Pyridazine derivatives and related compounds part 24.1 synthesis and antimicrobial activity of some sulfamoylpyrazolo[3,4-c]pyridazine derivatives

Article abstract of DOI:10.1080/10426500701242871

A series of new sulfamoylpyrazolo[3,4-c]pyridazine derivatives was synthesized. Some of these compounds show interesting antimicrobial activity. Copyright Taylor and Francis Group, LLC.

Full text of DOI:10.1080/10426500701242871

This article was downloaded by: [York University Libraries]
On: 24 September 2013, At: 09:06
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Phosphorus, Sulfur, and Silicon
and the Related Elements
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Pyridazine Derivatives
and Related Compounds
Part 24. Synthesis and
Antimicrobial Activity of
Some Sulfamoylpyrazolo[3,4-
c]pyridazine Derivatives
Mona Hosny a , Fatma El-Mariah 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
Published online: 07 Jun 2007.
To cite this article: Mona Hosny , Fatma El-Mariah & Ali Deeb (2007) Pyridazine
Derivatives and Related Compounds Part 24. Synthesis and Antimicrobial Activity of
Some Sulfamoylpyrazolo[3,4-c]pyridazine Derivatives, Phosphorus, Sulfur, and Silicon
and the Related Elements, 182:7, 1475-1482, DOI: 10.1080/10426500701242871
To link to this article: http://dx.doi.org/10.1080/10426500701242871
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and

are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur, and Silicon, 182:1475–1482, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701242871
Pyridazine Derivatives and Related Compounds Part 24.1
Synthesis and Antimicrobial Activity of Some
Sulfamoylpyrazolo[3,4-c]pyridazine Derivatives
Mona Hosny
Fatma El-Mariah
Department of Chemistry, Faculty of Girls, Ain Shams University,
Cairo, Egypt
Ali Deeb
Department of Chemistry, Faculty of Science, Zagazig University,
Zagazig, Egypt
A series of new sulfamoylpyrazolo[3,4-c]pyridazine derivatives was synthesized.
Some of these compounds show interesting antimicrobial activity.
Keywords 3-substituted sulfamoylpyrazolo[3,4-c]pyridazine; antimicrobial activity
INTRODUCTION
During the last years, we have been interested in the synthesis of
substituted heterocycles containing the pyrazolo[3,4-c]pyridazine sys-
tem with the aim of finding compounds with promising biological
activities.2−5
On the other hand, the sulfonamides group forms the bioactive
moiety of many compounds with therapeutical interest, such as an-
tibacterials, diuretics, antidiabetics, and antibiotics.6 In this arti-
cle, we report the preparations and structural confirmations of 3-
sulfamoylpyrazolo[3,4-c]pyridazine derivatives, and reported the an-
timicrobial activity of these compounds against some gram (positive)
and gram (negative) bacteria, Candida albicans, and Aspergillus niger.
Received September 11, 2006; accepted December 4, 2006.
The author acknowledges the help of Dr. Gamal El-Sherbeny Department of Microbi-
ology, Faculty of Science, El-Azhar University, Cairo, for carrying out the antimicrobial
activity.
Address correspondence to Ali Deeb, Department of Chemistry, Faculty of Science,
Zagazig University, Zagazig, Egypt. E-mail: dralideeb@hotmail.com
1475

