One-pot synthesis and antibacterial activities of novel 1H-pyridazino[1,2-a]indazole-1,6,9(2H,11H)-triones

Article abstract of DOI:10.1248/cpb.56.1289

Synthesis of novel 1H-pyridazino[1,2-a]indazole-1,6,9(2H,11H)-triones using one-pot, three components reaction of 1,2-dihydropyridazine-3,6-dione, dimedone and aldehydes under solvent-free conditions has been reported. These products were evaluated in vitro for their antibacterial activities.

Full text of DOI:10.1248/cpb.56.1289

September 2008
Chem. Pharm. Bull. 56(9) 1289—1291 (2008)
1289
One-Pot Synthesis and Antibacterial Activities of Novel
1H-Pyridazino[1,2-a]indazole-1,6,9(2H,11H)-triones
Maryam SAYYAFI,a Ali ABOLHASANI SOORKI,b and Ayoob BAZGIR*,a
a Department of Chemistry, Shahid Beheshti University; and b Research Institute of Petroleum, Academic Center of
Education, Culture & Research, Shahid Beheshti University; Tehran 1983963113, Iran.
Received May 6, 2008; accepted June 17, 2008; published online June 18, 2008
Synthesis of novel 1H-pyridazino[1,2-a]indazole-1,6,9(2H,11H)-triones using one-pot, three components
reaction of 1,2-dihydropyridazine-3,6-dione, dimedone and aldehydes under solvent-free conditions has been
reported. These products were evaluated in vitro for their antibacterial activities.
Key words dimedone; pyridazino[1,2-a]indazole-1,6,9(2H,11H)-trione; aldehyde; solvent-free
Polyfunctionalized heterocyclic compounds play important g) A mixture of dimedone (0.14 g, 1 mmol), 1,2-dihydropyridazine-3,6-
dione (0.11 g, 1 mmol), benzaldehyde (0.13 g, 1.2 mmol) and p-TSA (0.1 g)
was heated at 80 °C for 30 min (TLC). After cooling, the reaction mixture
was washed with water (15 ml) and residue recrystallized from ethyl acetate :
n-hexane (1 : 3) to afford the pure product 4a as a yellow powder.
roles in the drug discovery process, and analysis of drugs in
late development or on the market shows that 68% of them
are heterocycles.1) Therefore, it is not surprising that research
in the field of synthesis of polyfunctionalized heterocyclic
compounds has received special attention.
3,3-Dimethyl-11-phenyl-3,4-dihydro-1H-pyridazino[1,2-a]indazole-
1,6,9(2H,11H)-trione (4a, C19H18N2O3) Yellow powder; mp 224—226 °C.
1H-NMR (DMSO-d6) d: 1.18 (6H, s), 2.31 (2H, s), 3.20 (2H, AB system,
3Jꢀ18.1 Hz), 6.29 (1H, s), 6.90 (2H, s), 7.34 (5H, br s). 13C-NMR (DMSO-
d6) d: 28.3, 28.6, 34.6, 37.5, 50.9, 65.4, 118.9, 127.1, 128.8, 128.9, 134.8,
135.1, 136.0, 150.3, 153.2, 154.8, 191.9. IR (KBr) cmꢁ1: 3071, 3026, 1666.
MS m/z: 322 (Mꢂ), 245, 217. Anal. Calcd for C19H18N2O3: C, 70.79; H,
5.63; N, 8.69. Found: C, 70.73; H, 5.68; N, 8.60.
