Pyridazine derivatives and related compounds, part 28.1 pyridazinesulfonamides: Synthesis and antimicrobial activity

Article abstract of DOI:10.1080/10426500802080246

The reaction of 3-chloropyridazine 1 with N -(un)Substituted 4-aminosulfonamides 3 gave the 3-substituted aminopyridazines 4. Also In addition, pyridazine-3-sulfonamides 7 were prepared from the reaction of pyridazine-3-sulfonylchloride 6 with different amines. All of these derivatives have been characterized by analytical and spectroscopic studies, and also were tested for their in vitro antibacterial and antifungal activity against a variety of microorganisms.

Full text of DOI:10.1080/10426500802080246

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Pyridazine Derivatives and
Related Compounds, Part
28. Pyridazinesulfonamides:
Synthesis and Antimicrobial
Activity
Fatma El-Mariah a , Ekhlass Nassar a , Mona Hosny a
& Ali Deeb b
a Department of Chemistry, Faculty of Girls, Ain
Shams University, Cairo, Egypt
b Department of Chemistry, Faculty of Science,
Zagazig University, Zagazig, Egypt
Version of record first published: 19 Dec 2008.
To cite this article: Fatma El-Mariah, Ekhlass Nassar, Mona Hosny & Ali Deeb (2008):
Pyridazine Derivatives and Related Compounds, Part 28. Pyridazinesulfonamides:
Synthesis and Antimicrobial Activity, Phosphorus, Sulfur, and Silicon and the Related
Elements, 184:1, 92-102
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Phosphorus, Sulfur, and Silicon, 184:92–102, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802080246
Pyridazine Derivatives and Related Compounds,
Part 28.1 Pyridazinesulfonamides: Synthesis
and Antimicrobial Activity
Fatma El-Mariah,1 Ekhlass Nassar,1 Mona Hosny,1
and Ali Deeb2
1Department of Chemistry, Faculty of Girls, Ain Shams University,
Cairo, Egypt
2Department of Chemistry, Faculty of Science, Zagazig University,
Zagazig, Egypt
The reaction of 3-chloropyridazine 1 with N –(un)Substituted 4-aminosulfonamides
3 gave the 3-substituted aminopyridazines 4. Also In addition, pyridazine-3-
sulfonamides 7 were prepared from the reaction of pyridazine-3-sulfonylchloride 6
with different amines. All of these derivatives have been characterized by analytical
and spectroscopic studies, and also were tested for their in vitro antibacterial and
antifungal activity against a variety of microorganisms.
Keywords 3-Substituted aminopyridazines; N-substituted pyridazine-3-sulfonamides
INTRODUCTION
Many pyridazines exhibit biological activity and some are used as
drugs.2,3
In the last few years our group has been interested in the synthesis
of pyridazine derivatives with potential biological activity, and we have
published several articles on this subject. On the other hand, the sul-
fonamides group form the bioactive moiety of many compounds with
therapeutical interest, such as antibacterials, diuretics, antidiabetics,
and antibiotics.4 For these reasons, we are interested in continuing our
work in this area5 to produce new pyridazine derivatives containing sul-
famoyl moiety and study their antibacterial and antifungal properties.
Received 11 December 2007; accepted 11 February 2008.
The author A.D. acknowledges the help of Quality Control and Propagation of Plants,
Department of Botany, Faculty of Girls, Ain Shams University for carrying out the an-
timicrobial activity.
Address correspondence to Ali Deeb, Department of Chemistry, Faculty of Science,
Zagazig University, Zagazig, Egypt. E-mail: dralideeb@hotmail.com
92

Pyridazine Derivatives and Related Compounds, Part 28
93
SCHEME 1
RESULTS AND DISCUSSION
Compounds were obtained as illustrated in Scheme 1, starting with
3-chloro-5,6-diphenylpyridazine-4-carbonitrile 1. The method utilized
for the synthesis of 1 is outlined in Scheme 2. The necessary benzil and
benzilmonohydrazone were commercially available or easily prepared
by following previously described methods.6 The desired pyridazinone
has been obtained by the reaction of benzilmonohydrazone with ethyl
cyanoacetate and sodium ethoxide.7 Compound 2 was transformed into
1 by treatment with phosphorus oxychloride.8
The N1-(un)substituted 4-aminobenzenesulfonamides 3 were pre-
pared using a previously described method.9 The spectroscopic char-
acterization and analysis are shown in the Experimental section.
SCHEME 2