1476
M. Hosny et al.
The precursor 3-diazo-4,5-diphenylpyrazolo[3,4-c]pyridazine 1 was
synthesized following the literature procedure by diazotization of 3-
amino-4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine with sodium nitrite
in glacial acetic acid at room temperature.7
The thiation of 3-diazo derivative 1 using thiourea in absolute
ethanol resulted in the formation of thiouronium derivative, which on
hydrolysis with 2 N sodium hydroxide followed by acidification with hy-
drochloric acid (pH 2), gave 3-mercapto-4,5-diphenyl-1H-pyrazolo[3,4-
c]pyridazine 2 in a 90% of yield. Compound 2 was used as a starting
material in the synthesis of the target heterocycles. Thus when 2 was
treated with chlorine gas in presence of 90% acetic acid at 0◦C the cor-
responding sulfonyl chloride 3 was obtained.
Because of the instability of the sulfonyl chloride 3, the crude product
was usually converted directly to the more stable sulfonamides by ami-
dation. In this manner, a number of new derivatives of sulfonamides
have been prepared (Scheme 1). Treatment with aqueous ammonia
yielded the sulfonamide, and the reaction with hydrazine hydrate gave
the sulfonhydrazide derivatives 4a,b, respectively, in good yields.
On the other hand, aliphatic amines such as methyl, n-propyl, i-
butyl, and benzyl amines reacted with 3 in refluxing benzene to fur-
nish the respective 3-alkanesulfamoyl-4,5-diphenyl-1H-pyrazolo[3,4-
c]pyridazine 4c–f. Likewise, reaction of sulfonyl chloride 3 with
aromatic amines such as aniline, anthranilic acid, p-aminobenzic
acid, p-anisidine, p-toluidine, p-chloroaniline, sulfanilic acid, and 1-
naphthylamine resulted in the formation of 3-arenesulfamoyl deriva-
tives 4g–n.
It was of considerable interest to study the reaction of compound
3 with glycine as a possible new route to design a tricyclic compound
containing a thiadiazine-1,1-dioxide ring. The reaction was carried out
in boiling benzene afforded 3-carboxymethylsulfamoyl derivative 4o.
An attempt to cyclize the acid 4o was unsuccessful. Further attempts
to carry out the cyclization under modified conditions, and on extension
of the synthetic scope of these reactions are under study.
The structural formulas of all newly synthesized compounds were
confirmed by elemental and spectroscopic analyses (c.f., Experimental
section).
Screening for Antimicrobial Activities
Applying the agar plate diffusion technique,8 the newly synthesized
compounds were screened in vitro for antimicrobial activity against rep-
resentative of gram positive bacteria (Bacillus subtilis and Staphylococ-
cus aureus), gram negative bacteria (Escherichia coli and Pseudomonas

Sulfamoylpyrazolo Pyridazine Derivatives
1477
SCHEME 1
aeruginosa), yeast (Candida albicans), and fungi (Asperggillus niger).
In this method, a standard 5 mm diameter sterilized filter paper disc
impregnated with the compound (0.3 mg/0.1 mL of dimethylformamide)
was placed on an agar plate seeded with the test organism. The plates
were incubated for 24 h at 37oC. The zone of inhibition of bacterial
growth around the disc was observed. The screening results given in
Table 1 indicated that all the compounds exhibited antimicrobial activ-
ity against all the test organisms.

1478
M. Hosny et al.
TABLE I Antibacterial and Antifungal Activity
Bacillus
subtitils
Staph.
Aureus
Pseud.
aeurgin
Candida
albicans
Asp.
Niger
No.
Esch. Coli
2
3
+ + +
+ + +
+ + +
++
+ + +
+ + +
++
++
++
−
++
++
−
++
++
−
−
−
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
Cipr
Nys
++
++
++
++
++
++
++
++
−
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
−
++
++
++
++
++
−
+
++
++
++
++
++
++
++
++
++
++
++
++
++
++
−
+ + +
+ + +
+ + +
++
++
++
++
++
−
+ + +
++
−
−
++
++
++
++
++
++
++
++
+ + +
−
++
++
++
++
++
++
++
+ + +
−
++
++
++
−
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
−
++
++
++
−
+ + +
−
Zone of inhibition : ++ = 15–20 mm; + + + = 25–30 mm; − = negative inhibition.
Most of the synthesized compounds showed a remarkable activity
against gram positive bacteria and less active against gram negative,
as well as yeast and fungi.
From these results, we can conclude that the biologically active com-
pounds 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. The IR spectra of the compounds were recorded on a Perkin-
Elmer spectrophotometer model 1430 as potassium bromide pellets.
The mass spectra were recorded on a mass spectrometer HP model MS
5988 E1 70 ev. Reactions were routinely followed by thin layer chro-
matography (tlc) on silica gel F254 aluminum sheets (Merck). The spots
were detected by uv irradiation at 254–365 nm.
Compound 1 was synthesized as reported previously.7
2-Mercapto-4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine 2
To a solution of 3-diazo-4,5-diphenylpyrazolo[3,4-c]pyridazine 1 (1.0 g,
3.35 mmoles) in ethanol (20 mL), thiourea (0.3 g, 3.44 mmoles) was

