Synthesis and antibacterial evaluations of new pyridazino[4,3-e][1,3,4] oxadiazines

Article abstract of DOI:10.1002/jhet.398

Several derivatives of the new pyridazino[4,3-e][1,3,4]oxadiazine ring system were prepared, and their antibacterial evaluations were performed on four different Gram-negative and Gram-positive bacteria.

Full text of DOI:10.1002/jhet.398

January 2011
Synthesis and Antibacterial Evaluations of New Pyridazino-
[4,3-e][1,3,4]oxadiazines
149
Mehdi Bakavoli,a* Mohammad Rahimizadeh,a Ali Shiri,a Hossein Eshghi,a
Parvaneh Pordeli,b Mehdi Pordel,a and Mohsen Nikpourc
aDepartment of Chemistry, School of Sciences, Ferdowsi University of Mashhad,
Mashhad 91775-1436, Iran
bDepartment of Biology, School of Sciences, Ferdowsi University of Mashhad,
Mashhad 91775-1436, Iran
cDepartment of Chemistry, School of Sciences, Islamic Azad University, Ahvaz, Iran
*E-mail: mbakavoli@yahoo.com
Received July 5, 2009
DOI 10.1002/jhet.398
Published online 6 October 2010 in Wiley Online Library (wileyonlinelibrary.com).
Several derivatives of the new pyridazino[4,3-e][1,3,4]oxadiazine ring system were prepared, and
their antibacterial evaluations were performed on four different Gram-negative and Gram-positive
bacteria.
J. Heterocyclic Chem., 48, 149 (2011).
INTRODUCTION
acid azide of hydrazine and phenylhydrazine in ethylene
glycol and sodium bicarbonate [3]. Furtheremore, thia-
zolo[4,3-b][1,3,4]oxadiazine-6(4H)-thiones were obtained
from the reaction of 3-aminorhodanine with 1,1,2,2-ethe-
netetracarbonitrile as by-product in low yields [15].
A perusal of the literature revealed that there is no
report on the synthesis of pyridazino[4,3-e][1,3,4]oxa-
diazine ring system. Since fused oxadiazines are biologi-
cally active compounds and due to our interest in the
synthesis of heterocyclic compounds of biological inter-
est [16], in this article we wish to report on the synthe-
sis of some new pyridazino[4,3-e][1,3,4]oxadiazines and
the outcome of our investigation on their antibacterial
properties.
Oxadiazines are a group of heterocyclic compounds
which their syntheses have been a challenge for organic
chemists. They have a diverse biological properties [1]
such as inhibitors of bacterial growth [2], antimicrobial
agents [2,3], and also useful intermediates in the synthe-
sis of tenidap prodrugs or b-lactam antibiotics, espe-
cially, in the synthesis of carbapenems and penems
[4,5], cardiovascular antibacterial, miticidal, nematoci-
dal, acricidal, insecticidal, and anticonvulsive activities
[6,7].
The published methods for the synthesis of oxadia-
zines especially fused [1,3,4]oxadiazines are limited.
These compounds have been prepared by treatment of
(–)-2-methyl-2-(a-methyl-b-hydroxyphenyl)benzoic acid
hydrazid with sulfuric acid [8] or treatment of N0-chlor-
oacetyl salicyl hydrazide with NaOH in DMF [9] which
leads to [1,3,4]oxadiazines derivatives. Elliot and Gib-
son in 1972 [10] and Shawali and Hassaneen in 1977
[11,12] reported the synthesis of 1,3,4-benzoxadiazines
from hydrazidoyl bromides. The reaction of o-mercapto-
benzohydrazide with chloroacetylchloride gave [1,3,4]
oxadiazines derivatives [13]. Mattinen and his co-
workers synthesized some tetrahydro[1,2-d][1,3,4]oxa-
diazine derivatives and studied the conformational pref-
erence by NMR spectroscopy and X-ray analysis [14].
