Studies with 2-(acetonylthio)benzothiazole: Novel synthesis of pyridazin-6(1H)-one, pyridazin-6(1H)-imine, and phthalazine derivatives of antimicrobial and antifungal activities

Article abstract of DOI:10.1002/jhet.527

A novel series of (Z)-1-(arylhydrazono)-1-(benzothiazol-2′-ylthio) propan-2-ones have been prepared and their utility as building blocks in the synthesis of novel derivatives of Pyridazin-6(1H)-ones, pyridazin-6(1H)-imines, and phthalazine incorporating a

Full text of DOI:10.1002/jhet.527

March 2011
Studies with 2-(Acetonylthio)benzothiazole: Novel Synthesis of
Pyridazin-6(1H)-one, Pyridazin-6(1H)-imine, and Phthalazine
Derivatives of Antimicrobial and Antifungal Activities
241
Fatima A. Al-Omran* and Adel A. El-Khair
Department of Chemistry, Faculty of Science, Kuwait University, 13060 Safat, Kuwait
*E-mail: fatima.alomran@ku.edu.kw
Received January 31, 2010
DOI 10.1002/jhet.527
Published online 27 October 2010 in Wiley Online Library (wileyonlinelibrary.com).
A novel series of (Z)-1-(arylhydrazono)-1-(benzothiazol-20-ylthio)propan-2-ones have been prepared
and their utility as building blocks in the synthesis of novel derivatives of Pyridazin-6(1H)-ones, pyrida-
zin-6(1H)-imines, and phthalazine incorporating a benzothiazole residue are investigated. All of the title
1
compounds were confirmed by elemental analysis, IR, H NMR, 13C NMR, NOE, and mass spectrome-
try. The synthesized compounds are screened for their antibacterial as well as antifungal activity. All
the tested compounds showed high to moderate activity against the selected microorganisms.
J. Heterocyclic Chem., 48, 241 (2011).
INRODUCTION
RESULT AND DISCUSSION
Aryl hydrazones are highly reactive intermediates in
organic synthesis. They are extensively used for the syn-
thesis of functionalized pyridazines [1–6]. Several publi-
cations have pointed out that pyridazines exhibit a wide
spectrum of the biological activities and pharmacologi-
cal properties, such as reduction of the blood pressure
[7], analgesic [8], anti-inflammatory [9], antibacterial,
and anticonvulsant [10]. On the other hand, 2–mercapto-
benzothiazole and its derivatives have also been reported
to have potent biological activities, such as antimicoba-
terial activity [11] and cyclooxygenase inhibitors [12].
As part of our recent research programmed dealing
with synthesis of heterocyclic system, particularly those
The key intermediates (Z)-1-(arylhydrazono)-1-(ben-
zothiazol-20-ylthio)propan-2-one (3a–c) are prepared in
excellent yield according to known method [3] by cou-
pling of 1-(benzothiazol-20-ylthio)propan-2-one 1 [13]
with aryl diazonium salts 2a–d in ethanoic sodium hy-
droxide solution. The reaction carried out at 0 to 5ꢀC
with relatively long reaction time of 2 h. The color of
hydrazones 3a–d range from red to yellow in excellent
yield. The structures of S-alkylated hydrazones 3a–d
were deduced from their elemental analysis and spectra
data. The mass spectrum of 3a revealed a molecular ion
peaks with m/z 327 (Mþ). The structure of hydrazone 3
was assigned as nonhydrogen bonded (Z)-conformation
basis on their IR spectra of 3a–d. It was believed that
due to the resonance effect involving the delocalization
of the hydrazone lone pair of electrons to the carbonyl
group created a delicate balance between the structures
3 and 4. This effect increases the carbonyl bond length
and reduces the frequencies of absorption at mmax about
1690 cmꢁ1. It is considered lower than the isolated car-
bonyl group in compound 1, which revealed carbonyl
containing
a 2–mercaptobenzothiazole moiety [13].