Sulfamoylpyrazolo Pyridazine Derivatives
1479
added. The reaction mixture was refluxed for 3 h. The solvent was evap-
orated under reduced pressure, and the residue was treated with 2N
sodium hydroxide (20 mL). The mixture was refluxed for 15 min, fil-
tered on hot, and the cooled filtrate was treated with 3N hydrochloric
acid (pH = 6). The precipitate was filtered off, washed with water, dried,
and recrystallized from ethanol to give 2, yield 0.9 g (88.2%), m.p. 260–
261◦C; IR: 3150 (NH), 3059 (CHarom.), 2400 (SH), 1620 (C N) cm−1
;
MS, m/z (%): 305 (M++ 1, 29), 304 (M+, 55), 303 (M+- H, 100), 271 (M+-
SH, 21, ion A), 245 (M+- C( N)SH, 10). Anal. Calcd. for C17H12N4S: C,
67.08; H, 3.98; N, 18.41. Found: C, 66.80; H, 3.80; N, 18.20.
4,5-Diphenyl-1H-pyrazolo[3,4-c]pyridazine-3-
sulfonylchloride 3
In a solution of 3-mercapto, derivative 2 (1.0 g, 3.28 mmoles) in acetic
acid (9 mL) and water (1 mL), chlorine gas was bubbled at 0oC. After
1 h, the precipitate was filtered, washed with water several times, and
dried to give 3-sulfonylchloride derivative 3, 0.9 g (74.4%).
4,5-Diphenyl-1H-pyrazolo[3,4-c]pyridazine-3-sulfonamide 4a
The sulfonylchloride 3 (1.0 g, 2.69 mmoles) was added to conc. ammo-
nium hydroxide (20 mL). The reaction mixture was heated on a steam
bath for 4 h; the volume was reduced to its half and neutralized with
6 N HCl to give a solid product. The solid product was filtered, washed
with water, dried, and recrystallized from ethanol to give 4a, yield 0.9
g (94.7%), m.p. 265–266◦C; IR: 3249 (NH2), 3150 (NH), 3055 (CHarom.),
1302, 1163 (SO2) cm−1; 1H-NMR (DMSO-d6): δ 14.5 (s, 1H, NH), 7.5 (s,
2H, NH2) and 7.3 (s, 10H, 2Ph); MS, m/z (%): 351 (M+,1.4), 271 (M+
-SO2NH2, 12.8). Anal. Calcd. for C17H13N5O2S: C, 58.11; H, 3.73; N,
19.93. Found: C, 57.80; H, 3.60; N, 19.80.
4,5-Diphenyl-1H-pyrazolo[3,4-c]pyridazine-3-
sulfohydrazide 4b
To a solution of sulfonylchloride 3 (1.0 g, 2.69 mmoles) in benzene (20
mL), hydrazine hydrate (0.5 mL, 80%) was added. The reaction mixture
was heated under reflux for 3 h. The solvent was evaporated under
reduced pressure. The residue was triturated with water, filtered, dried,
and recrystallized from ethanol to give 4b, yield 0.95 g (96.1%), m.p.
260–261◦C; IR: 3400 (br, NH2), 3149 (NH), 3056 (CHarom.), 1303, 1163
1
(SO2) cm−1; H-NMR (DMSO-d6): δ 14.95 (s, 1H, pyrazole NH), 8.4 (s,
1H, NHNH2), 7.2–7.3 (m, 10H, 2Ph), 4.1 (br s, 2H, NH2); MS m/z (%):