Pyridazine and fused pyridazine derivatives continue to
attract considerable attention, which mainly arises from the
large variety of interesting pharmacological activities, herbi-
cides, insecticides and fungicides.2) Moreover, pyridazine de-
rivatives are useful as antituberculosis agents3) and related to
the cardiovascular system.4) Similarly, indazole derivatives,
which are bioisosteres of indoles, are also an important class
of compounds in the medicinal arena.5) In fact, compounds
containing the indazole skeleton are known to show a variety
of biological activities, such as high binding affinity for
estrogen receptor,6) inhabitation of protein kinase C-b,7)
5-HT2 and 5-HT3 receptor antagonisms,8) human immunode-
ficiency virus (HIV) protease inhibition,9) and anti-tumor
activity.10)
11-(4-Chlorophenyl)-3,3-dimethyl-3,4-dihydro-1H-pyridazino[1,2-
a]indazole-1,6,9(2H,11H)-trione (4b, C19H17ClN2O3) Yellow powder;
1
mp 196—198 °C. H-NMR (DMSO-d6) d: 1.17 (3H, s), 1.19 (3H, s), 2.31
(2H, s), 3.21 (2H, AB system, 3Jꢀ18.3 Hz), 6.26 (1H, s), 6.92 (2H, s),
7.27—7.30 (4H, m). 13C-NMR (DMSO-d6) d: 28.2, 28.4, 34.6, 37.2, 50.7,
64.4, 117.7, 128.6, 129.8, 133.1, 135.8, 136.1, 151.5, 153.6, 155.2, 192.2. IR
(KBr) cmꢁ1: 3051, 2962, 1693. MS m/z: 356 (Mꢂ), 275, 245, 218. Anal.
Calcd for C19H17ClN2O3: C, 63.96; H, 4.80; N, 7.85. Found: C, 63.91; H,
4.76; N, 7.92.
3,3-Dimethyl-11-(4-nitrophenyl)-3,4-dihydro-1H-pyridazino[1,2-a]in-
dazole-1,6,9(2H,11H)-trione (4c, C19H17N3O5) Orange powder; mp 200—
202 °C. 1H-NMR (DMSO-d6) d: 1.16 (3H, s), 1.20 (3H, s), 2.32 (2H, s),
Considering the above reports and in continuation of our
previous works on synthesis of heterocyclic compounds,11—16)
we wish to report a one-pot and three-component method for
the preparation of 11-aryl-3,3-dimethyl-3,4-dihydro-1H-pyri-
3
3.22 (2H, AB system, Jꢀ18.2 Hz), 6.36 (1H, s), 6.95 (2H, s), 7.54 (2H, d,
3Jꢀ6.7 Hz), 8.21 (2H, d, 3Jꢀ6.6 Hz). 13C-NMR (DMSO-d6) d: 28.3, 28.6,
34.7, 37.4, 50.8, 64.5, 117.7, 124.1, 128.1, 135.4, 135.7, 142.2, 147.9,
151.2, 153.3, 154.7, 191.9. IR (KBr) cmꢁ1: 3051, 2962, 1660. MS m/z: 367
(Mꢂ), 286, 245. Anal. Calcd for C19H17N3O5: C, 62.12; H, 4.66; N, 11.44.
Found: C, 62.17; H, 4.60; N, 11.50.
dazino[1,2-a]indazole-1,6,9(2H,11H)-trione derivatives
4
under solvent-free conditions (Chart 1).
11-(2-Chlorophenyl)-3,3-dimethyl-3,4-dihydro-1H-pyridazino[1,2-
a]indazole-1,6,9(2H,11H)-trione (4d, C19H17ClN2O3) Yellow powder;
Experimental
1
mp 214—216 °C. H-NMR (DMSO-d6) d: 1.17 (3H, s), 1.19 (3H, s), 2.29
Apparatus Melting points were measured on an Electrothermal 9100
apparatus and are uncorrected. Mass spectra were recorded on a FINNI-
GAN-MAT 8430 mass spectrometer operating at an ionization potential of
70 eV. IR spectra were recorded on a Shimadzu IR-470 spectrometer. 1H-
and 13C-NMR spectra were recorded on a BRUKER DRX-300 AVANCE
spectrometer at 300.13 and 75.47 MHz, respectively. Elemental analyses
were performed using a Heracus CHN-O-Rapid analyzer.