It is thought of interest to accommodate 2–mercaptoben-
zothiazole with pyridazin-6(1H)one, or pyridazin-
6(1H)imine or phthalazine moieties in one single molec-
ular framework by using hitherto unreported (Z)-1-(aryl-
hydrazono)-1-(benzothiazol-20-ylthio)propan-2-one
(3)
and screen them for antibacterial as well as antifungal
activity.
C
V
2010 HeteroCorporation

242
F. A. Al-Omran and A. A. El-Khair
Vol 48
Scheme 1
stretching band at mmax1720 cmꢁ1 [13]. Under the influ-
ence of both the conjugated C¼¼N group and hydrogen
bonding, one might expected the absorption of carbonyl
group should be lower frequency at mmax about 1625
cmꢁ1 for the (E)-conformer. Moreover, the 13C NMR
spectra show a larger downfield shift of carbonyl signal
dc 189 ppm for the (Z)-conformation. The 1H NMR
spectra of 3a–d showed, in addition to an aromatic mul-
tiple, singlet signals for methyl at dH 2.32 ppm and NH
hydrazone’s which appears at low field signals at dH
about. 13.75 ppm. The latter signal underwent ready H/
D exchange upon addition of deuterium oxide. If the
product is (E)–conformer, one would expected that NH-
hydrazone proton appear at higher field. Firm evidence
of this conclusion was obtained from nuclear Over-
hauser effect (NOE) experiments for 3d; on irradiating
the methyl proton at dH 2.32 ppm has no effect on aro-
matic and NH protons (Scheme 1).
The reactivity of (Z)-S-alkylated hydrazones 3a–d
toward methylene carbonitriles was investigated. Treat-
ment of compounds 3a–d with malononitrile in refluxing
ethanol and the presence of a catalytic amount of
piperidine afforded in each case the corresponding pyri-
dazin-6(1H)-one (7a–b) and pyridazin-6(1H)-imine (7c–
d) derivatives in excellent yield. The structures of the
isolated products 7a–d were confirmed on the basis of
their elemental analysis and spectral data. The mass
spectrum of 7c revealed a molecular ion peak with m/z
405. The IR spectra of 7a–d showed, a strong absorp-
tion band at mmax about 2205cmꢁ1 corresponding to
nitrile functional group. The absence of carbonyl ketone
group absorption in their IR spectra indicates that car-
1
bonyl ketone group is involved in the reaction. The H
NMR spectra also indicated the disappearance of hydra-
zone NH proton. Moreover, 13C NMR spectra for 7a–b
and 7c–d revealed highest frequency signal at dc about
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011 Studies with 2-(Acetonylthio)benzothiazole: Novel Synthesis of Pyridazin-6(1H)-one,
Pyridazin-6(1H)-imine, and Phthalazine Derivatives of Antimicrobial and Antifungal Activities
243
Scheme 2
164 and 155 ppm assignable to the amide carbonyl and
imine carbons, respectively. The formation of compound
7 is considered most likely based on its similarity to
well established behavior, which was assumed to pro-
ceed via condensation of malononitrile with carbonyl
group hydrazone via formation of intermediate 6 and
subsequence cyclization into pyridazine derivatives 7 [4]
(cf. Scheme 2).
reported [3,14]. The mass spectrum of compound 10
revealed a molecular ion peak with m/z 559 (Mþ-HCl).
1
The H NMR spectrum of tetrahydrophthalazine deriva-
tive 10 was revealed the presence of both NH2 and NH
groups, which readily underwent H/D exchange upon
addition of deuterium oxide. However, the absence of
1
methyl singlet dH 2.39 ppm in the H NMR spectrum
indicate that methyl group in pyridazin-6-(1H)-imine 7c
is involved in the reaction. Moreover, the 13C NMR
spectrum for 10 is characterized by two signals at dC
113.2 and 114.2 ppm corresponding to the two CN
groups. In addition two lowest frequency signals at dC
25.0 and 38.9 ppm corresponding to the two sp3 carbon.
The signal at dC 25.0 corresponding to the carbon
coupled with proton (C-7). The formation of 10 is con-
sidered most likely based on its similarity to well estab-
lished behavior, which was assumed to proceed via ini-
tial Michael addition of the methyl group under basic
condition in compound 7c to an activated double bond
in benzylidenemalononitrile via formation of intermedi-
ate 9 and subsequence cyclization to form adduct 10.
