1049 (sym.)
1
1
1
1
1
1
1
2a
3a
4a
4b
5a
6a
7a
1650
1680
1657
-
-
-
-
The rearrangement of O-substituted derivatives of cyclic
amides to the corresponding N-substituted derivatives was
also described by Pring and Swahn [22]. The authors
found that 4-(2-chloroethoxy)-2-methylphthalazin-1(2H)-
one (A) (i.e., an O-derivative of phthalazinone) isomerized
to the thermodynamically more stable N-isomer (B) upon
heating in DMF (Figure 2).
1222 (asym.), 1034 (sym.)
1650
1658
1657
-
-
-
The proportion of N-alkylation versus O-alkylation of
the cyclic amides is controlled by the equilibrium between
their enol and ketone forms. The position of the equilib-
rium depends not only on the type of amide, but also to a
large extent on solvent [17-20].
In order to find whether the formation of 14a and 14b
was the result of N- and O-alkylation of the corresponding
tautomeric forms of quinoxalin-2(1H)-one (7) with 3, or,
the result of rearrangement of the isomers formed, pure
1
4a and 14b were subjected to the same reaction condi-
tions as those used for the condensation (i.e. to K CO in
2
3
DMF at room temperature). The reaction progress was
monitored by thin layer chromatography. It was found that
after 24 h of the reaction time, 14a did not change, while in
Figure 2. Isomerization of 4-(2-chloroethoxy)-2-methylphthalazin-
1
(2H)-one (A) into 2-(2-chloroethyl)-2,3-dihydro-3-methylphthalazine-
1,4-dione (B) [22].

Jul-Aug 2005
Synthesis and Prediction of Bioactivity of New Nitroimidazole Derivatives
885
Prediction of Pharmacological Activity.
compound to pass through biological membranes [23,24].
The parameter of organic molecules that strongly corre-
lates with membrane permeability is their polar surface
area (PSA) [24,25]. The upper limit of PSA for good oral
Keeping in mind that the compounds 11-17 contained
two pharmocophoric moieties in their structures (i.e. imida-
zole and azanaphthalene rings), we estimated their biologi-
cal activity spectra by computer prediction. For this pur-
pose we applied the computer program PASS [12], which
on the basis of structural formulae of compounds predicts
more than 900 pharmacological effects for any drug-like
compound. Based on the analysis of structure-activity rela-
tionships of a training set consisting of about 52,000 of
drugs, drug-candidates and lead compounds, the program
PASS estimates probability for a compound to be active
2
absorption is ~ 140-150 Å , while the upper PSA threshold
2
for blood-brain barrier penetration is ~ 90 Å [24,25].
The PSA is defined as the sum of Van-der-Waals sur-
face areas of polar atoms (i.e., oxygen and nitrogen) in a
molecule [26,27]. The calculation of PSA in a classical
way requires special software to generate 3D structures
of molecules, which makes the prediction process time
consuming [28].
(
Pa) and inactive (Pi) for each type of activity from the bio-
Recently, fast algorithms for PSA calculation that do not
need a 3D structure have been developed by Ertl et al.
[25]. The method, called "topological PSA" (TPSA), pro-
vides results which are practically identical with the 3D
PSA. The correlation coefficient between the 3D PSA and
the fragment-based TPSA is 0.99 for over 34,000 mole-
cules from the World Drug Index [25]. The TPSA algo-
rithm does not require any computationally demanding
steps, because it is based on identification and summation
logical activity spectrum. High value of Pa offers a high
chance for a compound to show the selected activity in real
experiments. On the other hand, low value of Pi is an indi-
cator that the molecule is likely to be inactive in the pre-
dicted type of biological activity. The most probable bio-
logical activities (Pa) of the compounds 11-17, predicted by
PASS, are collected in Table 2. Predicted Pi values for all
the activities shown in the Table 2 were less than 3%.