94
F. El-Mariah et al.
TABLE I Physical and Spectroscopic Data of N1-Substituted
4-Aminobenzenesulfonamides 3
Compound
No.
Yield
R
Color
M.p. (◦C) (%)
IR (kBr) γ max cm−1
3a
3b
H
n-Pr
Color less 161–162
Color less 158–159
90
70 3435, 3251, 3036, 2949,
1640, 1307, 1151
3c
3d
3e
3f
CH2Ph
NHPh
Brown
167–168
60–61
90 3400, 3336, 3263, 3012,
2958, 1646, 1319, 1151
70 3470, 3376, 3236, 3059,
2969, 1623, 1309, 1150
85 3410, 3340, 3120, 3040,
1639, 1329, 1150
Color less
Ph
Color less 180–181
C6H4Me (p-)
Color less 186–187 80 3413, 3343, 3125, 3046,
2918, 1636, 1321, 1153
3g
3h
3i
C6H4OMe (p-) Color less 182–183
95 3486, 3397, 3263, 1632,
1318, 1150
80 3412, 3344, 3108, 1633,
1315, 1153
65 3491, 3389, 3299, 3093,
1628, 1343, 1152
C6H4Cl (p-) Pale yellow 178–179
C6H4NO2 (p-)
Yellow
112–113
The nucleophilic substitution of the 4-amino group of 3 with the
3-chloro group of compound 1 yielded the corresponding 3-substituted
aminopyridazines 4a–i. The structure of the synthesized compounds
was established on the basis of their IR, and mass spectral stud-
ies. Physical and analytical data of compounds 3 and 4 are given in
Tables I–III.
As an extension of our studies, we have been interested in prepar-
ing the interesting sulfonamide derivatives in which the sulfur atom
is joined directly to a carbon of the pyridazine ring. They have
usually been prepared via an alternate route starting from the 3-
mercaptopyridazine derivative. Thus, when compound 1 was allowed to
react with ethanolic thiouronium, salt in 90 % yield was obtained, which
on hydrolysis with 2.5 N sodium hydroxide followed by acidification
with hydrochloric acid (pH 6), gave 4-cyano-5,6-diphenylpyridazine-
3(2H)-thione 5.10 The structure of 5 was inferred from microanalytical
data and by comparison with the product obtained by the action of
phosphorus pentasulphide on 2 (Scheme 3).
The precursor pyridazine-3-chlorosulfonyl was synthesized similar
to the literature procedure.11 The low temperature oxidative chlori-
nation of thiopyridazine 5 gave the corresponding sulfonyl chloride 6.
Because of the instability of the sulfonyl choride, the crude product was

Pyridazine Derivatives and Related Compounds, Part 28
95
TABLE II Spectral Data of 3-Substituted Aminopyridazines 4
Compound
No.
IR (KBr) cm−1
Ms (m/z, %)
4a
3266, 3127, 3062, 2228, 1663,
1329, 1157
3239, 3180, 3060, 2939, 2222,
1660, 1332, 1152
3440, 3291, 2225, 1666, 1406,
1155
3361, 3057, 2225, 1666, 1406,
1153
3351, 3251, 3062, 2229, 1664,
1320, 1156
3380, 3289, 3053, 2920, 2227,
1598, 1329, 1154
427 (M+, 00), 363 (50), 345 (50),
244 (24), 214 (53)
4b
4c
4d
4e
4f
469 (M+, 11), 411 (7), 347 (28), 273
(100)
517 (M+, 15), 516 (14), 490 (14),
411 (17), 273 (19)
516 (M+- 2,8), 515 (29), 504 (22),
503 (29), 380 (65), 379 (100)
504 (M++ 1,28), 503 (69), 411 (22),
347 (100)
517 (M+, 21), 263 (17), 349 (77),
348 (91), 269 (3), 244 (10), 106
(100)
4g
4h
4i
3407, 3291, 3060, 2996, 2229,
1596, 1330, 1154
3290, 3133, 3064, 2227, 1597,
1330, 1156, 700
3330, 3234, 3058, 2232, 1666,
1529, 1342, 1156
533 (M+, 19), 454 (4), 347 (10), 122
(100)
538 (M+, 26), 412 (4), 382 (47) 381
(98), 347 (100)
548 (M+, 28), 499 (35), 393 (39),
392 (84), 347 (100)
usually converted directly to the more stable sulfonamides 7a–k by the
action of amines (Scheme 4). The structure of compounds 7 was estab-
1
lished on the basis of their IR, H-NMR, and mass spectral studies.
Physical and analytical data are given in Tables IV and V.
SCHEME 3