The formed adduct did not aromatize by losing
Treatment of S-alkylated hydrazone 3d with acetyl ac-
etone in pyridine under reflux gives the 1,2-dihydropyri-
dazine 8 in good yield. The structure of 1,2-dihydropyri-
dazine 8 was confirmed on the basis of elemental analysis
and spectral data. The 13C NMR spectrum of the reaction
product revealed highest frequency signal at dc 198.8
ppm assignable to the an acetyl carbon and three signals
at lower frequency at dc 25.0, 27.1, and 29.8 ppm corre-
1
sponding three methyl groups. Moreover, the H NMR
spectrum revealed the presence of one D2O exchangeable
proton attributed to the NH function at dH 8.24 ppm.
On the other hand, treatment of 7c with benzylidene-
malonitrile in refluxing pyridine afforded tetrahydroph-
thalazine derivative 10 similar to that which have been
Journal of Heterocyclic Chemistry
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244
F. A. Al-Omran and A. A. El-Khair
Vol 48
Scheme 3
hydrogen cyanide. Perhaps in this case, 10 is more sta-
ble than the product that would be obtained by elimina-
tion of hydrogen cyanide [3,14] (cf. Scheme 3).
nals at dc 162 and 172ppm, described to ring carbonyl
and amide carbonyl groups, respectively. The formation
of the product 14 is considered most likely based on its
similarity to the well-established behaviors of hydrazones
towards hippuric acid [4,6]. This was assumed to pro-
ceed via initial cyclization of hippuric acid would gener-
ate in situ the oxazolone 12. The oxazolone condenses
with each 3a, 3c, and 3d to form the phenyl hydrazones
13. The intermediate 13 then rearrange into the pyridazi-
nones 14 via attack of nuclophilic nitrogen of hydrazone
moiety at the ring carbonyl group (cf. Scheme 4).
Treatment of each of the (Z)-S-alkylated hydrazones
3a, 3c, and 3d with hippuric acid in refluxing acetic an-
hydride afforded color crystalline products identified as
1-aryl-5-benzamido-(3-benzothiazol-2,-ylthio)-4-methyl-
6-oxo-1,6-dihydropyridazine hydrochloride 14a–c on
the basis of spectral data (Scheme 4). The mass spec-
trum of 14c reveals a molecular ion peak at m/z
515(Mþ-HCl). The H1 NMR spectra of compounds
14a–c were free from the hydrazone NH proton of 3 at
dH 13.75 ppm. The spectra revealed the presence of
D2O exchangeable proton attributed to the NH function
of benzamido group at dH 8.05 ppm. Also, it revealed,
in addition to aromatic signals, one up field signal at dH
about 2.23 ppm corresponding to methyl group. More-
over, 13C NMR spectra revealed highest frequency sig-
BIOLOGICAL ACTIVITY
The biological activities of some newly synthesized
compounds were screened for their antifungal activity
against Aspergillus niger and Penicillium digitatum,
whereas the antibacterial activity was tested against
Journal of Heterocyclic Chemistry
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March 2011 Studies with 2-(Acetonylthio)benzothiazole: Novel Synthesis of Pyridazin-6(1H)-one,
Pyridazin-6(1H)-imine, and Phthalazine Derivatives of Antimicrobial and Antifungal Activities
245
Scheme 4
were performed on a Vario Micro Cube. Abbreviation: Ac2O
¼ acetic anhydride, EtOH ¼ ethanol, DMF ¼ N,N-dimethyl-
formamide, DMSO-d6 ¼ dimethyl-d6-sulfoxide, TMS ¼ tetra-
methylsilane, CDCl3 ¼ deuteriochloroform.
Escherichia coli, Bacillus subtilis, and Staphylococcus
aureus. Most of the tested sample showed strongly anti-
bacterial and fungicidal activity (Table 1).