Table 2
Probabilities of biological activity (Pa) of the compounds 11-17
Activity Type
Compound
11a
11b
12a
13a
14a
14b
15a
16a
17a
Antiprotozoal
Antileishmanial
Antitrichomonal
Antiamebic
0.835
0.684
0.699
0.669
0.655
0.849
0.662
0.680
0.652
0.651
0.875
0.619
0.877
0.651
0.650
0.825
0.621
0.644
0.636
0.636
0.842
0.699
0.713
0.691
0.677
0.847
0.660
0.703
0.674
0.656
0.813
0.643
0.707
0.654
0.624
0.838
0.666
0.723
0.686
0.653
0.840
0.717
0.713
0.677
0.675
Radiosensitizer
The data in Table 2 indicate that all of the compounds
studied exhibit high probability of antiprotozoal activity
reaching 81-88%. The probability of antileishmanial activ-
ity of 11-17 is in the range 62-72%, which is close to that
of antitrichomonal and antiamebic activities, except for
of tabulated surface contributions of polar fragments in the
molecule. The PSA parameters of the targeted compounds,
2
calculated by the use of TPSA methodology, are 85.6 Å
2
2
for 11a and 12a, and 85.8 Å for 11b; 98.5 Å for 13a-16a,
2
and 98.7 and 114.4 Å for 14b and 17a respectively. In
Figure 3 example values of atomic contributions of polar
atoms, used for PSA calculation of the compound 11a, are
shown.
1
2a. Moreover, the PASS predictions suggest that the com-
pounds 11-17 should be able to act as radiosensitizers.
The biological activity of 11-17 within a selected activ-
ity group practically does not depend on the type of amide
and depends only slightly on the amide substitution. In
fact, the predicted by PASS pharmacological activities of
1
1-17 are the same as the activities found for metronida-
zole. Hence it can be concluded that the new derivatives of
-methyl-5-nitroimidazole (11-17) do not change the
2
activity profile characteristic for metronidazole and no
other significant pharmacological properties show up.
Prediction of Bioavailability.
One of the features the bioactive compounds should
have is their bioavailability defined as the ability of the
2
Figure 3. Atomic contribution (Å ) of polar atoms in 11a, taken to its
PSA calculation.

886
P. Kowalski, K. Nowak and B. Szpakiewicz
Vol. 42
Comparison of the PSA values of the compounds 11-17
General Procedure for the Reaction of 3 with the Cyclic Amides
4-10.
2
and metronidazole (PSA = 83.9 Å ) with the upper limit of
PSA for compounds with good blood-brain barrier pene-
A mixture of 6.4 mmol of 3, 6.4 mmol of the respective cyclic
amide 4-10, 19.1 mmol of anhydrous potassium carbonate, and a
few crystals (~ 0.01 g) of potassium iodide in 15-20 mL of
dimethylformamide was stirred with magnetic stirrer at room
temperature for 48 hours. Next, the reaction mixture was poured
into 100-150 mL of water, and, the precipitate was either col-
lected by filtration or extracted with chloroform. The crude prod-
ucts 12a, 13a and 15a-17a, were purified by crystallization. The
mixtures of 11a with 11b and 14a with 14b were separated by
column chromatography, using chloroform:methanol (95:5) as
eluent, and then recrystallized. The yields of 11a, 11b, 12a, 13a,
2
tration (PSA ~ 90 Å ) indicate that all of the compounds
studied should have poor blood-brain barrier permeability.
On the other hand, the PSA values much lower than 140
2
Å indicate that the compounds 11-17 and metronidazole
should show good oral absorbtivity. Very close PSA value
of metronidazole to that of 11a-b and 12a, indicate very
close bioavailability of these compounds. In conclusion it
has to be pointed out that all the compounds 11-17 are
good candidates for study as drug-like, orally adminis-
tered, agents.
1
4a, 14b, and 15a-17a were collected in the Table 1.
1
2
-[3-(2-Methyl-5-nitro-1H-imidazol-1-yl)propyl]quinolin-
(1H)-one (11a).