96

Pyridazine Derivatives and Related Compounds, Part 28
97
SCHEME 4
Screening for Antimicrobial and Antifungal Activity:
Experimental Procedure
The preliminary antimicrobial activity of the synthesized derivatives
was determined in vitro by the filter paper disc method.12 Four bacterial
isolates (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus au-
reus, and Bacillus subtilis) and two fungal isolates (Candida albicans
and Asperggillus niger) were used as test organisms. The culture media
were normal nutrient agar for bacteria, and Sabouraud dextrose agar
for Candida spp. and Asperggillus niger. Filter paper discs (7.0 mm
diameter) punched from No.1 Whatman filter paper were sterilized by
autoclaving followed by drying at 40◦C for 1 h. They were then impreg-
nated with 50 µg/ml tested compound in dimethylformamide (DMF).
The sterile medium was inoculated onto the surface with the test or-
ganism so that each 100 mL of the medium received 1 mL of a 24-h old
culture of the bacterium or 3-day-old culture of spore suspension of the
fungus. After the inoculum had dried, the dried discs were placed on
the medium. A control disc (DMF) was also placed onto the medium.

98

99

100
F. El-Mariah et al.
TABLE VI Antibacterial and Antifungal Activity
Esch.
coli
Pseud.
aerugin aureus
Staph.
Bacillus Candida
Asp.
niger
No.
subtilis
albicans
4a
4b
4c
4d
4e
4f
4g
4h
4i
7a
7b
7c
7d
7e
7f
7g
7h
7i
++
++
−
++
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
+ + +
++
−
−
−
−
++
−
++
−
−
++
−
−
++
−
++
−
++
−
−
++
−
−
−
−
−
++
−
−
++
−
−
−
+ + +
+ + +
+ + +
−
−
++
−
−
−
−
++
++
+ + +
+ + +
++
+ + +
+ + +
++
−
−
−
++
++
++
++
+ + +
+ + +
−
−
−
−
+ + +
+ + +
−
−
−
−
−
−
−
−
−
−
+ + +
+ + +
−
−
−
7j
7k
+ + +
−
++
++
+ + +
−
−
++
+ + +
−
−
Cipr + + +
+ + +
−
−
Nys
−
+ + +
Zone of inhibition: + + + = 25–30 mm; ++ = 15–20 mm; – =
negative inhibition.
The plates were incubated at 37◦C, and the resulting inhibition zones
were measured. The screening results are given in Table VI.
RESULTS
As revealed from the results, most of the synthesized compounds
showed antibacterial activity. The most toxic compounds against bac-
terial isolates were compounds 4c, 7a, 7b, 7c, 7d, 7e, 7f, 7g, 7h, 7i,
and 7j.
The test microorganisms were less sensitive to compounds 4a, 4b,
4d, 4e, 4f, 4g, 4h, 4i, and 7k.
These compounds were slightly effective only on Pseudomonas
Aeruginosa.
All compounds did not exert inhibition zone against fungal iso-
lates. From these results, we can conclude that the biologically active