General procedure for synthesis of 3a–d. A cold solution
of p-aryl diazonium chloride 2a–d (10 mmoles) was prepared
by adding of a solution sodium nitrite (0.69 g into 3 mL H2O)
to a cold solution of aryl amine 2a–d (10 mmoles in 3 mL
HCl) with stirring as described earlier [3]. The result of solu-
tion of the aryl diazonium salt was then added to cold of 1
(2.23 g, 10 mmoles) in EtOH (100 mL) containing sodium hy-
droxide (0.20 g, 10 mmoles). The mixture was stirred at 5ꢀC
for 2 h. The solid products, so formed, were collected by filtra-
tion and recrystallised from EtOH.
EXPERIMENTAL
All melting points are uncorrected. The IR spectra (KBr)
were recorded on a Jasco FT/IR-6300. 1H, 13C NMR spectra
and NOE experimenter were recorded on a Brucker 400 MHz
spectrometer in DMSO–d6 or CDCl3 as solvent using TMS as
an internal standard, chemical shifts are reported as d unit
(ppm)and TMS ¼ 0.00 ppm. Mass spectra were measured on
GC/MS INCOL XL Finnegan MAT instrument. Microanalyses
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F. A. Al-Omran and A. A. El-Khair
Vol 48
Table 1
In vitro antimicrobial and fungicidal activity of some newly synthesized compounds.
Compound
Escherichia coli
Bacillus subtilis
Staphylococcus aureus
Aspergillus niger
Penicillium sp
3d
7a
7b
8
10
14c
þ
ꢁ
þ
NT
þþ
ꢁ
ꢁ
þ
ꢁ
þ
ꢁ
ꢁ
ꢁ
þþþ
þþþ
ꢁ
þþþ
þþ
ꢁ
þþ
þ
þþþ
þþþ
ꢁ
þþþ
ꢁ
þþþ
ꢁ
ꢁ
NT
Inactive ¼ ꢁ(no inhibition zone); slightly active ¼ þ(inhibition zone 7.5–9.0 mm); moderately active ¼ þþ(inhibition zone active 9.5–11.0 mm);
highly active ¼ þþþ(inhibition zone 11–17.5 mm); TN, not tested.
(Z)-1-(Benzothiazol-20-ylthio)-1-(phenylhydrazono)propan-2-
one (3a). Compound 3a was obtained as orange crystal, 2.32g
malononitrile (0.66 g, 10 mmoles) and 2–3 drops of piperidine
were added. The reaction was refluxed for 1 h, left to cool at
room temperature, then poured onto ice-cold water and acidify
with 10% HCl. The solid product, so formed, was collected by
filtration and recrystallized from the EtOH.
(71%), mp. 191–192ꢀC. IR: m 3429 (NH), 1686 (C¼¼O) cmꢁ1
;
1H NMR (DMSO–d6): d 2.32 (s, 3H, CH3), 7.12–8.00 (m, 9H,
aromatic and benzothiazole protons), 13.81 (br.s, 1H, NH,
D2O exchangeable) ppm; 13C NMR (DMSO–d6): d 25.0
(CH3), 115.3, 118.3, 121.8, 121.9, 124.2, 125.4, 129.4, 134.8,
141.3, 148.3, 152.5, 156.8 (aromatic and benzothiazole car-
bons), 189.8 (C¼¼O) ppm; ms: m/z 327(Mþ). Anal. Calcd. for
C16H13N3OS2 (327.42): C, 58.69; H, 4.00; N, 12.83. Found: C,
58.73; H, 4.00; N, 12.780.
3-(Benzothiazol-20-ylthio)-4-methyl-6-oxo-1-phenyl-1,6-dihy-
dropyridazine-5-carbonitrile (7a). Compound 7a was obtained
as pale brown crystal, 3.04 g (81%), mp. 96–98ꢀC. IR: m 1621
1
(ring C¼¼O), 2207(CN) cmꢁ1; H NMR (DMSO-d6): d 2.28 (s,
3H, CH3), 6.83–7.89 (m, 9H, aromatic and benzothiazole pro-
tons) ppm; 13C NMR (DMSO-d6): d 24.9 (CH3), 115.9, 119.6,
121.0, 122.1, 122.9, 124.2, 125.5, 125.7, 130.0, 135.6, 148.2,
152.4, 154.6, 156.9, 158.6 (aromatic, benzothiazole carbons
and CN), 162.3 (ring C¼¼O) ppm. Anal. Calcd. for
C19H12N4OS2 (376.45): C, 60.62; H, 3.21; N, 14.88. Found: C
60.38, H, 3.13; N, 14.65.