EXPERIMENTAL
This compound was obtained as colorless needles (methyl
Melting points were determined on a Böetius melting point
apparatus and are uncorrected. Elemental analyses were per-
formed on a Perkin-Elmer 2400 analyzer located in the Regional
Laboratory of Jagiellonian University, and the results are within
alcohol), mp 225-226,5 °C; 1H nmr: δ 2.19-2.44 (m, 2H,
CH CH CH ), 2.42 (s, 3H, CH ), 4.09 (t, 2H, CH -N-imidazole),
2
2
2
3
2
4.45 (t, 2H, CH -N-quinolinone), 6.71 (d, 1H, quinolinone 3-H),
2
7.44-7.70 (m, 4H, quinolinone 5-8-H), 7.74 (d,1H, quinolinone
4-H), 7.82 ppm (s, 1H, imidazole 4-H), J = 9.7 Hz; ms: m/z (%)
±
0.4% of the calculated values. IR spectra were recorded on a
3
,4
1
+
Bio-Rad FTS – 175C spectrophotometer in KBr pellets. H NMR
spectra were taken on a Tesla 487C (80 MHz) spectrometer in
312 (M , 9); R 0.22 (chloroform:methanol 95:5).
F
Anal. Calcd. for C H N O : C, 61.53; H, 5.16; N, 17.94.
1
6 16 4 3
CDCl solution, using TMS as an internal standard; the chemical
Found: C, 61.18; H, 5.27; N, 17.82.
-[3-(2-Methyl-5-nitro-1H-imidazol-1-yl)propoxy]quinoline
11b).
This compound was obtained as colorless plates (methyl alco-
3
shifts are given in ppm (δ); and, the coupling constants are taken
from the expanded spectra. Mass spectra (EI) were recorded with
a Varian – MAT 112 spectrometer at 70 eV. The reactions and the
product purification were monitored by TLC on silica-gel plates
2
(
1
(
Merck 60F254) using chloroform/methanol (95:5) mixture as
hol), mp 147-149 °C; H nmr: δ 2.24-2.48 (m, 2H,
eluent. For column chromatography, silica gel (Merck) was used.
Starting materials, solvents, and reagents were purchased from
commercial sources (Aldrich and Merck) and were used without
further purification, except for DMF, which was purified by dis-
tillation shortly before use. The semiempirical AM1 calculations
CH CH CH ), 2.44 (s, 3H, CH ), 4.13 (t, 2H, CH -N-imidazole),
2
2
2
3
2
4.56 (t, 2H, CH -N-quinoline), 6.87 (d,1H, quinoline 3-H), 7.44-
2
8.00 (m, 4H, quinoline 5-8-H), 7.83 (s, 1H, imidazole 4-H), 8.02
+
ppm (d,1H, quinoline 4-H), J3,4 = 9,4 Hz; ms: m/z (%) 312 (M ,
11); R 0.40 (chloroform:methanol 95:5).
F
(
full geometry optimization at the gradient norm < 0.1
Anal. Calcd. for C H N O : C, 61.53; H, 5.16; N, 17.94.
1
6 16 4 3
kcal/Å(radian)) were done using MOPAC 6.0 (QCPE) program.
The cyclic amides 4-10 were prepared according to the litera-
ture data: quinolin-2(1H)-one (4) [29], isoquinolin-1(2H)-one (5)
Found: C, 61.45; H, 5.18; N, 18.08.
2
1
-[3-(2-Methyl-5-nitro-1H-imidazol-1-yl)propyl]isoquinolin-
(2H)-one (12a).
[30], quinazolin-4(3H)-one (6) [31], quinoxalin-2(1H)-one (7)
[32], phthalazin-1(2H)-one (8) [33], 1,8-naphthyridin-2(1H)-one
(9) [34], and pyrido[2,3-b]pyrazin-6(5H)-one (10) [35].
This compound was obtained as colorless needles (methyl
1
alcohol), mp 182-184 °C; H nmr: δ 2.12-2.50 (m, 2H,
CH CH CH ), 2.41 (s, 3H, CH ), 4.03 (t, 2H, CH -N-isoquinoli-
2
2
2
3
2
Synthesis of 1-(3-Chloropropyl)-2-methyl-5-nitroimidazole (3).
none), 4.11 (t, 2H, CH -N-imidazole), 6.55 (d, 1H, isoquinoli-
2
A mixture of 22.8 g (0.18 mol) of 2-methyl-5-nitroimidazole
none 4-H), 7.01 (d,1H, isoquinolinone 3-H), 7.44-8.47 (m, 4H,
(
(
1), 31.5 g (0.20 mol) of 1-bromo-3-chloropropane (2) and 38.6 g
0.28 mol) of anhydrous potassium carbonate in 200 mL of
isoquinolinone 5-8-H), 7.84 ppm (s, 1H, imidazole 4-H); J3
7.3 Hz; ms: m/z (%) 312 (M+, 4).
=
,4
dimethylformamide was stirred at room temperature for 48 hours.