Pyridazine Derivatives and Related Compounds, Part 28
101
compounds are nearly as active as standard antibiotic Ciprofloxacin
and less active than the fungicide Nystin.
EXPERIMENTAL
Melting points were determined in open glass capillaries and are un-
corrected. IR spectra were recorded on a BRUKER Vector 22 Germany
spectrometer (KBr) (Germany). The 1H-NMR spectra were obtained on
Varian Gemini 200 MHz spectrometer (USA), and chemical shifts are
expressed in δ ppm using TMS as an internal standard. Electron im-
pact mass spectra were obtained at 70 eV using a GCMS-qp 1000 EX
Shimadzu spectrometer (Japan). Reactions were routinely followed by
thin layer chromatography (TLC) on silica gel F 254 aluminium sheets
(Merck). The spots were detected by UV irradiation at 254–365 nm.
4-Aminobenzenesulfonamide 3a was prepared by the reported
method9 mp 161–162◦C.
N1-Substituted 4-aminobenzenesulfonamides 3b–i : General
Procedure
To a solution of appropriate amines, namely n-propylamine, ben-
zyl amine, phenylhydrazine, aniline, p-toluidine, p-anisidine, 4-
chloroaniline, and 4-nitroaniline (10 mmol) in dry pyridine (10 mL),
crude p-acetamidobenzenesulfonyl chloride (2.34 g, 10 mmol) was
added. The reaction mixture was heated at 70◦C for 15 min, and set
aside overnight at room temperature. The separated solid was filtered
off, washed several times with water, and dried. The material was suf-
ficiently pure for use in the following stage.
A mixture of acetamido derivative and sodium hydroxide (10 mL,
2 N) was gently heated under reflux for 1 h. The solution, when cooled
to room temperature, neutralized with 50% dilute acetic acid until
pH = 6.5. The solid product produced was filtered off with suction,
dried, and recrystallized from ethanol (Table I).
General Procedure for the Preparation of 3-Substituted
Amino-pyridazines 4a–i
A
mixture of 3-chloro-5,6-diphenylpyridazine-4-carbonitrile
1
(1.0 mmol) and 4-aminobenzenesulfonamide derivatives 3a–i
(1.0 mmol) was refluxed in 1-butanol (20 mL) for 3 h. The reac-
tion mixture was cooled to room temperature, and the separated solid

102
F. El-Mariah et al.
was filtered off, washed with water, dried, and recrystallized from
ethanol (Tables II and III).
4-Cyano-5,6-diphenylpyridazine-3-sulfonylchloride 6
In a solution of 3-mercapto derivative 5 (1.0 g, 3.45 mmol) in acetic
acid (9 mL) and water (1 mL), chlorine gas was bubbled at 0◦C. After
2 h, the precipitate was filtered, washed with water several times, and
dried to give 3-sulfonylchloride 6, 1.10 g (95%). The respective crude
sulfonylchloride, was used in the next step without further purification.
General Procedure for the Preparation of N-Substituted
4-Cyano-5,6-diphenylpyridazine-3-sulfonsmides 7a–k
To a solution of 4-cyano-5,6-diphenylpyridazine-3-sulfonylchloride 6
(1.0 g, 2.8 mmol) in benzene (20 mL), substituted amines (2.8 mmol)
was added. The reaction mixture was heated under reflux for 3 h, then
the solvent was concentrated. The solid product was collected, dried,
and recrystallized from ethanol (Tables IV and V).
REFERENCES
[1] A. Deeb, El. S. Mourad, and D. Elenany, Part 27, Z.Naturforsch. (in press).
[2] M. Tisler and B. Stanovnik, In Comperhensive Heterocyclic Chemistry, ed. by A. R.
Katritzky and C. W. Rees (Pergamon Press, Oxford, 1984), Vol. 3, pp. 1–56.
[3] A. Kleemann and J. Engel, Pharmazeutische Wirkstoffe: Synthen, Patente, Anwen-
dungen (Thieme Verlag, Stuttgart, 1982).
[4] D. Lednicer, L. A. Mitscher, The Organic Chemistry of Drug Synthesis (Wiley,
New York, 1984), Vol. 1, pp. 120, 1977; Vol. 2, pp. 112, 1980; Vol. 3, pp. 61.
[5] M. Hosny, F. El-Mariah, and A. Deeb, Phosphorus, Sulfur, and Silicon, 182, 1475–
1482, 2007.
[6] Org. Syntheses (Wiley, New York, 1976), Coll. Vol. III, p. 357.
[7] P. Schmidt and J. Druey, Helv. Chim. Acta., 37, 134 (1954).
[8] A. Deeb, S. A. Said, M. M. Hamed, and F. Yasin, J. Chin. Chem. Soc., 37, 287 (1991).
[9] Vogel’s Textbook of Practical Organic Chemistry (Longman Group Limited, London,
1980), 4th ed., pp. 651.
[10] M. F. Ismail, N. A. Shams, and O. M. El-Sawy, Synthesis, 410 (1980).
[11] (a) R. O. Roblin and J. W. Clapp, J. Am. Chem. Soc., 72, 4890 (1950); (b) A. Deeb,
A. Essawy, A. M. El-Gendy, and A. Shaban, Monatshefte fur Chemie, 121, 281 (1990).
[12] P. J. Spendley and J. P. Ride, Mycol. Soc., 82, 283 (1984).