(Z)-1-(Benzothiazol-2 -ylthio)-1-(p-methylphenylhydrazono)
propan-2-one (3b). Compound 3b was obtained as red crystal,
2.48 g (73%), mp.107–109ꢀC. IR: m 3439 (NH), 1684 (C¼¼O)
1
cmꢁ1; H NMR (CDCl3) :d 2.39 (s, 3H, p-CH3), 2.55 (s, 3H,
CH3), 6.94–7.83 (m, 8H, aromatic and benzothiazole protons),
13.77 (br.s, 1H, NH, D2O exchangeable) ppm; 13C
NMR(DMSO-d6): d 18.0 (p-CH3), 25.0 (CH3), 118.4, 121.8,
121.9, 124.4, 125.8, 128.3, 129.4, 135.9, 140.3, 148.1, 152.6,
157.7(aromatic and benzothiazole carbons), 189.2 (C¼¼O)
ppm; ms: m/z 341 (Mþ). Anal. Calcd. for C17H15N3OS2
(341.45): C, 59.79; H 4.42 ; N 12.30. Found: C 59.68; H,
4.68; N, 12.48.
3-(Benzothiazol-20-ylthio)-4-methyl-1-(p-methylphenyl)-6-oxo-
1,6-dihydropyridazine-5-carbonitrile hydrochloride (7b). Compound
7b was obtained as brown crystal, 3.23 g (76ꢁ%1), mp. 84–
86ꢀC. IR: m 1631 (ring C¼¼O), 2204 (CN) cm
;
1H NMR
(DMSO-d6): d 2.37 (s, 3H, CH3),: 2.51 (s, 3H, p-CH3), 7.26–
8.27 (m, 8H, aromatic and benzothiazole protons) ppm; 13C
NMR (DMSO-d6): d 18.0, 21.7 (2 CH3), 111.0, 115.1, 121.1,
121.4, 121.8, 124.5, 125.6, 126.4, 129.4, 130.7, 134.8, 141.3,
146.1, 152.5, 153.7 (aromatic, benzothiazole carbons and CN),
164.9 (ring C¼¼O) ppm. ms: m/z 390 (Mþ-HCl). Anal. Calcd.
for C20H15ClN4OS2 (426.94): C, 56.27; H, 3.54; N 13.12.
Found: C, 56.15; H, 3.80; N, 13.21.
(Z)-1-(Benzothiazol-20-ylthio)-1-(p-methoxyphenylhydrazono)-
propan-2-one (3c). Compound 3c was obtained as yellow crys-
tal, 2.42g (68%), mp.101–103ꢀC. IR: m 3431 (NH), 1685
1
(C¼¼O) cmꢁ1; H NMR (DMSO-d6) d: 2.53 (s, 3H, CH3), 3.81
(s, 3H, p-OCH3), 7.09–7.86 (m, 8H, aromatic & benzothiazole
protons), 13.77 (br.s, 1H, NH, D2O exchangeable) ppm; 13C
NMR (DMSO-d6): d 25.4 (CH3), 56.0 (p-OCH3), 114.6, 118.7,
125.7, 125.9, 127.6, 128.9, 131.4, 141.3, 147.1, 152.6, 157.4,
159.1 (aromatic and benzothiazole carbons), 189.8(C¼¼O)
ppm. Anal. Calcd. for C17H15N3O2S2 (357.45): C, 57.12; H,
4.22; N, 11.75. Found: C 56.90; H, 4.15; N, 11.86.
3-(Benzothiazol-20-ylthio)-6-imino-1-(p-methoxyphenyl)-4-
methyl-1,6-dihydropyridazine-5-carbonitrile (7c). Compound
7c was obtained as pale green, 3.16 g (78%), mp.120–122ꢀC.