1480
M. Hosny et al.
368 (M++ 2, 2.2), 367 (M++ 1, 1.8), 271 (M+ - SO2NHNH2, 63). Anal.
Calcd. for C17H14N6O2S: C, 55.72; H, 3.85; N, 22.94. Found: C, 55.50;
H, 3.60; N, 22.70.
3-Substituted sulfamoyl-4,5-diphenyl-1H-pyrazolo-
[3,4-c]pyridazines 4c-o
General Procedure
To a solution of sulfonylchloride derivative 3 (1.0 g, 2.69 mmoles) in
benzene (20 mL), substituted amines (3.0 mmoles) was added. The re-
action mixture was heated under reflux for 3 h. The solvent was concen-
trated. The solid product was collected and recrystallized from ethanol.
4c (R = Me): Mp 240–241◦C; yield 96.9%; 3250, 3141 (NH groups),
IR: 3055 (CHarom.), 2967 (CHaliph.), 1653 (C N), 1302, 1163 (SO2); MS
m/z (%): 365 (M+, 1.5), 271 (M+ - SO2NHCH3, 69). Anal. Calcd. for
C18H15N5O2S: C, 59.16; H, 4.14; N, 19.17. Found: C, 58.90; H, 4.00; N,
18.90.
4d (R = n-Pr): Mp 260–261◦C; yield 84.9%; IR: 3300, 3139 (NH
groups), 3056 (CHarom.), 2941 (CHaliph.), 1640 (C N), 1303, 1164 (SO2)
cm−1. MS m/z (%): 393 (M+, 0.08), 350 (M+ - CH2CH2CH3, 0.09),
335 (M+- NHPr, 0.08), 271 (M+ - SO2NHPr, 7.8). Anal. Calcd. for
C20H19N5O2S: C, 61.05; H, 4.87; N, 17.80. Found: C, 60.80; H, 4.60;
N, 17.50.
4e (R = i-Bu): Mp 195-196◦C; yield 77.98%; IR: 3200, 3150 (NH
groups), 3058 (CHarom.), 2961 (CHaliph.), 1679 (C N), 1313, 1166 (SO2)
cm−1; 1H-NMR (DMSO-d6): δ 14.9 (s, 1H, pyrazol-NH), 7.6 (s, 1H, NH),
7.4–7.3 (m, 10H, 2Ph), 2.7 (t, 2H, CH2), 1.9–1.7 (m, 1H, CH), 0.9 (d,
6H, 2CH3). Anal. Calcd. for C21H21N5O2S: C, 61.89; H, 5.19; N, 17.19.
Found: C, 61.70; H, 5.00; N, 16.90.
4f (R = Bn): Mp 204–205◦C, yield 67.2%; IR: 3200, 3100 (NH groups),
3058 (CHarom.), 2966 (CHaliph.), 1640 (C N), 1356, 1162 (SO2) cm−1
;
1H-NMR (DMSO-d6): δ 15 (s, 1H, pyrazol NH), 7.4 (s, 1H, NH), 7.3–
7.2 (m, 15H, 3Ph), 3.4 (d, 2H, CH2); MS m/z (%): 441 (M+, 8), 335
(M+- PhCH2NH), 271 (M+ - PhCH2NHSO2, 40), 91 (PhCH2, 100). Anal.
Calcd. for C24H19N5O2S: C, 65.29; H, 4.34; N, 15.86. Found: C, 65.00;
H, 4.10; N, 15.60.
4g (R = Ph): MP 115–116◦C, yield 82.6%; IR : 3500 (NH), 3110 (NH),
1
3054 (CHarom.), 1627 (C N), 1360, 1162 (SO2); H-NMR (DMSO-d6): δ
7.4–7.1 (m, 15m, 3Ph), 6.8 (d, 1H, NH); MS m/z (%): 427 (M+, 9.9), 271
(M+ - PhNHSO2, 12). Anal. Calcd. for C23H17N5O2S: C, 64.62; H, 4.01;
N, 16.38. Found: C, 64.40; H, 3.90; N, 16.10.
4h (R = C6H4CO2H (o-)): Mp 210–211◦C, yield 66.9%; IR: 3422 (OH),
3200, 3158 (NH groups), 3059 (CHarom.), 1652 (C N), 1368, 1120 (SO2);