After evaporation of the solvent almost to dryness, 100 mL of
acetone was added to the residue and the precipitate was filtered
off. The acetone solution was poured into 200 mL of water, and
the mixture was extracted with chloroform. Evaporation of chlo-
roform gave brown, semisolid product. The row material was
recrystallized from 2-propanol to yield 18.5 g (60%) of 1-(3-
chloropropyl)-2-methyl-5-nitroimidazole (3) with mp 65-67 °C,
Anal. Calcd. for C H N O : C, 61.53; H, 5.16; N, 17.94.
16 16 4 3
Found: C, 61.40; H, 5.13; N, 17.58.
3
4
-[3-(2-Methyl-5-nitro-1H-imidazol-1-yl)propyl]quinazolin-
(3H)-one (13a).
This compound was obtained as colorless plates (acetonitrile),
1
mp 252-254 °C; H nmr: δ 2.29-2,38 (m, 2H, CH CH CH ), 2.45
2
2
2
(s, 3H, CH ), 4.10 (t, 2H, CH -N-imidazole), 4.07 (t, 2H, CH -N-
3
2
2
1
H nmr: δ 2.31 (m, 2H, CH CH CH ), 2.48 (s, 3H, CH ), 3.55 (t,
quinazolinone), 7.53-8.33 (m, 4H, quinazolinone 5-8-H), 7.84
(s,1H, imidazole 4-H), 8.00 ppm (s,1H, quinazolinone 2-H); ms:
2
2
2
3
2
H, CH -Cl, J = 5.7 Hz), 4.15 (t, 2H, CH -N-imidazole, J = 7.1
2
2
+
Hz,), 7.71 ppm (s, 1H, imidazole 4-H).
Anal. Calcd. for C H ClN O : C, 41.29; H, 4.95; N, 20.64.
m/z (%) 313 (M , 45).
Anal. Calcd. for C H N O : C, 57.50; H, 4.83; N, 22.35.
7
10
3
2
15 15 5 3
Found: C, 41.18; H, 5.20; N, 20.82.
Found: C, 57.31; H, 4.83; N, 22.41.

Jul-Aug 2005
Synthesis and Prediction of Bioactivity of New Nitroimidazole Derivatives
887
1
2
-[3-(2-Methyl-5-nitro-1H-imidazol-1-yl)propyl]quinoxalin-
(1H)-one (14a).
Isomerization Experiments.
The isomerization reactions of 14a and 14b in dimethylfor-
mamide in the presence of potassium carbonate were followed by
means of TLC, using chloroform:methanol (95:5) as eluent. The
component spots were visualized under a short-wave ultraviolet
lamp.
This compound was obtained as colorless needles (acetoni-
1
trile), mp 248-250 °C; H nmr: δ 2.21-2.49 (m, 2H,
CH CH CH ), 2.43 (s, 3H, CH ), 4.12 (t, 2H, CH -N-imidazole),
2
2
2
3
2
4
.40 (t, 2H, CH -N-quinoxalinone), 7.40-8.10 (m, 4H, quinoxali-
2
none 5-8-H), 7.84 (s, 1H, imidazole 4-H), 8.33 ppm (s,1H,
1
2
-[3-(2-methyl-5-nitro-1H-imidazol-1-yl)propyl]quinoxalin-
(1H)-one (14a).
+
quinoxalinone 3-H); ms: m/z (%) 313 (M , 29); R 0.23 (chloro-
F
form:methanol 95:5).
Compound 14a (0.31 g, 1 mmol) and 0.28 g (2 mmol) of
Anal. Calcd. for C H N O : C, 57.50; H, 4.83; N, 22.35.