1
IR: m 3431–3321(NH), 2206 (CN) cmꢁ1; H NMR (CDCl3): d
2.39 (s, 3H, CH3), 3.84 (s, 3H, p-OCH3), 7.00–7.91 (m, 8H,
aromatic and benzothiazole protons), 8.05 (br.s, 1H, NH, D2O
exchangeable) ppm;13C NMR (CDCl3): d 26.2 (CH3), 55.6 (p-
OCH3), 114.0, 116.2, 115.7, 117.8, 121.6, 121.9, 124.2, 126.5,
133.3, 142.2, 146.9, 148.1, 151.9, 152.8 (aromatic, benzothia-
zole carbons and CN), 154.5 (C-6), 157.4(ipso-OCH3) ppm;
ms:m/z 405 (Mþ). Anal. Calcd. for C20H15N5OS2 (405.48): C,
59.24; H 3.73; N 17.27. Found: C, 59.39; H, 4.00; N, 17.43.
3-(Benzothiazol-20-ylthio)-6-imino-4-methyl-1-(p-nitrophenyl)-
1,6-dihydropyridazine-6-carbonitrile hydrochloride (7d). Compound
7d was obtained as pale red crystal, 3.14 g (69%), mp.135–
(Z)-1-(Benzothiazol-20-ylthio)-(p-nitrophenylhydrazono)pro-
pan-2-one (3d). Compound 3d was obtained as yellow crystal,
3.0 g (81%), mp.119–120ꢀC. IR: m 3107 (NH), 1692 (C¼¼O)
cmꢁ1 1H NMR (CDCl3): d 2.44 (s, 3H, CH3), 7.23–8.30 (m,
;
8H, aromatic and benzothiazole protons), 13.73 (br.s, 1H, NH,
D2O exchangeable) ppm; 13CNMR(DMSO-d6): d 26.1 (CH3),
119.5, 122.1, 122.9, 123.2, 125.3, 125.6, 134.6, 143.5, 145.6,
149.5, 154.5, 156.5 (aromatic and benzothiazole carbons),
189.2 (C¼¼O) ppm. Anal. Calcd. for C16H12N4O3S2 (372.29):
C, 51.61; H, 3.24; N, 15.04. Found: C, 51.49; H, 3.02; N,
15.27.
137ꢀC. IR: m 3444–3454 (NH), 2229(CN) cmꢁ1 1H NMR
;
(DMSO-d6): d 2.37 (s, 3H, CH3), 7.25–8.30 (m, 8H, aromatic
and benzothiazole protons), 10.42 (br.s, 1H, NH, D2O
exchangeable) ppm; 13C NMR(DMSO-d6): d 25.7(CH3), 111.7,
General procedure for synthesis of 7a–d. To a suspension
of each compounds 3a–d (10 mmoles) in EtOH (20 mL),
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247
5-Benzamido-3-(benzothiazol-20-ylthio)-1-(p-methoxyphenyl)-
4-methyl-6-oxo-1,6-dihydropyridazine hydrochloride (14b). This
compound was recrystallized from EtOH to give orange crystals,
in 74% yield, mp. 90–92ꢀC. IR: v 3432 (NH), 1684 (amide
116.1, 117.5, 121.5, 121.9, 122.8, 125.3, 126.8, 135.3, 136.2,
143.8, 144.4, 147.9, 149.25, 153.6 (aromatic, benzothiazole
carbons and CN), 156.3 (C-6) ppm; ms:m/z 420 (Mþ-HCl).
Anal. Calcd. for C19H13Cl N6O2S2 (456.92): C, 49.94; H 2.87;
N 18.39. Found: C, 49.75, H,02.98: N, 18.58.