More recently 1,3,4-oxadiazine-5,10-dione derivatives
were obtained by the reaction of p-chloranil with acetic
RESULTS AND DISCUSSION
Chemistry. 4-Bromo-3,6-dichloro pyridazine which
was prepared according to ref. 17 was treated with
methylhydrazine in CHCl3 at 0–5ꢀC giving 3,6-dichloro-
4-(1-methylhydrazino) pyridazine (1) [18]. The hetero-
cyclization of compound (1) as precursor with various
aroyl halides in the presence of NaNH2 at room temper-
ature yielded the new corresponding pyridazino[4,3-
e][1,3,4]oxadiazine derivatives (Scheme 1).
The structures of the synthesized compounds were
elucidated by their spectral and microanalytical data.
1
For example, the H NMR spectrum of compound (2h)
C
V
2010 HeteroCorporation

150
M. Bakavoli, M. Rahimizadeh, A. Shiri, H. Eshghi, P. Pordeli, M. Pordel, and M. Nikpour
Vol 48
Scheme 1
therefore prevents initiation of protein synthesis and
leads to death of microbial cell) was chosen as a stand-
ard drug at a concentration of 10 lg mL–1. Streptomycin
is an antibiotic that inhibits both gram positive and
gram negative bacteria, and is therefore a useful broad
spectrum antibiotic (Table 1).
As it can be concluded from the data in Table 1,
compound (2d) and (2g) has shown the highest sensitiv-
ity against E. coli, and moderately sensitive against the
other organisms. Compound (2e) exhibited the best ac-
tivity against B. subtilis while compound (3a) showed
activity against S. aureus. All the other compounds were
found to exhibit slight to moderate sensitivity against
the mentioned organisms.
did not exhibit the signal at d 4.2 ppm belonging to
NH2 moiety of the precursor but showed an AB quartet
peak at the aromatic region indicating the occurrence of
the heterocyclization step. The IR spectrum was devoid
of the stretching vibration bands belonging to the pre-
cursor at 3360 and 3280 cm–1 resembling the NH2 moi-
ety, and at 1660 cm–1 for carbonyl group, but instead
exhibited the CAO stretching vibration band at 1110
cm–1. The molecular ion peak of compound (2h) which
was observed at m/z 274 (Mþ) and 276 (Mþ þ 2) to-
gether with the result of microanalytical data are fully
supportive of the molecular formula C13H11ClN4O.
Further treatment of the pyridazino[4,3-e][1,3,4]oxa-
diazines with few secondary amines, as examples, led to
the replacement of the chlorine atom and gave the sub-
stituted products (3a–f) (Scheme 2).
Biological activities. The in vitro antibacterial activ-
ity of the newly synthesized compounds (2a–h) and
(3a–f) were screened for the antibacterial activity
against several pathogenic representative Gram-positive
bacteria (Staphylococcus aureus PTCC 1074 and Bacil-
lus subtilis PTCC 1365); Gram-negative bacteria (Esche-
richia coli HB101 BA 7601C and Pseudomonas aerugi-
nosa PTCC 1431) using disc diffusion sensitivity test
[19,20]. Mueller-Hinton agar media were sterilized
(15 min at 121ꢀC) and poured into the plates to a uni-
form depth of 5 mm and allow it to solidify. The micro-
bial suspension (1.2 ꢁ 108 CFU/mL) (0.5 McFarland
Nephelometery Standards) was streaked over the surface
of media using a sterile cotton swab (15 min at 180ꢀC)
to ensure confluent growth of the organisms. The tested
compounds were dissolved in DMF and diluted with
ethanol to get a solution of 100–600 lg mL–1 concentra-
tion. The discs measuring 6.25 mm in diameter (What-
man no. 1 filter paper) were impregnated with prepared
solution of compounds (2a–h) and (3a–f) by 1 mL of
the chemical solution which was added to each bottle
contained 12 discs and placed on Muller-Hinton agar
media previously inoculated with bacterial suspension.
