Novel synthesis and antibacterial activity of some pyridazine derivatives

Article abstract of DOI:10.1002/jccs.200400143

Various pyridazin-3(2H)-ones, 3-chloropyridazines and pyridazin-3(2H)- thiones were synthesized and treated with the sulpha drug (knowing by sulphamethoxazole). All the new compounds were evaluated for their antibacterial activity. They showed significant antibacterial activity against Staphylococcus aureus and Bacillus subtilis (Gram + ve) and E. coli, Pseudomonas aeruginosa and Yersinia enterocolitica (Gram - ve) bacteria by agar plate diffusion method. All proposed structures were confirmed by IR, ¹H NMR, Mass spectra and Elemental analysis.

Full text of DOI:10.1002/jccs.200400143

Journal of the Chinese Chemical Society, 2004, 51, 963-968
963
Novel Synthesis and Antibacterial Activity of Some Pyridazine Derivatives
M. I. Mohamed,* H. T. Zaky and N. G. Kandile
Department of Chemistry, Faculty of Girls, Ain Shams University, Helipolis post code No. 11757, Cairo, Egypt
Various pyridazin-3(2H)-ones, 3-chloropyridazines and pyridazin-3(2H)-thiones were synthesized and
treated with the sulpha drug (knowing by sulphamethoxazole). All the new compounds were evaluated for
their antibacterial activity. They showed significant antibacterial activity against Staphylococcus aureus and
Bacillus subtilis (Gram + ve) and E. coli, Pseudomonas aeruginosa and Yersinia enterocolitica (Gram - ve)
bacteria by agar plate diffusion method.
All proposed structures were confirmed by IR, 1H NMR, Mass spectra and Elemental analysis.
Keywords: Pyridazin-3(2H)-one; Antibacterial activity.
INTRODUCTION
As a part of our research program directed to the selec-
solid product formed was washed with water, collected by fil-
tration, and recrystallized to give (2a).
tion of new heterocycles as analogues to useful drugs,1-2 we
have previously described the synthesis and chemothera-
peutic activity of pyridazine derivatives.3-9 Our interest in the
field of organosulphur compounds10 and the fact added by
Bailey (1993) and Karen et. al., (1997),11-12 that the combina-
tion of trimethoprim and sulphamethoxazole is more effec-
tive in delaying the emergence of bacterial resistance which
prevents bacterial division and is also bactericidal, opens a
new target for conversion of these pyridazines to their sulpha
derivatives and leads to investigation of their potential activ-
ity on some (Gram + ve) bacteria and (Gram - ve) bacteria
pathogens and non pathogens.
Synthesis of 4-(3,4,5-trimethoxybenzyl)-6-methyl-
pyridazin-3(2H)-thione 3a
A solution of (2a) (0.015 mol) in ethanol (50 mL) and
thiourea (0.12 mol) was heated under reflux for 3 hrs. The
solid product formed was collected by filtration and
recrystallized to give (3a).
Synthesis of 4-aroyl-6-aryl-pyridazin-3(2H)-ones 4a-c and
4-aroyl-6-aryl-pyridazin-3(2H)-thiones 5a-c
A mixture of (1a-c) or (3a-c) (0.01 mol) and (0.01 mol)
seleniumdioxide was heated under reflux in acetic acid (20
mL) for 3 hrs; the reaction mixture was poured into crushed
ice. The solid product formed in each case was washed with
water, collected by filtration and recrystallized to give the ti-
tle compounds.
EXPERIMENTAL
Melting points are not corrected. I.R. spectra in KBr
were recorded on a Pye Unicom SP 1200 spectrophotometer.
1H NMR spectra were recorded on a EMNMR spectrometer
200 MHZ PMR using DMSO as a solvent and TMS as inter-
nal reference (Chemical shifts in d ppm). Mass spectra and
analysis were carried out by the Microanalytical Laboratory
of Cairo University.
Synthesis of 4-(sulphamethoxazole)-aryl-6-aryl-
pyridazin-3(2H)-ones 6a-c and 4-(sulphamethoxazole)-
aryl-6-aryl-pyridazine-3(2H)-thiones 7a-c
A mixture of (4a-c) or (5a-c) (0.01 mol) and sulphameth-
axazole (0.01 mol) was heated under reflux in ethanol (20
mL) for 24 hrs. The reaction mixture evaporated, the solid
product formed and recrystallized to give (6a-c) and (7a-c).
Synthesis of 4-(3,4,5-trimethoxybenzyl)-6-methyl-3-
chloropyridazine 2a
Synthesis of N-methyl-4-[(sulphamethoxazole)-(o-meth-
oxyphenyl)]-6-phenylpyridazin-3(2H)-one 8b and
N-methyl-4-[(sulphamethoxazole)-(o-methoxyphenyl)]-6-
tolylpyridazin-3(2H)-thione 8c
A suspension of 4-(3,4,5-trimethoxybenzyl)-6-methyl-
pyridazin-3(2H)-one (1a) (0.01 mol) in phosphorus oxychlo-
ride (5 mL), was heated under reflux for 3 hrs, then poured
into crushed ice containing sodium hydroxide (10%). The
a) Dimethylsulphate (0.01 mol) was added to ethanolic
solution 6c or 7b (0.01 mol) in 20% NaOH solution (50 mL)