Sulfamoylpyrazolo Pyridazine Derivatives
1481
MS m/z (%): 475 (M+ - 4, 10), 354 (M+ - C6H4COOH, 1.9). Anal. Calcd.
for C24H17N5O4S: C, 61.13; H, 3.63; N, 14.85. Found: C, 60.90; H, 3.50;
N, 14.70.
4i (R = C6H4CO2H (p-)): Mp 240–241◦C; yield 74.8%; IR: 3500 (OH),
3200, 3150 (NH groups), 3056 (CHarom.), 1702 (C O), 1606 (C N), 1337,
1165 (SO2); MS m/z (%): 471 (M+, 0.4), 334 (M+ - NHC6H4COOH, 0.4).
Anal. Calcd. for C24H17N5O4S: C, 61.13; H, 3.63; N, 14.85. Found: C,
61.00; H, 3.50; N, 14.60.
4j (R = C6H4OMe (p-)): Mp 200–201◦C, yield 77.23%; IR: 3210, 3150
(NH groups), 3056 (CHarom.), 2838 (CHaliph.), 1509 (OCH3), 1361, 1121
1
(SO2); H NMR (DMSO-d6): δ 14.9 (s, 1H, pyrazol−NH), 6.79 (s, 1H,
NH), 7.40–7.14 (m, 14H, phenyl protons), 2.51 (s, 3H, OCH3); MS m/z
(%): 457 (M+, 1.5), 427 [M++ 1 – OCH3, 0.2 (ion A)], 350 [ion A–C6H4,
0.5 (ion B)], 336 [ion B–NH, 0.2 (ion C)], 305 [ion C–O2, 100 (ion D)],
271 [ion D – S, 22.9]. Anal. Calcd. for C24H19N5O3S: C, 63.00; H, 4.18;
N, 15.31. Found: C, 62.80; H, 4.00; N, 15.00.
4k (R = C6H4Me (p-)), Mp 210–211◦C, yield 75.6%; IR: 3300, 3150
(NH groups), 3056 (CHarom.), 2919 (CHaliph.), 1620 (C N), 1361, 1164
(SO2). Anal. Calcd. for C24H19N5O2S: C, 65.29; H, 4.34; N, 15.86. Found:
C, 65.00; H, 4.10; N, 15.60.
4l (R = C6H4Cl (p-)), Mp 180–181◦C, yield 68.5%; IR: 3300, 3100 (NH
groups), 3056 (CHarom.), 2967 (CHaliph.), 1621 (C N), 1303, 1162 (SO2);
1H NMR (DMSO-d6): δ 14.6 (s, 1H, pyrazol NH), 7.4–7.3 (m, 14H, phenyl
protons), 7.1 (s, 1H, NH); MS m/z (%): 461 (M+, 0.58), 349 (M+ - C6H4Cl,
0.2), 335 (M+ - NHC6H4Cl, 0.37), 271 (M+ - SO2NHC6H4Cl, 28). Anal.
Calcd. for C23H16ClN5O2S: C, 59.80; H, 3.49; N, 15.16. Found: C, 59.60;
H, 3.20; N, 15.00.
4m (R = C6H4SO3H (p-)): Mp 210–211◦C, yield 73.1%; IR: 3400, 3147
1
(NH groups), 3058 (CHarom.), 1654 (C N), 1366, 1120 (SO2); H NMR
(DMSO-d6): δ 14.97 (s, 1H, pyrazol NH), 7.6–7.2 (m, 14H, phenyl pro-
tons), 6.4 (br s, 1H, NH); MS m/z (%): 409 (M++ 2, 0.07), 507 (M+,
0.06), 350 (M+ - HO3SC6H4, 0.18), 335 (M+ - HO3SC6H4NH, 0.15), 303
(M+ - HO3SC6H4NHO2, 0.21), 271 (M+ - HO3SC6H4NHSO2, 100). Anal.
Calcd. for C23H17N5O5S2: C, 54.43; H, 3.38; N, 13.80. Found: C, 54.20;
H, 3.10; N, 13.60.
4n (R = 1-Naphthyl), Mp 198–199◦C, yield 62.2%; IR: 3400, 3200
(NH groups), 3056 (CHarom.), 1363, 1162 (SO2); MS m/z (%): 478 (M++ 1,
0.59), 477 (M+, 1.37), 350 (M+ - naphthyl, 1.46), 335 (M+ - HN-naphthyl,
0.5), 271 (M+ - SO2NH-naphthyl, 87.8). Anal. Calcd. for C27H19N5O2S:
C, 67.91; H, 4.01; N, 14.67. Found: C, 67.70; H, 3.90; N, 14.40.
4o (R = CH2COOH), Mp 220–221◦C, yield 67.6%; IR: 3400, 3100
(NH groups), 3057 (CHarom.), 2921 (CHaliph.), 1655 (C=O), 1366, 1118
(SO2); MS m/z (%): 409 (M+, 0.05), 350 (M+- CH2COOH, 0.13), 335

1482
M. Hosny et al.
(M+- HNCH2COOH, 0.17), 271 (M+- SO2HNCH2COOH, 46.3), 270 (M+-
SO2HNCH2COOH, H, 100). Anal. Calcd. for C19H15N5O4S: C, 55.74; H,
3.69; N, 17.11. Found: C, 55.50; H, 3.40; N, 17.00.
REFERENCES
[1] Part 23: A. Deeb, F. Yasine, N. Auef, and W. Shehta, Dyes & Pigments, in press.
[2] A. Deeb and M. Kotb, Heterocycles, 63, 1143 (2004).
[3] A. Deeb, F. El-Mariah, and M. Hosny, Bioorg. Med. Chem. Lett., 14, 15013 (2004).
[4] A. Amer, M. Zayed, A. Deeb, and A. Ali, J. Chem. Res., 643 (2005).
[5] F. El-Mariah, M. Hosny, and A. Deeb, Phosphorus, Sulfur, and Silicon, 181, 809
(2006).
[6] (a) Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, (Wiley,
New York, 1977), Vol. 1, pp. 120; (b) Lednicer and L. A. Mitscher, The Organic Chem-
istry of Drug Synthesis, (Wiley, New York, 1980), Vol. 2, pp. 112; (c) Lednicer and L.
A. Mitscher, The Organic Chemistry of Drug Synthesis (Wiley, New York, 1984), Vol.
3, pp. 61.
[7] A. Deeb, B. Bayoumy, A. Hataba, and R. Fikry, Heterocycles, 32, 901 (1991).
[8] A. W. Bauer, W. W. Mkriby, J. C. Scherris, and M. Turck, Am. J. Clin. Pathol. 45, 493
(1966).