The inhibition zones as a criterion for antimicrobial ac-
tivity were measured in millimeter at the end of an incu-
bation period of 24 h at 37ꢀC. The results of these eval-
uations are given in Table 1. Streptomycin (binds to the
16SrRNA of the bacterial ribosome, interfering with the
binding of formyl-methionyl-tRNA to the 30S subunit
In summary, we have developed a simple, one-pot
synthesis of new pyridazino[4,3-e][1,3,4]oxadiazines
through intermediates formed by reaction of 3,6-
dichloro-4-(1-methylhydrazino) pyridazine with various
aroyl halides and tested for their antibacterial activities.
EXPERIMENTAL
Melting points were recorded on an Electrothermal type
9100 melting point apparatus and are not corrected. The IR
spectra were obtained on a 4300 Shimadzu spectrometer. The
1H NMR (100 MHz) spectra were recorded on a Bruker AC
l00 spectrometer. The mass spectra were obtained on a Varian
Mat CH-7 instrument at 70 eV. Elemental analysis was per-
formed on a ThermoFinnigan Flash EA 1112 micro analyzer.
General procedure for the preparation of pyridazino[4,3-
e][1,3,4]oxadiazine (2a–h). All of these reactions were carried
out under an atmosphere of nitrogen. To a magnetically stirred
solution of 3,6-dichloro-4-(1-methylhydrazino) pyridazine (1)
(0.38 g, 2 mmol) and various aroyl halides (2 mmol) in dry ace-
tonitrile (20 mL), NaNH2 (0.2 g, 5 mmol) was added and the
mixture stirred for 5–6 h at room temperature (monitored by
TLC using chloroform-methanol 9:1 as the eluent). After the
reaction was completed, the solvent was removed under reduced
pressure. Water (20 mL) was added, and the resultant was neu-
tralized with 5% HCl solution. The precipitate was filtered off,
washed with water, and recrystallized from ethanol-water.
7-Chloro-1-methyl-3-phenyl-1H-pyridazino[4,3-e][1,3,4]oxa-
diazine (2a). This compound was obtained as yellow plate,
yield: 65%; mp 185–186ꢀC; 1H NMR: (DMSO-d6, ppm), d
3.09 (s, 3H, CH3), 6.66 (s, 1H, pyridazine), 7.51–7.70 (m, 5H,
Phenyl protones). ir (KBr disc) m 3010, 2950, 1150 cm–1. ms:
(m/z) 260 (Mþ), 262 (Mþ þ 2). Anal. Calcd. for C12H9ClN4O:
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2011
Synthesis and Antibacterial Evaluations of New Pyridazino[4,3-e][1,3,4]oxadiazines
151
Table 1
Antibacterial data of the synthesized compounds 2(a–h) and 3(a–f).a
Gram-negative bacteria
Gram-positive bacteria
Escherichia coli
HB101 BA 7601C
Pseudomonas aeruginosa
PTCC 1431
Staphylococcus aureus
PTCC 1074
Bacillus subtilis
PTCC 1365
Compound
2a
2b
2c
2d
2e
2f
2g
2h
3a
3b
3c
3d
3e
14(þ)
12(þ)
12(þ)
15(þþ)
12(þ)
11(ꢂ)
16(þþ)
12(þ)
12(þ)
11(ꢂ)
12(þ)
12(þ)
11(ꢂ)
12(þ)
13
11(ꢂ)
10.5(ꢂ)
12(þ)
12(þ)
10(ꢂ)
11(ꢂ)
10.5(ꢂ)
12(þ)
13(þ)
11(ꢂ)
8(ꢂ)
14(þ)
10(ꢂ)
11(ꢂ)
13(þ)
11(ꢂ)
10(ꢂ)
12(þ)
12(þ)
15(þþ)
9(ꢂ)
11(ꢂ)
11(ꢂ)
11(ꢂ)
12(þ)
15(þþ)
11(ꢂ)
10.5(ꢂ)
12(þ)
12(þ)
11(ꢂ)
9(ꢂ)
9(ꢂ)
8(ꢂ)
10(ꢂ)
10(ꢂ)
10(ꢂ)
13
13(þþ)
11(ꢂ)
11(ꢂ)
10
9(ꢂ)
3f
Streptomycin (standard)
9(ꢂ)
15
þþ, Highly Sensitive; þ, Moderately Sensitive; ꢂ, Slightly Sensitive.
a Zones of inhibition in millimeter.