3
3
(2H, s), 3.20 (2H, AB system, Jꢀ18.8 Hz), 6.49 (1H, s), 6.88 (1H, d, Jꢀ
9.7 Hz), 6.93 (1H, d, Jꢀ9.8 Hz), 7.28—7.44 (4H, m). 13C-NMR (DMSO-d6)
d: 28.3, 28.8, 34.6, 37.4, 50.8, 64.6, 116.8, 127.3, 130.1, 130.6, 131.6,
132.2, 135.1, 135.5, 151.4, 153.1, 155.0, 192.0. IR (KBr) cmꢁ1: 3064. 2962,
1668. MS m/z: 356 (Mꢂ), 321, 275, 245. Anal. Calcd for C19H17ClN2O3: C,
63.96; H, 4.80; N, 7.85. Found: C, 63.92; H, 4.85; N, 7.79.
11-(3-Bromophenyl)-3,3-dimethyl-3,4-dihydro-1H-pyridazino[1,2-
a]indazole-1,6,9(2H,11H)-trione (4e, C19H17BrN2O3) Yellow powder;
Synthesis of 1H-Pyridazino[1,2-a]indazole-1,6,9(2H,11H)-trione (4a—
1
mp 175—177 °C. H-NMR (DMSO-d6) d: 1.18 (6H, s), 2.32 (2H, s), 3.19
3
(2H, AB system, Jꢀ18.5 Hz), 6.23 (1H, s), 6.93 (2H, s), 7.20—7.44 (4H,
m). 13C-NMR (DMSO-d6) d: 28.2, 28.4, 34.7, 37.2, 50.7, 64.5, 117.4, 121.9,
127.0, 130.6, 130.8, 131.4, 135.7, 135.9, 139.7, 151.7, 153.7, 155.3, 192.2.
IR (KBr) cmꢁ1: 3070, 2959, 1667. MS m/z: 402 (Mꢂꢂ2), 400 (Mꢂ), 321,
245. Anal. Calcd for C38H28BrN7O: C, 67.26; H, 4.16; N, 14.45. Found: C,
67.31; H, 4.11; N, 14.52.
3,3-Dimethyl-11-(3-nitrophenyl)-3,4-dihydro-1H-pyridazino[1,2-a]in-
dazole-1,6,9(2H,11H)-trione (4f, C19H17N3O5) Yellow powder; mp 197—
199 °C. 1H-NMR (DMSO-d6) d: 1.19 (3H, s), 1.25 (3H, s), 2.33 (2H, s),
3
3
3.24 (2H, AB system, Jꢀ18.5 Hz), 6.37 (1H, s), 6.92 (1H, d, Jꢀ9.5 Hz),
Chart 1. Synthesis of 1H-Pyridazino[1,2-a]indazole-1,6,9(2H,11H)-tri-
ones
6.99 (1H, d, Jꢀ9.4 Hz), 7.54—8.19 (4H, m). 13C-NMR (DMSO-d6) d: 28.3,
∗ To whom correspondence should be addressed. e-mail: a_bazgir@sbu.ac.ir
© 2008 Pharmaceutical Society of Japan

1290
Vol. 56, No. 9
such as butanal or pentanal, the TLC and 1H-NMR spectra of
the reaction mixture showed a combination of starting mate-
rials and numerous products; the expected product was ob-
tained in only trace amount.
The nature of these compounds as 1 : 1 : 1 adducts was ap-
parent from their mass spectra, which displayed, in each case,
the molecular ion peak at appropriate m/z values. Com-
pounds 4a—g are stable solids whose structures are fully
supported by IR, 1H- and 13C-NMR spectroscopy, mass spec-
trometry, and elemental analysis.
28.7, 34.7, 37.7, 50.8, 64.5, 117.5, 121.4, 123.9, 129.8, 134.2, 135.4, 135.7,
137.3, 148.5, 151.3, 153.4, 154.7, 191.9. IR (KBr) cmꢁ1: 3064, 2962, 1661.