1
5 15 5 3
potassium carbonate in 4 mL of dimethylformamide was stirred
at room temperature for 24 h. Only one spot, that due to the start-
ing material (R 0.23) was observed; no other product appeared.
Found: C, 57.29; H, 4.80; N, 22.34.
2
-[3-(2-Methyl-5-nitro-1H-imidazol-1-yl)propoxy]quinoxaline
F
(14b).
2
-[3-(2-methyl-5-nitro-1H-imidazol-1-yl)propoxy]quinoxaline
This compound was obtained as colorless needles (1-
(14b).
1
propanol), mp 157-159 °C; H nmr: δ 2.22-2.55 (m, 2H,
CH CH H ), 2.46 (s, 3H, CH ), 4.19 (t, 2H, CH -N-imidazole),
Compound 14b (0.31g, 1 mmol) and 0.28 g (2 mmol) of potas-
2
2
2
3
2
sium carbonate in 4 mL of dimethylformamide was stirred at
room temperature. A distinct spot on the TLC plate, correspond-
ing to the compound 14a (RF 0.23), appeared after 24 hours.
Prolongation of the reaction time increased the intensity of the
spot corresponding to 14a compared to that of the starting com-
4
5
.56 (t, 2H, CH -N-quinoxaline), 7.59-8.17 (m, 4H, quinoxaline
2
-8-H), 7.83 (s, 1H, imidazole 4-H), 8.54 ppm (s, 1H, quinoxa-
+
line 3-H); ms: m/z (%) 313 (M , 27); R 0.31 (chloroform:
F
methanol 95:5).
Anal. Calcd. for C H N O : C, 57.50; H, 4.83; N, 22.35.
1
5 15 5 3
pound 14b (R 0.31).
F
Found: C, 57.40; H, 4.80; N, 22.37.
Acknowledgements.
2
1
-[3-(2-Methyl-5-nitro-1H-imidazol-1-yl)propyl]phthalazin-
(2H)-one (15a).
Authors wish to thank the Research Group of Institute of
Biomedicinal Chemistry of Russian Academy of Medicinal
Sciences (www.ibmh.msk.su/PASS) for the access to the com-
puter program applied for the research presented in this paper.
This compound was obtained as colorless needles (ethyl alco-
1
hol), mp 190-193 °C; H nmr: δ 2.22-2.53 (m, 2H,
CH CH CH ), 2.44 (s, 3H, CH ), 4.06 (t, 2H, CH -N-imidazole),
2
2
2
3
2
4
.36 (t, 2H, CH -N-phthalazinone), 7.66-8.42 (m, 4H, phthalazi-
2
none 5-8-H), 7.85 (s, 1H, imidazole 4-H), 8.20 ppm (s,1H, phtha-
lazinone 4-H); ms: m/z (%) 313 (M , 24).
REFERENCES AND NOTES
+
Anal. Calcd. for C H N O : C, 57.50; H, 4.83; N, 22.35.
Found: C, 57.15; H, 4.82; N, 22.27.
1
5
15
5
3
[1] T. C. Kuehler, M. Swanson, B. Christenson, A-Ch.
Klintenberg, B. Lamm, J. Faegerhag, R. Gatti, M. Oelwegard-
Halvarsson, V. Shcherbuchin, T. Elebring, and J-E. Sjoestroem, J. Med.
Chem., 45, 4282 (2002).
1
-[3-(2-Methyl-5-nitro-1H-imidazol-1-yl)propyl]-1,8-naph-
thyridin-2(1H)-one (16a).
[
2] O. Josse, D. Labar, B. Georges, V. Gregoire, and J. Marchand-
Brynaert, Bioorg. Med. Chem., 9, 665 (2001).
3] I. Parveen, D. P. Naughton, W. J. D. Whish, and M. D.
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Chem., 7, 2591 (1999).