1
C, 55.29; H, 4.48; N, 21.49. Found: C, 55.16; H, 4.41; N,
21.45.
low plate, yield: 68%; mp 247ꢀC; H NMR: (DMSO-d6, ppm),
d 3.14 (s, 3H, CH3), 6.72 (s, 1H, pyridazine), 7.9 (2H, d, J ¼
8 Hz, Phenyl protones), 8.3 (2H, d, J ¼ 8 Hz, Phenyl proto-
nes). ir (KBr disc) m 3015, 2965, 1150 cm–1. ms: (m/z) 305
(Mþ), 307 (Mþ þ 2). Anal. Calcd. for C12H8ClN5O3: C,
47.15; H, 2.64; N, 22.91. Found: C, 46.85; H, 2.63; N, 23.27.
7-Chloro-1-methyl-3-(3-nitrophenyl)-1H-pyridazino[4,3-e]
[1,3,4]oxadiazine (2g). This compound was obtained as yel-
low plate, yield: 73%; mp 220–221ꢀC; 1H NMR: (DMSO-d6,
ppm), d 3.13 (s, 3H, CH3), 6.72 (s, 1H, pyridazine), .7.71–8.41
(m, 4H, Phenyl protones). ir (KBr disc) m 3045, 2925, 1130
cm–1. ms: (m/z) 305 (Mþ), 307 (Mþ þ 2). Anal. Calcd. for
C12H8ClN5O3: C, 47.15; H, 2.64; N, 22.91. Found: C, 47.03;
H, 2.75; N, 23.08.
7-Chloro-3-(2-chlorophenyl)-1-methyl-1H-pyridazino[4,3-e]
[1,3,4]oxadiazine (2b). This compound was obtained as yellow
plate, yield: 70%; mp 210ꢀC; 1H NMR: (DMSO-d6, ppm), d
3.07 (s, 3H, CH3), 6.71 (s, 1H, pyridazine), 7.31–7.81 (m, 4H,
Phenyl protones). ir (KBr disc) m 3020, 2980, 1160 cm–1. ms:
(m/z) 295 (Mþ), 297 (Mþ þ 2), 299 (Mþ þ 4). Anal. Calcd.
for C12H8Cl2N4O: C, 48.84; H, 2.73; N, 18.96. Found: C,
48.95; H, 3.58; N, 19.44.
7-Chloro-3-(3-chlorophenyl)-1-methyl-1H-pyridazino[4,3-e]
[1,3,4]oxadiazine (2c). This compound was obtained as yellow
plate, yield: 63%; mp 221–222ꢀC; 1H NMR: (DMSO-d6,
ppm), d 3.09 (s, 3H, CH3), 6.68 (s, 1H, pyridazine), 7.45–7.64
(m, 4H, Phenyl protones). ir (KBr disc) m 3020, 2940, 1140
cm–1. ms: (m/z) 295 (Mþ), 297 (Mþ þ 2), 299 (Mþ þ 4).
Anal. Calcd. for C12H8Cl2N4O: C, 48.84; H, 2.73; N, 18.96.
Found: C, 48.75; H, 2.59; N, 18.45.
7-Chloro-1-methyl-3-(4-methylphenyl)-1H-pyridazino[4,3-e]
[1,3,4]oxadiazine (2h). This compound was obtained as yellow
plate, yield: 78%; mp 212–214ꢀC; 1H NMR: (DMSO-d6,
ppm), d 2.34 (s, 3H, CH3), 3.07 (s, 3H, CH3), 6.64 (s, 1H, py-
ridazine), 7.3 (2H, d, J ¼ 8 Hz, Phenyl protones), 7.6 (2H, d,
J ¼ 8 Hz, Phenyl protones). ir (KBr disc) m 3015, 2930, 1110
cm–1. ms: (m/z) 274 (Mþ), 276 (Mþ þ 2). Anal. Calcd. for
C13H11ClN4O: C, 56.84; H, 4.04; N, 20.40. Found: C, 55.37;
H, 4.00; N, 20.38.