MS m/z: 367 (Mꢂ), 286, 245. Anal. Calcd for C19H17N3O5: C, 62.12; H,
4.66; N, 11.44. Found: C, 62.18; H, 4.61; N, 11.38.
3,3-Dimethyl-11-(4-methylphenyl)-3,4-dihydro-1H-pyridazino[1,2-
a]indazole-1,6,9(2H,11H)-trione (4g, C20H20N2O3) Yellow powder; mp
1
220—222 °C. H-NMR (DMSO-d6) d: 1.19 (6H, s), 2.32 (5H, s), 3.22 (2H,
AB system, 3Jꢀ18.9 Hz), 6.27 (1H, s), 6.90 (2H, s), 7.14—7.27 (4H, m).
13C-NMR (DMSO-d6) d: 21.24, 28.3, 28.7, 34.7, 37.5, 50.9, 65.3, 119.1,
127.0, 129.5, 132.1, 134.7, 136.1, 138.8, 150.2, 153.5, 192.1. IR (KBr)
cmꢁ1: 3013, 2975, 1666. MS m/z: 336 (Mꢂ), 245, 217. Anal. Calcd for
C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found: C, 71.47; H, 5.38; N, 8.26.
The formation of products 4 can be rationalized by initial
formation of intermediate 5 by standard Knoevenagel con-
Results and Discussion
To achieve suitable conditions for the above transforma- densation of the dimedone 2 and aldehyde 3. Then, the sub-
tion, we investigated the reaction of 1,2-dihydropyridazine- sequent Michael-type addition of the 1,2-dihydropyridazine-
3,6-dione 1, dimedone 2 and 4-chlorobenzaldehyde 3b in the 3,6-dione 1 to the intermediate 5, followed by cyclization and
presence of p-TSA as an inexpensive and available catalyst in tautomerization affords the corresponding products 4 (Chart
various solvents, ionic liquid [bmim]Br and under solvent- 2).
free classical heating conditions. In refluxing various solvent
Finally, all synthesized compounds were screened for an-
and ionic liquid the reaction was very slow and the yield of timicrobial activity using disc diffusion method.17) The mi-
product was very low. We found that the best result was ob- croorganisms used in this study were Escherichia coli ATCC
tained in the presence of p-TSA at 80 °C under solvent-free 25922, Pseudomonas aeruginusa ATCC 85327 (Gram-nega-
conditions (Table 1).
tive bacteria), Bacillus subtilis ATCC 465, Staphylococcus
To explore the scope and limitation of this reaction, we aureus ATCC 25923 (Gram-positive bacteria). All of the
have extended the reaction of 1,2-dihydropyridazine-3,6- compounds were dissolved in DMSO (100 mg/ml) and 25 ml
dione 1 and dimedone 2 with a range of aromatic alde- of them were loaded to 6 mm paper discs. One hundred mi-
hydes 3a—g under similar conditions (solvent-free/p-TSA), croliters of 109 cell/ml suspension of the microorganisms
furnishing the respective 1H-pyridazino[1,2-a]indazole- were spread on sterile Muller Hilton Agar plates and the
1,6,9(2H,11H)-trione derivatives 4a—g. The optimized re- discs were placed on the surface of culture plates. Table 3
sults are summarized in Table 2. Varying the substituents on shows the inhibition zones of compounds around the discs.
the aldehydes did not detrimentally affect the yields and
moderate yields were obtained using aromatic aldehydes car-
rying electron-donating or electron-withdrawing substituents
in the presence of p-TSA, while without it for long period of
time (5—6 h) and under solvent-free conditions the yields of
products were low (ꢃ30%).