964 J. Chin. Chem. Soc., Vol. 51, No. 5A, 2004
Mohamed et al.
and the reaction mixture warmed in a water bath for 6 minutes
and left to cool. The solid product was filtered off and recrys-
tallized to give (8b or 8c).
6-aryl-4-(aryl methyl)pyridazin-3(2H)-ones (1a-c) and in an
attempt to obtain 4,6-disubstituted pyridazin-3(2H)-thiones
(3a-c) using a new methodolgy for thiation.7 These key start-
ing materials were prepared by the reaction of 4,6-disubsti-
tuted pyridazin-3(2H)-one (la-c) with phosphorus oxychloride
to give 3-chloropyridazines (2a-c), followed by treatment with
thiourea in refluxing ethanol to give (3a-c) via the thioronium
salt formation as shown in Scheme I.
b) A mixture of (9b) or (9c) (0.01 mol) and sulphometh-
oxazole (0.01 mol) was heated under reflux in ethanol (20
mL) for 24 hrs; the reaction mixture was evaporated. The
solid product formed was recrystallized to give (8b) or (8c).
Synthesis of N-methyl-4-(o-methoxybenzoyl)-6-phenyl-
pyridazinone 9b and N-methyl-4-(o-methoxybenzoyl)-6-
p-tolylpyridazin-3(2H)-thione 9c
These compounds were also obtained in a similar yield
as a one pot reaction of phosphorus pentasulphide in boiling
xylene with 4,6-disubstituted pyridazin-3(2H)-one (1a-c).
The oxidation of pyridazin-3(2H)-ones with selenium
dioxide in refluxing acetic acid for three hours occurs with
formation of the ketonic derivatives.
Dimethyl sulphate (0.01 mol) was added to an ethanolic
solution of (4c) or (5b) (0.01 mol) in 20% NaOH solution (50
mL), and the reaction mixture was warmed on a water bath
for 10 minutes and left to cool. The solid product was filtered
off and recrystallized to give (9b) or (9c).
Initially we oxidized both (1a-c) and (3a-c) with selenium
dioxide to give the corresponding 6-aryl-4-aroyl pyridazin-
3(2H)-one (4a-c) and 6-aryl-4-aroyl pyridazin-3(2H)-thione
(5a-c). The 1H NMR and GC/Ms data showed evidence for the
formation of all products as shown in experimental part.
As an extension to those investigations, we examined
the reaction of 6-aryl-4-aroyl pyridazin-3(2H)-one (4a-c) and
6-aryl-4-aroyl pyridazin-3(2H)-thione (5b,c) with an equiva-
lent mole of sulphamethoxazole-[4-amino-N-(5-methyl-3-
isoxazolyl)benzenesulphonamide], in refluxing ethanol for
24 hrs; we obtained new sulpha products (6a-c) and (7b,c) in
good yield which reacted with dimethylsulphate in the pres-
ence of sodium hydroxide to give the N-methyl derivatives
(8b,c). Also compounds (8b,c)\were prepared by reaction of
Synthesis of 4-aryl-6-aryl-pyridazine-3-sulphameth-
oxazole 10a-c
A mixture of (2a-c) (0.01 mol) and sulphamethoxazole
(0.01 mol) was heated under reflux in ethanol (20 mL) for 24
hrs. The reaction mixture evaporated, a solid product formed
and was recrystallized to give (10a-c).
RESULTS AND DISCUSSION
This is in continuation of our previous investigation on
Scheme I
3b* , 3c* Ref. [7]

Synthesis of Novel Antibacterial Active of Pyridazines
J. Chin. Chem. Soc., Vol. 51, No. 5A, 2004 965
(4c,5b) with dimethylsulphate in the presence of sodium hy-
droxide to give the N-methyl derivatives (9b,c), which reacted
with an equivalent mole of sulphamethoxazole, in refluxing
ethyl alcohol for 24 hrs; forming sulpha derivatives (8b,c) as
shown in Scheme II.
Also, the reaction of chloro derivatives (2a-c) with an
Scheme II
Scheme III
* The only non pathogens bacteria in this study.