General procedure for the preparation of compounds
(3a–f). To a mixture of compounds (2a), (2d), or (2h) (1
mmol) in ethanol (15 mL), morpholine or pyrrolidine
(2 mmol) was added, and the solution was refluxed for 3–4 h.
After the solution was cooled, water was added and the result-
ing precipitant was filtered, washed with water and recrystal-
lized from ethanol.
7-Chloro-3-(4-chlorophenyl)-1-methyl-1H-pyridazino[4,3-e]
[1,3,4]oxadiazine (2d). This compound was obtained as yel-
low plate, yield: 75%; mp 195–197ꢀC; 1H NMR: (DMSO-d6,
ppm) d 3.08 (s, 3H, CH3), 6.66 (s, 1H, pyridazine), 7.57 (AB
quartet, 4H, Phenyl protones). ir (KBr disc) m 3060, 2950,
1150 cm–1. ms: (m/z) 295 (Mþ), 297 (Mþ þ 2), 299 (Mþ
þ
4). Anal. Calcd. for C12H8Cl2N4O: C, 48.84; H, 2.73; N,
18.96. Found: C, 48.58; H, 2.86; N, 19.60.s
3-(4-Bromophenyl)-7-chloro-1-methyl-1H-pyridazino[4,3-e]
[1,3,4]oxadiazine (2e). This compound was obtained as yellow
plate, yield: 71%; mp 255–256ꢀC; 1H NMR: (DMSO-d6,
ppm), d 3.08 (s, 3H, CH3), 6.71 (s, 1H, pyridazine), 7.87 (AB
quartet, 4H, Phenyl protones). ir (KBr disc) m 3030, 2930,
1-Methyl-7-(morpholin-4-yl)-3-phenyl-1H-pyridazino[4,3-e]
[1,3,4]oxadiazine (3a). This compound was obtained as
creamy plate, yield: 65%; mp 253–254ꢀC; H NMR: (DMSO-
d6, ppm), d 3.19 (s, 3H, CH3), 3.45 (t, 4H, NACH2), 3.88 (t,
4H, OACH2), 6.27 (s, 1H, pyridazine), 7.4–7.7 (m, 5H, Phenyl
protones). ir (KBr disc) m 3045, 2930, 1160 cm–1. ms: (m/z)
1120 cm–1. ms: (m/z) 338 (Mþ), 340 (Mþ þ 2), 342 (Mþ
þ
1
4). Anal. Calcd. for C12H8BrClN4O: C, 42.44; H, 2.37; N,
16.50. Found: C, 42.50; H, 2.30; N, 16.30.
7-Chloro-1-methyl-3-(4-nitrophenyl)-1H-pyridazino[4,3-e]
[1,3,4]oxadiazine (2f). This compound was obtained as yel-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

152
M. Bakavoli, M. Rahimizadeh, A. Shiri, H. Eshghi, P. Pordeli, M. Pordel, and M. Nikpour
Vol 48
311 (Mþ). Anal. Calcd. for C16H17N5O2: C, 61.72; H, 5.50; N,
22.49. Found: C, 61.59; H, 5.33; N, 22.22.
REFERENCES AND NOTES
[1] Barbaric, M.; Kraljvic, S.; Grce, M.; Zorc, B. Acta Pharm
1-Methyl-3-phenyl-7-(pyrrolidin-1-yl)-1H-pyridazino[4,3-e]
[1,3,4]oxadiazine (3b). This compound was obtained as
creamy plate, yield: 60%; mp 267–268ꢀC; 1H NMR:
(DMSO-d6, ppm), d 1.91 (m, 4H, CH2ACH2), 3.19 (s, 3H,
CH3), 3.31 (t, 4H, CH2AN), 5.88 (s, 1H, pyridazine),
7.4A7.8 (m, 5H, Phenyl protones). ir (KBr disc) m 3055,
2940, 1150 cm–1. ms: (m/z) 295 (Mþ). Anal. Calcd. for
C16H17N5O: C, 65.07; H, 5.80; N, 23.71. Found: C, 64.89;
H, 5.33; N, 23.52.