When this reaction was carried out with aliphatic aldehyde
Table 1. Conditions Effect on the Reactiona)
Entry
Solvent
Yield (%)b)
Time (h)
1
2
3
4
5
6
7
EtOH (reflux)
MeOH (reflux)
CHCl3 (reflux)
CH3CN (reflux)
[bmim]Br/100 °C
Solvent-free/80 °C
Solvent-free/100 °C
Trace
Trace
Trace
Trace
30
6
6
6
6
5
0.5
0.5
50
48
Chart 2. Mechanism for the Synthesis of 1H-Pyridazino[1,2-a]indazole-
triones
a) 1,3-Diphenyl-1H-pyrazol-5-amine (1 mmol), dimedone (1 mmol), 4-chloroben-
zaldehyde (1.2 mmol) and p-TSA (0.1 g). b) Isolated yield.
Table 3. Antibacterial Activity of Products 4a—g
Zone of inhibition (mm)
Table 2. Synthesis of 1H-Pyridazino[1,2-a]indazole-triones 4a—g
Product
Escherichia
coli
Pseudomonas
aeruginusa
Bacillus Staphylococcus
Product
R
Time (min) Yield (%)a)
mp (°C)
subtilis
aureus
a)
a)
a)
a)
a)
a)
a)
a)
a)
a)
4a
4b
4c
4d
4e
4f
C6H5
30
20
25
40
20
20
30
50
49
48
55
54
47
46
224—226
196—198
200—202
214—216
175—177
197—199
220—222
4a
4b
4c
4d
4e
4f
14
15
14
15
20
20
8
4-Cl–C6H4
4-NO2–C6H4
2-Cl–C6H4
3-Br–C6H4
3-NO2–C6H4
4-Me–C6H4
7
a)
11
a)
a)
14
8
10
7
a)
a)
4g
4g
a) Isolated yield.
a) Not active.

September 2008
1291
Table 4. MIC (mg/ml) Values of Products 4a—g
found to be more active than Amoxicillin against P. aerugi-
nusa.
Escherichia coli
Acknowledgements We gratefully acknowledge financial support from
the Research Council of Shahid Beheshti University.
Product
Escherichia
coli
Pseudomonas Bacillus Staphylococcus
aeruginusa
subtilis
aureus
References and Notes
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a)
a)
a)
a)
a)
a)
a)
a)
a)
a)
4a
4b
4c
4d
4e
4f
4g
16
8
16
16
8
8
12
2
60
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16
a)
a)
8
64
16
60
a)
a)
Amoxycillin
Norfloxacin
128
ꢃ2
—
20
16
16
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compounds which showed antibiotic activity in disc diffusion
tests, were also determined by microdillution method18) and
compared to two commercial antibiotics (Table 4).
None of the compounds have antibiotic activity against S.
aureus. Most of the compounds have a narrow spectrum anti-
microbial activity. All the compounds were effective against
B. subtilis ATCC 465 (MIC: 8—16 mg/ml). Compounds 4e
and 4f exhibited activity against P. aeruginusa (60, 64 mg/ml)
and E. coli (8, 16 mg/ml). Compounds 4c (16 mg/ml), 4e
(8 mg/ml) and 4f (16 mg/ml) were found to be more active
than Amoxicillin against E. coli (128 mg/ml). Although, all
of the compounds were found to be less active than nor-
flaxacin against the screened Gram-positive and Gram-nega-
tive bacterial strains.
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Conclusions
In summary, we have described a clean and simple method
for the preparation of 1H-pyridazino[1,2-a]indazole-1,6,9
(2H,11H)-trione derivatives in condensation reaction of 1,2-
dihydropyridazine-3,6-dione, dimedone and aldehyde under
solvent-free conditions. Most of the compounds exhibited
moderate antibacterial activity against all the tested strains.
These products were evaluated in vitro for their antibacterial 18) NCCLS, “Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria, which Grows Aerobically,” 5th ed., Approved Standard M7-
A5, NCCLS, Villanova, PA, 2000.
activities. Most of the compounds have a narrow spectrum
antimicrobial activity. All synthesized compounds were