966 J. Chin. Chem. Soc., Vol. 51, No. 5A, 2004
Mohamed et al.
Table 1. Biological activity of some new compounds on some bacteria in (mm/iml bore) of
10-4 mol in 20 mL acetone
Staphylococcus
aureus
Bacillus
subtilis
Pseudomonas
aeruginosa
Yersinia
enterocolitica
No
E. coli
Sulfamet-hoxazole
(10-4 mol in 20 mL
50
1
- ve
- ve
- ve
acetone)
3a
4a
5a
5b
5c
6a
6b
6c
7b
8
10a
10b
10c
- ve
- ve
- ve
> 90
- ve
> 90
45
- ve
> 90
15
1
1
1
1
- ve
20
- ve
- ve
- ve
10
- ve
- ve
20
- ve
- ve
- ve
- ve
- ve
15
- ve
- ve
- ve
20
- ve
- ve
- ve
- ve
- ve
- ve
- ve
- ve
- ve
10
> 90
> 90
> 90
- ve
> 90
- ve
15
> 90
25
> 90
> 90
35
- ve
25
- ve
- ve
10
20
- ve
- ve
25
> 90
Table 2. Physical data of compounds 1-10
Analysis (%) (Calcd/Found)
Molecular
Formula
Comp.
M.P.
Yield; Colour
C
H
N
Cl
S
68%
White
69%
White
57%
Yellow
50%
White
49%
62.07
6.21
6.45
5.51
5.20
5.88
5.62
5.26
4.91
5.00
5.10
9.66
10.10
9.08
8.88
9.15
9.50
9.21
9.63
8.75
9.17
1a
2a
3a
4a
5a
130-131
150-151
185-186
176-177
73-75
C15H18N2O4
C15H17N2O3Cl
C15H18N2O3S
C15H16N2O5
62.50
58.35
57.91
58.82
59.42
59.21
58.73
56.25
56.83
11.51
11.97
10.46
10.91
10.00
9.72
C15H16N2O4S
Brown
51%
Pale brownish
Yellow
47%
Brown
72%
Pale yellow
76%
67.08
66.78
4.35
4.19
8.70
8.30
9.94
10.21
5b
89-91
C18H14N2O2S
67.86
67.55
55.66
56.05
62.11
61.87
62.70
62.45
60.32
59.91
60.95
61.25
57.14
56.83
63.76
64.08
64.33
64.00
67.86
68.00
71.86
72.18
60.95
61.32
63.27
63.68
4.76
4.93
4.64
4.31
4.25
4.52
4.50
4.23
4.13
4.47
4.38
4.10
5.14
4.91
4.74
4.42
4.99
5.13
4.76
5.01
5.39
5.12
4.38
4.52
4.75
4.52
8.33
7.90
9.52
9.27
5.94
6.23
5.91
6.21
5.77
5.30
11.49
11.10
11.21
10.83
6.10
5.83
6.07
6.47
5.91
6.23
9.52
9.99
5c
78-80
C19H16N2O2S
C25H25N5O7S
C28H23N5O5S
C29H25N5O5S
C28H23N5O4S2
C29H25N5O4S2
C25H27N5O6S
C28H25N5O4S
C29H27N5O4S
C19H16N2O2S
C20H18N2O3
12.99
13.17
12.94
13.21
12.61
12.20
12.57
12.13
12.26
12.50
13.33
13.62
13.28
12.98
12.94
13.25
8.33
8.00
8.38
8.76
12.26
12.02
12.30
12.52
6a
6b
6c
148-150
138-140
144-146
120-122
140-142
222-224
168-170
130-132
110-112
207-209
133-135
181-183
Beige
74%
White
80%
7b
7c
Reddish Brown
79%
Orange
77%
Yellow
75%
Beige
73%
White
43%
Beige
45%
Beige
47%
Brown
49%
Yellow
8a
8b
8c
9b
9c
11.21
11.65
5.62
10b
10c
C29H25N5O4S2
C30H27N5O5S
5.43