2003, 53, 175.
[2] Berkowitz, P. T.; Long, R. A.; Dea, P.; Robins, R. K.;
Mathews, T. R. J Med Chem 1977, 20, 134.
[3] Shindy, H. A.; El-Maghraby, M. A.; Eissa, F. M. Dyes
Pigm 2006, 70, 110.
[4] Robinson, R. P.; Donahue, K. M.; J Heterocycl Chem 1994,
31, 1541.
[5] Gravestock, M. B. Eur Pat Appl EP 1987, 265, 169; Grave-
stock, M. B. Chem Abstr 1988, 109, P110160d.
[6] Khan, K. M.; Rahat, S.; Choudhary, M. I.; Rahman, A.;
Ghani, U.; Perveen, S.; Khatoon, S.; Dar, A.; Malik, A. Helv Chim Acta
2002, 85, 559.
3-(4-Chlorophenyl)-1-methyl-7-(morpholin-4-yl)-1H-pyrida-
zino[4,3-e][1,3,4]oxadiazine (3c). This compound was obtained
1
as creamy plate, yield: 67%; mp 215–216ꢀC; H NMR: (DMSO-
[7] Kornet, M. J. J Heterocycl Chem 1996, 33, 2047.
[8] Trepanier, D. L.; Spramanis, V.; Tharpe, D. S.; Krieger, P.
E. J Heterocycl Chem 1965, 2, 403.
d6, ppm), d 3.20 (s, 3H, CH3), 3.42 (T, 4H, NACH2), 3.69 (t, 4H,
OACH2), 6.21 (s, 1H, pyridazine), 7.6 (2H, d, J ¼ 8 Hz, Phenyl
protones), 7.8 (2H, d, J ¼ 8 Hz, Phenyl protones). ir (KBr disc) m
3035, 2940, 1135 cm–1. ms: (m/z) 345 (Mþ), 347 (Mþ þ 2).
Anal. Calcd. for C16H16ClN5O2: C, 55.58; H, 4.66; N, 20.25.
Found: C, 55.71; H, 4.09; N, 20.16.
[9] Gaozza, C. H.; Lamdan, S. J Heterocycl Chem 1970, 7,
927.
[10] Elliot, A. J.; Gibson, M. S. J Chem Soc Perkin Trans 1
1972, 2915.
3-(4-Chlorophenyl)-1-methyl-7-(pyrrolidin-1-yl)-1H-pyrida-
[11] Shawali, A. S.; Hassaneen, H. M. Bull Chem Soc Jpn 1977,
50, 2827.
zino[4,3-e][1,3,4]oxadiazine (3d). This
compound
was
obtained as creamy plate, yield: 73%; mp 243–245ꢀC; 1H
NMR: (DMSO-d6, ppm), d 1.91 (m, 4H, CH2ACH2), 3.18
(s, 3H, CH3), 3.38 (t, 4H, NACH2), 5.82 (s, 1H, pyrida-
zine), 7.6 (2H, d, J ¼ 8 Hz, Phenyl protones), 7.8 (2H, d,
J ¼ 8 Hz, Phenyl protones). ir (KBr disc) m 3045, 2930,
1145 cm–1. ms: (m/z) 329 (Mþ), 331 (Mþ þ 2). Anal.
Calcd. for C16H16ClN5O: C, 58.27; H, 4.89; N, 21.24.
Found: C, 58.01; H, 4.79; N, 21.19.
[12] Shawali, A. S.; Parkanyi, C. J Heterocycl Chem 1980, 17,
833.
[13] Freeman, J. P.; Kassner, J. A.; Grabiak, R. C. J Org Chem
1975, 40, 3402.
[14] Rosling, A.; Klika, K.; Fulop, F.; Sillanpaa, R.; Mattinen, J.
Heterocycles 1999, 51, 2575.