5-Acetyl-3-(benzothiazol-2 -ylthio)-4,6-dimethyl-1-(p-nitro-
phenyl)-1,2-dihydropyridazine hydrochloride (8). A mixture
of 3d (3.72 g, 10 mmoles) and acetyl acetone (1.00g, 10
mmoles) in pyridine (20 mL) was refluxed for 3 h. The reaction
mixture poured onto ice-cold water and acidified with HCl
(10%). The solid product, so formed, was collected by filtration
and recrystallized from EtOH as pale yellow crystals, 2.64 g
C¼¼O), 1607(ring CO) cmꢁ1
;
1H NMR(DMSO-d6): d 2.39 (s,
3H, CH3), 4.20 (s, 3H, p-OCH3), 7.02–7.98 (m, 13H, aromatic
and benzothiazole protons), 8.05 (br.s, 1H, NH, D2O exchange-
able) ppm; 13C NMR (DMSO-d6): d 26.2(CH3), 56.3 (p-OCH3),
118.5, 115.9, 121.1, 121.9, 122.6, 123.2, 123.7, 124.0, 124.8,
126.5, 133.3, 136.3, 136.4, 142.1, 146.7, 151.9, 154.5, 157.5(ar-
omatic and benzothiazole carbons), 162.9(ring C¼¼O), 171.0ppm
(amide C¼¼O). Anal. Calcd. for C26H21ClN4O3S2 (537.05): C,
58.14; H, 3.94; N, 10.43. Found: C, 58.36; H, 4.13; N, 10.30.
5-Benzamido-3-(benzothiazol-20-ylthio)-4-methyl-1-(p-nitro-
phenyl)-3-oxo-1,6-dihydropyridazine hydrochloride (14c). This
compound was recrystallized from a mixture of EtOH/ DMF
(1:2) to give yellowish brown crystals, in 63% yield, mp.75–
77ꢀC. IR: v 3444 (NH), 1670 (amide C¼¼O), 1622 (ring CO)
(71%), mp. 96–98. IR: m 3447 (NH), 1670 (C¼¼O) cmꢁ1
;
1H
NMR(DMSO-d6): d 2.28 (s, 6H, 2CH3), 2.39 (s, 3H,COCH3),
7.37–8.25 (m, 9H, aromatic, benzothiazole protons & NH, D2O
exchangeable) ppm; 13C NMR (DMSO-d6): d 25.0, 27.1, 29.8
(2CH3 and COCH3), 111.4, 113.3, 115.5, 122.3, 122.7, 123.0,
124.6, 125.4, 134.5, 135.6, 137.9, 139.7, 142.1, 148.5, 153.8
(aromatic and benzothiazole carbons), 198.8(C¼¼O) ppm. Anal.
Calcd. for C21H19ClN4O3S2 (474.48): C, 53.10; H, 4.03; N,
11.79. Found: C, 53.29; H, 3.82; N, 11.76.
1
cmꢁ1; H NMR(DMSO-d6): d 2.23 (s,3H, CH3), 7.11–8.2 (m,
13H, aromatic and benzothiazole protons), 8.31 ppm (br.s, 1H,
NH, D2O exchangeable) ppm; 13C NMR (DMSO-d6): d 24.9
(CH3), 119.9, 122.3, 122.7, 123.2, 124.0, 124.6, 125.4, 127.3,
128.5, 131.0, 132.1, 133.4, 135.7, 144.9, 145.1, 148.7, 151.8,
155.3 (aromatic and benzothiazole carbons), 162.3(ring C¼¼O),
172.0 (amide C¼¼O) ppm; ms:m/z 515 (Mþ -HCl). Anal.