Synthesis of Novel Antibacterial Active of Pyridazines
J. Chin. Chem. Soc., Vol. 51, No. 5A, 2004 967
Table 3. Spectroscopic data of compounds 1-10
Compd. No
IR spectra (nmax in cm-1)
1H NMR (d in ppm), Mass spectra
1a
3140 (NH), 2937.2 (CH3), 2492.3 (CH2), d 1.928 (s, 3H, CH3), d 3.84-3.93 (s, 9H, 3OCH3 of CH3O-Ar), d 4.14 (s, 2H,
1651 (C=O), 1603 (C=N).
CH2), d 6.47 (s, 1H, CH hetero), d 7.09-7.26 (m, 2H, Ar-H), d 12.07 (s, 1H,
NH), M.S: m/z (290).
2a
3a
2904 (CH3), 2483.1 (CH2), 1592 (C=N)
3146.3 (NH), 2924.5 (CH3),
2427.2 (CH2), 1593.4 (C=N).
M.S: m/z (308.5)
d 2.32 (s, 3H, CH3), d 3.82-3.86 (s, 9H, 3OCH3 of CH3O-Ar), d 4.08 (s, 2H,
CH2), d 6.59 (s, 1H, CH hetero), d 7.26-7.42 (m, 2H, Ar-H), d 12.59 (s, 1H,
NH), M.S: m/z (306).
4a
5a
3141.6 (NH), 2939.3 (CH3), 1651 (C=O), M.S: m/z (304)
1605.6 (C=N).
3055-3093 (NH), 2941.9 (CH3),
1639.8 (C=O), 1586.2 (C=N),
1110 (C=S).
d 2.8 (s, 3H, CH3), d 3.72-3.93 (s, 9H, 3OCH3 of CH3O-Ar), d 6.45 (s, 1H,
CH hetero), d 7.79-7.93 (m, 2H, Ar-H), d 12.23 (s, 1H, NH), M.S: m/z (320).
5b
5c
3056.4 (NH), 1656.5 (C=O),
1595.9 (C=N), 1158.3 (C=S).
3143.3 (NH), 2922.5 (CH3),
1660.1 (C=O), 1597.8 (C=N),
1184.3 (C=S).
d 3.65 (s, 3H, OCH3 of CH3O-Ar), d 6.25 (s, 1H, CH hetero), d 7.32-7.99 (m,
9H, 2Ar-H), d 11.92 (s, 1H, NH), M.S: m/z (322).
d 2.72 (s, 3H, CH3), d 3.55 (s, 3H, OCH3 of CH3O-Ar), d 6.31 (s, 1H, CH
hetero), d 7.35-7.87 (m, 8H, 2Ar-H), d 12.01 (s, 1H, NH), M.S: m/z (336).
6a
6b
6c
7b
7c
8b
8c
9b
3155.8-3230.3 (NH),
2935.7-2967.4 (CH3),
1598.2-1605.5 (C=N), 1324.2 (SO2).
3140.5-3260 (NH), 2893.1 (CH3),
1595-1621 (C=N), 1381.2 (SO2).
d 2.19-2.35 (s, 6H, 2CH3 hetero), d 3.59-3.87 (s, 9H, 3OCH3 of CH3O-Ar),
d 6.20-6.63 (s, 2H, 2CH hetero), d 7.26-7.62 (m, 6H, 2Ar-H), d 8.04 (s, 1H,
NH), d 10.92 (s, 1H, NH pyridazine), M.S: m/z (539).
d 2.34 (s, 3H, CH3 hetero), d 3.81 (s, 3H, OCH3 of CH3O-Ar), d 6.55-6.60 (s,
2H, 2CH hetero), d 7.26-7.69 (m, 13H, 3Ar-H), d 11.30 (s, 1H, NH), d 12.14
(s, 1H, NH pyridazine), M.S: m/z (541).
d 2.27 (s, 3H, CH3 hetero), d 2.81 (s, 3H, CH3), d 3.77 (s, 3H, OCH3 of
CH3O-Ar), d 6.27-6.53 (s, 2H, 2CH hetero), d 7.13-7.84 (m, 12H, 3Ar-H),
d 10.57 (s, 1H, NH), d 11.94 (s, 1H, NH pyridazine), M.S: m/z (538).
d 2.33 (s, 3H, CH3 hetero), d 3.73 (s, 3H, OCH3 of CH3O-Ar), d 6.56-6.61 (s,
2H, 2CH hetero), d 7.36-7.60 (m, 13H, 3Ar-H), d 8.21 (s, 1H, NH), d 11.9 (s,
1H, NH pyridazine), M.S: m/z (556).
d 2.22 (s, 3H, CH3 hetero), d 2.61 (s, 3H, CH3), d 3.52 (s, 3H, OCH3 of
CH3O-Ar), d 6.38-6.52 (s, 2H, 2CH hetero), d 7.32-7.71 (m, 12H, 3Ar-H),
d 8.42 (s, 1H, NH), d 12.1 (s, 1H, NH pyridazine), M.S: m/z (570).