This compound was obtained as colorless plates (methyl
[
1
alcohol), mp 201-204 °C; H nmr: δ 2.25-2.51 (m, 2H,
CH CH CH ), 2.42 (s, 3H, CH ), 4.06 (t, 2H, CH -N-imida-
2
2
2
3
2
[
zole), 4.65 (t, 2H, CH -N-1,8-naphthyridone), 6.75 (d, 1H, 1,8-
2
naphthyridone 3-H), 7.22 (t, 1H, 1,8-naphthyridone 6-H), 7.68
d,1H,1,8-naphthyridone 4-H), 7.92 (dd, 1H, 1,8-naphthyri-
[
5] K. Maeda, T. Osata and H. Umezawa, J. Antibiot., 6A, 182
(
(1953).
done 5-H), 8.62 ppm (dd, 1H, 1,8-naphthyridone 7-H); J3,4
=
[6] Rote Liste, Editio Cantor Verlag, Aulendorf, 10, pp. 418-435
(2002).
[7] Martindale, Thirty-third Edition, S. C. Sweetman (Ed.),
Pharmaceutical Press, London – Chicago, pp. 594-597 (2002).
8] P. Kowalski, M. J. Mokrosz, Z. Majka, T. Kowalska, and B.
Duszyńska, J. Heterocyclic Chem., 37, 187 (2000).
9] P. Kowalski, T. Kowalska, M. J. Mokrosz, A. J. Bojarski, and
S. Charakchieva-Minol, Molecules, 6, 784 (2001).
9
3
,5 Hz, J5 = 7.8 Hz, J6,7 = 4.6 Hz, J5,7 = 1.8 Hz; ms: m/z (%)
,6
+
13 (M , 8).
Anal. Calcd. for C H N O : C, 57.50; H, 4.83; N, 22.35.
1
5 15 5 3
[
Found: C, 57.37; H, 4.89; N, 22.22.
[
5
-[3-(2-Methyl-5-nitro-1H-imidazol-1-yl)propyl]pyrido[2,3-b]-
pyrazin-6(5H)-one (17a).
[
10] A. J. Bojarski, P. Kowalski, T. Kowalska, B. Duszyńska, S.
This compound was obtained as colorless needles (2-
Charakchieva-Minol, E. Tatarczyńska, A. Kłodzińska, and E. Chojnacka-
Wójcik, Bioorg. Med. Chem., 10, 3817 (2002).
1
propanol), mp 205-206 °C; H nmr: δ 2.22-2.53 (m, 2H, CH
2
[
11] A. J. Bojarski, B. Duszyńska, M. Kołaczkowski, P. Kowalski,
CH CH ), 2.44 (s, 3H, CH ), 4.07 (t, 2H, CH -N-imidazole),
2
2
3
2
and T. Kowalska, Bioorg. Med. Chem. Lett., 14, 5863 (2004).
4
.56 (t, 2H, CH -N-pyridopyrazinone), 7.00 (d, 1H, pyridopy-
2
[12] http://www.ibmh.msk.su/PASS.
[13] V. Poroikov, D. Filimonov, W.-D. Ihlenfeldt, T. Gloriozova,
razinone 3-H), 7.92 (s, 1H, imidazole 4-H), 7.95 (d,1H, pyri-
dopyrazinone 4-H), 8.55 ppm (s, 2H, pyridopyrazinone 6,7-H);
A. Lagunin, Yu. Borodina, and A. Stepanchikova, J. Chem. Inform.
Comput. Sci., 43, 228 (2003).
[14] S. Anzali, G. Barnickel, B. Cezanne, M. Krug, D. Filimonov,
and V. Poroikov, J. Med. Chem., 44, 2432 (2001).
+
J3,4 = 9,8 Hz; ms: m/z (%) 314 (M , 14).
Anal. Calcd. for C H N O : C, 53.50; H, 4.49; N, 26.74.
1
4
14
6
3
Found: C, 53.34; H, 4.47; N, 22.35.

888
P. Kowalski, K. Nowak and B. Szpakiewicz
Vol. 42
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[
[
17] S. F. Mason, J. Chem. Soc., 4874 (1957).
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1
407 (1972).
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[
[
3
[31] S. Niementowski, J. Prakt. Chem., 51, (2), 566 (1895).
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[
[
21] J. J. P. Stewart, MOPAC 6.0, QCPE, (1990).
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(
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[