Calcd. for C25H18 ClN5O4S2 (551.94): C, 54.40; H, 3.29; N,
12.69. Found: C, 54.48; H, 3.41; N, 12.81.
5-Amino-1-(benzothiazol-20-ylthio)-4-imino-3-(p-methoxy-
phenyl)-7-phenyl-3,4-dihydrophthalazine-6,6(7H)-dicarboni-
trile hydrochloride (10). A solution of 7c (3.57 g,10 mmoles)
in pyridine (20 mL) was treated with benzylidenemalononitrile
(1.54 g, 10 mmoles). The reaction mixture was refluxed for
4 h then poured onto ice-cold water and acidify with 10%
HCl. The solid product, so formed, was collected by filtration
and recrystallized from EtOH as green crystal, in 75% yield,
mp.150–152ꢀC. IR: m 3436–3198 (NH, NH2), 2205(2CN)
BIOLOGICAL TESTING
cmꢁ1 1H NMR (DMSO-d6): d 2.44(m, 1H, H-7), 3.73(s, 3H,
;
The newly synthesized compounds were tested against
the specified microorganism, using 400 lg /mL (w/v) sol-
utions in sterile dimethyl sulfoxide (DMSO). A solution
of the tested compound (0.01 mol) was poured aseptically
in a well of 0.01 mL diameter made by a Cork borer in
the nutrient agar for fungal test. After placing the same
volume in wells of all tested microorganism nutrient agar
plates were incubated at 37ꢀC for 24 h and sabaurdies
dextrose agar were incubated at 25ꢀC for 48 h. The activ-
ities were expressed as inhibition zones (mm, diameter,
as clear areas) as antibacterial and antifungal effect. The
least concentration, which showed inhibitory effect on
any specify microorganism, was considered as the mini-
mum inhibitory concentration (MIC) that was determined
using streptomycin (50 lg/mL) as the references.
p-OCH3), 7.00–8.55 (m, 16H, aromatic, benzothiazole protons
& NH2, D2O exchangeable), 10.52 (br.s, 1H, NH, D2O
exchangeable) ppm; 13C NMR (DMSO-d6): d 25.0 (C-7), 38.9
(C-6), 52.4 (p-OCH3), 101.7, 113.2, 114.2, 117.0, 118.3,
121.2, 122.0, 123.4, 125.4, 126.4, 127.1, 128.3, 130.4, 134.4,
135.3, 138.2, 140.6, 148.3, 149.5, 150.1, 152.1(aromatic, ben-
zothiazole carbons & 2CN), 156.0, 156.8 (C-4 & ipso- OCH3)
ppm; ms:m/z 559 (Mþ- HCl). Anal. Calcd. for C30H22ClN7OS2
(596.13): C, 60.44; H 3.71; N 16.44. Found: C, 60.57; H,
3.76; N, 16.34.
General procedure for the synthesis of 14a-c. A solution
of each compounds 3a, 3c, and 3d (10 mmoles) and hippuric
acid (1.79 g, 10mmoles) in Ac2O (20 mL) was refluxed for
2 h. The reaction mixture was poured into ice-cold water
and acidified with 10% HCl. The solid product, so formed,
was collected by filtration and recrystallized from a proper
solvent.
5-Benzamido-3-(benzothiazol-20-ylthio)-4-methyl-6-oxo-1-
phenyl-1,6-dihydropyridazine hydrochloride (14a). This
compound was recrystallized from EtOH to give brown crys-
tals, in 69% yield, mp 168–170ꢀC. IR: v 3430 (NH), 1686
Acknowledgment. This work was financed by University of Ku-
wait, Research Grant SC 07/04. We are grateful to the Faculty of
Science, Chemistry Department, SAF facility for the analytical
and spectral measurement (Project GS 01/01, GS 03/01, GS 01/
05 & GS 01/ 03). The authors are also grateful to Dr. S. A. Abdel-
Gahny for the biological activity tests.
1
(amide C¼¼O), 1622 (ring CO) cmꢁ1; H NMR (DMSO-d6): d
2.28 (s, 3H, CH3), 7.03–7.92 (m,14H, aromatic and benzothia-
zole protons), 8.03 (br.s,1H, NH, D2O exchangeable) ppm; 13C
NMR (DMSO-d6): d 24.9 (CH3), 119.2, 121.0, 121.8, 123.2,
125.4, 126.4, 126.8, 127.9, 128.5, 128.7, 129.0, 135.7, 138.1,
147.2, 148.3, 149.1, 150.1, 153.4 (aromatic and benzothiazole
carbons), 161.6 (ring C¼¼O), 172.0 (amide C¼¼O) ppm. Anal.
Calcd. for C25H19 ClN4O2S2 (507.03): C, 59.22; H, 3.77; N,
11.04. Found: C, 59.27; H, 3.89; N, 11.22.
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