d 2.34 (s, 3H, CH3 hetero), d 3.88 (s, 3H, OCH3 of CH3 O-Ar), d 4.05 (s, 3H,
N-CH3), d 6.2-6.57 (s, 2H, 2CH hetero), d 7.3-7.85 (m, 13H, 3Ar-H), d 9.87
(s, 1H, NH), M.S: m/z (571).
3134.6-3209.7 (NH),
2902.2-2966.2 (CH3),
1592.7-1607.6 (C=N), 1324.1 (SO2).
3068-3210.3 (NH), 2965.8 (CH3),
1596.1-1620.4 (C=N), 1313.4 (SO2),
1158 (C=S).
3100-3220 (NH), 2920-2960 (CH3),
1550-1600 (C=N), 1318 (SO2),
1130 (C=S).
3056.4 (NH), 2967.5 (CH3),
1446.8-1598.9 (C=N), 1384.3 (SO2),
1158.9 (C=S), 1023.5 (N-CH3).
3214 (NH), 2929.6-2965.6 (CH3),
1655.1 (C=O), 1499.4-1600.8 (C=N),
1312.7 (SO2), 1094.7 (N-CH3).
1658.4 (C=O), 1521-1598.9 (C=N),
1158.9 (C=S), 1070.2 (N-CH3).
d 2.29 (s, 3H, CH3 hetero), d 2.51 (s, 3H, CH3), d 3.79 (s, 3H, OCH3 of CH3
O-Ar), d 4.10 (s, 3H, N-CH3), d 6.10-6.62 (s, 2H, 2CH hetero), d 7.12-7.58
(m, 12H, 3Ar-H), d 10.93 (s, 1H, NH), M.S: m/z (569).
d 2.36 (s, 3H, CH3), d 3.67-3.74 (s, 3H, OCH3 of CH3 O-Ar), d 3.97 (s, 3H,
N-CH3), d 6.89 (s, 1H, CH hetero), d 7.27-7.56 (m, 8H, 2Ar-H) M.S: m/z
(336).
9c
2967.5 (CH3), 1642-1670 (C=O),
1554-1583 (C=N), 1100.7 (N-CH3).
3147.1-3180.2 (NH),
M.S: m/z (334).
10a
d 2.14-2.2 (s, 6H, 2CH3 hetero), d 3.54-3.77 (s, 9H, 3OCH3 of CH3 O-Ar),
d 4.26 (s, 2H, CH2), d 6.17-6.71 (s, 2H, 2CH hetero), d 7.61-7.88 (m, 6H,
2Ar-H), d 9.71 (s, 1H, NH hetero), d 11.41 (s, 1H, NH), M.S: m/z (524).
d 2.25 (s, 3H, CH3 hetero), d 3.47 (s, 3H, OCH3 of CH3 O-Ar), d 4.15 (s, 2H,
CH2), d 6.25-6.69 (s, 2H, 2CH hetero), d 7.23-7.9 (m, 13H, 3Ar-H), d 9.82
(s, 1H, NH hetero), d 11.85 (s, 1H, NH), M.S: m/z (527).
d 2.39 (s, 3H, CH3 hetero), d 2.75 (s, 3H, CH3), d 3.51 (s, 3H, OCH3 of CH3
O-Ar), d 4.27 (s, 2H, CH2), d 6.16-6.58 (s, 2H, 2CH hetero), d 7.17-7.83 (m,
12H, 3Ar-H), d 10.03 (s, 1H, NH hetero), d 12.00 (s, 1H, NH), M.S: m/z
(541).
2938.2-2975.1 (CH3), 2584.5 (CH2),
1544.6-1607 (C=N), 1331.6 (SO2).
3134.2-3205.1 (NH), 2958.6 (CH3),
2370 (CH2), 1602.3-1650.3 (C=N),
1366.3 (SO2).
10b
10c
3170.3-3200 (NH), 2915-2990 (CH3),
2410 (CH2), 1595-1610 (C=N),
1315 (SO2).

968 J. Chin. Chem. Soc., Vol. 51, No. 5A, 2004
Mohamed et al.
equivalent mole of sulphamethaxazole, in refluxing ethyl al-
cohol for 24 hrs; formed sulpha derivative (10a-c) as shown in
Scheme III.
Received March 31, 2003.
All the synthesized target compounds have been tested
for their antibacterial activity against Staphylococcus aureus
and Bacillus subtilis (Gram + ve) and E. coli, Pseudomonas
aeruginosa and Yersinia enterocolitica (Gram - ve) bacteria
by agar plate diffusion method. The results of antibacterial
activity indicate variable results as shown in Table 1.
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