[15] Mourad, A. E.; Hassan, A. A.; Aly, A. A.; Mohamed, N. K.;
Ali, B. A. Phosphorus Sulfur Silicon 2007, 182, 321.
[16] (a) Bakavoli, M.; Nikpour, M.; Rahimizadeh, M. J Hetero-
cycl Chem 2006, 43, 1327; (b) Rahimizadeh, M.; Nikpour, M.; Baka-
1-Methyl-3-(4-methylphenyl)-7-(morpholin-4-yl)-1H-pyrida-
zino[4,3-e][1,3,4]oxadiazine
(3e). This
compound
was
obtained as creamy plate, yield: 75%; mp 247–249ꢀC; 1H
NMR: (DMSO-d6, ppm), d 2.35 (s, 3H, CH3), 3.14 (s, 3H,
CH3), 3.45 (m, 4H, NACH2), 3.65 (m, 4H, OACH2), 6.20 (s,
1H, pyridazine), 7.3 (2H, d, J ¼ 8 Hz, Phenyl protones), 7.7
(2H, d, J ¼ 8 Hz, Phenyl protones). ir (KBr disc) m 3065,
2940, 1160 cm–1. ms: (m/z) 325 (Mþ). Anal. Calcd. for
C17H19N5O2: C, 62.75; H, 5.89; N, 21.52. Found: C, 62.66; H,
5.57; N, 21.46.
voli, M.
J Heterocycl Chem 2007, 44, 463; (c) Bakavoli, M.;
Mollashahi, E.; Seyyedi, S. M.; Rahimizadeh, M.; Shiri, A.; Nikpour,
M. J Sulfur Chem 2007, 28, 613; (d) Bakavoli, M.; Nikpour, M.; Rahi-
mizadeh, M.; Saberi, M. R.; Sadeghian, H. Bioorg Med Chem 2007,
15, 2120; (e) Bakavoli, M.; Sadeghian, H.; Tabatabaei, Z.; Rezaei, E.;
Rahimizadeh, M.; Nikpour, M. J Mol Model 2008, 14, 471; (f) Baka-
voli, M.; Rahimizadeh, M.; Shiri, A.; Eshghi, H.; Nikpour, M. Hetero-
cycles 2008, 75, 1745; (g) Bakavoli, M.; Bagherzadeh, G.; Vaseghifar,
M.; Shiri, A.; Pordel, M.; Mashreghi, M.; Pordeli, P.; Araghi, M. Eur J
Med Chem 2010, 45, 647.
1-Methyl-3-(4-methylphenyl)-7-(pyrrolidin-1-yl)-1H-pyrida-
zino[4,3-e][1,3,4]oxadiazine (3f). This compound was obtained
[17] Alazawe, S.; Elvidge, J. A. J Chem Soc Perkin Trans 1
1974, 696.
1
as creamy plate, yield: 70%; mp 243–246ꢀC; H NMR: (DMSO-
[18] Bakavoli, M.; Mollashahi, E.; Seyyedi, S. M.; Rahimizadeh,
M.; Shiri, A.; Nikpour, M. J Sulfur Chem 2007, 28, 613.
[19] Cruickshank, R.; Duguid, J. P.; Marion, B. P.; Swain, R. H.
A. Medicinal Microbiology, 12th ed.; Churchil Livingstone: London,
1975; Vol. II, pp 196–202.
d6, ppm), d 1.95 (m, 4H, CH2ACH2), 2.33 (s, 3H, CH3), 3.14 (s,
3H, CH3), 3.33 (m, 4H, NACH2), 5.85 (s, 1H, pyridazine), 7.3
(2H, d, J ¼ 8 Hz, Phenyl protones), 7.7 (2H, d, J ¼ 8 Hz, Phenyl
protones). ir (KBr disc) m 3055, 2940, 1155 cm–1. ms: (m/z) 309
(Mþ). Anal. Calcd. for C17H19N5O: C, 66.00; H, 6.19; N, 22.64.
Found: C, 66.06; H, 6.07; N, 22.59.
[20] Collins, A. H. Microbiological Methods, 2nd ed.; Butter-
worth: London, 1976.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet