Synthesis of new annulated pyridazine derivatives and studying their antioxidant and antimicrobial activities

Article abstract of DOI:10.1080/00397911.2019.1658786

Benzil was reacted with cyanoacetohydrazide under microwave irradiation to give 3-oxo-5,6-diphenyl-2,3-dihydropyridazine-4-carbonitrile 1 which used as starting material for the synthesis of new heterocyclic compounds. Chlorination of pyridazinone 1 with

Full text of DOI:10.1080/00397911.2019.1658786

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis of new annulated pyridazine derivatives
and studying their antioxidant and antimicrobial
activities
Heba E. Hashem, David S. A. Haneen, Khaled F. Saied & Ahmed S. A. Youssef
To cite this article: Heba E. Hashem, David S. A. Haneen, Khaled F. Saied & Ahmed S. A.
Youssef (2019): Synthesis of new annulated pyridazine derivatives and studying their antioxidant
and antimicrobial activities, Synthetic Communications, DOI: 10.1080/00397911.2019.1658786
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https://doi.org/10.1080/00397911.2019.1658786
Synthesis of new annulated pyridazine derivatives and
studying their antioxidant and antimicrobial activities
a
b
c
Heba E. Hashem , David S. A. Haneen
, Khaled F. Saied , and
b
Ahmed S. A. Youssef
a
b
Department of Chemistry, Faculty of Women, Ain Shams University, Cairo, Egypt; Department of
c
Chemistry, Faculty of Science, Ain Shams University, Cairo, Egypt; Basic Science Department, Faculty of
Oral and Dental Medicine, Nahda University, Beni-Suef, Egypt
ABSTRACT
ARTICLE HISTORY
Benzil was reacted with cyanoacetohydrazide under microwave
irradiation to give 3-oxo-5,6-diphenyl-2,3-dihydropyridazine-4-car-
bonitrile 1 which used as starting material for the synthesis of new
heterocyclic compounds. Chlorination of pyridazinone 1 with POCl3
afforded the chloro-pyridazine derivative 3, which then condensed
with 2-aminothiazole or hydrazine hydrate to produce 3,4-diphenyl-
Received 19 May 2019
KEYWORDS
Antimicrobial activity;
antioxidant; pyrazole;
pyridazine; pyrimidine
0 0
H-thiazolo[3 ,2 :1,2]pyrimido[4,5-c]pyridazin-5-one 5 or 3-hydra-
5
zinyl-5,6-diphenylpyridazine-4-carbonitrile 6, respectively. New Schiff
bases were obtained by condensation reactions of compound 6
with different aldehydes. On the other hand, compound 6 reacted
with different carbon electrophiles naming acetyl acetone, diethyl
malonate, and phenyl isothiocyanate producing new pyarazolo-pyri-
dazine derivatives 11, 12, and 14, respectively. Chemical structures
of all newly synthesized compounds were confirmed on the basis of
spectral data and had been screened for antimicrobial and antioxi-
dant activity.
GRAPHICAL ABSTRACT
CONTACT Heba E. Hashem
hebahashem89@yahoo.com
Department of Chemistry, Faculty of Women, Ain Shams
University, Heliopolis, P.O. Box 11757, Cairo 13013, Egypt.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
H. E. HASHEM ET AL.
Introduction
Pyridazine derivatives attract considerable research due to their structures stability and
[
1,2]
pharmacological activities.
cidal, fungicidal,
Many of pyridazine derivatives possess analgesics, insecti-
[
3]
[4,5]
[6]
[7]
cardiotonic, and bactericidal activities. Also, other five-mem-
bered heterocyclic compounds such as pyrazole, triazole, tetrazole, and thiodiazole have
[
8–10]
been used in medicinal chemistry
due to their important biological activities. Such
[
11,12]
[13]
[14]
[15]
as anti-inflammatory,
antifungal,
herbicidal,
insecticidal,
antitumor, anti-
[
16]
[17]
HCV,
and antiviral activities.
Pyrazole is a very important constituent in drug development. Over the years, grow-
ing interest has been paid to pyrazole derivatives due to their importance in agrochem-
[
18,19]
ical, pharmaceutical, and chemical industries.
Pyrazole derivatives showing
[
19,20]
[21]
[22]
significant bioactivities
such as anti-inflammatory,
anticonvulsant,
anti-
[
23]
[24]
cancer,
and antifungal behavior.
On the basis of this view, our work was aimed to synthesis some new heterocyclic
system annulated with pyridazine ring as a central moiety to improve their bio-
logical activity.
Results and discussion
Chemistry
Green synthesis of 3-oxo-5,6-diphenyl-2,3-dihydropyridazine-4-carbonitrile (1) was
achieved by reacting equimolar amounts of benzil and cyanoacetohydrazide under
microwave irradiation for 2 min. It was found to be identical in all respects with which
[
25]
prepared under conventional thermal method.
However, the microwave irradiation
method gave better yield and needs short reaction time (Scheme 1).
Refluxing of the pyridazinone 1 with malononitrile in ethanol and in the presence of
tri-ethylamine as a base gave 5-amino-7-oxo-3,4-diphenyl-7,8-dihydropyrido[2,3-c]pyri-
dazine-6-carbonitrile (2) (cf. Scheme 2).
Scheme 1. Synthesis of pyridazin-6-one 1 using microwave irradiation or conventional thermal reflux.
Scheme 2. Reactions of pyridazinone 1 with malononitrile or POCl3.

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3
Scheme 3. Reaction of chloropyridazine 3 with different N-nucleophile.
The structure of compound 2 was evidenced from its spectral data. The IR spectrum
showed absorptions characteristic for NH, CN, and C¼O groups.
1
H NMR spectrum exhibited two broad singlet signals attributable to protons of NH
and NH groups as well as multiplet signals for aromatic protons. Further evidence was
2
gained from its mass spectrum that revealed its molecular ion peak together with some
important peaks (cf. “Experimental” section).
On the other hand, treatment of compound 1 with POCl in refluxed dioxane pro-
3
[
26]
duced 3,4-diphenyl-5-cyano-6-chloro-pyridazine (3).
The IR spectrum of compound
3
was devoid of any absorption for carbonyl group but it showed a band for CN group
(cf. Scheme 2).
Chloropyridazine 3 was utilized as synthons for some annulated systems by reacting
with some nitrogen nucleophiles.
Heating of chloropyridazine 3 with sodium azide afforded the fused tetrazolo-pyrida-
zine derivative 4 (cf. Scheme 3).
The structure of 4 was substantiated from its IR spectrum that exhibited absorption
bands corresponding to C¼N, N¼N and CN groups. Further proof for the assigned
structure of compound 4 was achieved from its mass spectrum, which revealed the cor-
rect molecular ion peak and some of the abundant peaks (cf. “Experimental” section).
Refluxing of compound 3 with 2-aminothiazole in n-butanol yielded 3,4-diphenyl-5H-
0
0
thiazolo[3 ,2 :1,2]pyrimido[4,5-c]pyridazin-5-one (5). The absence of any absorption corre-
sponding to CN group in its IR spectrum was in accordance with the complete cyclization
1
which afforded the three-fused heterocyclic ring (cf. Scheme 3). Moreover, its H NMR spec-
trum was in a good agreement with proposed structure, where it was devoid of any signals
for NH protons in the downfield region. Further proof for the assigned structure of com-
pound (5) is gained from its mass spectrum (cf. “Experimental” section).
On the other hand, treatment of chloropyridazine 3 with hydrazine hydrate in reflux-
ing ethanol furnished 3-hydrazinyl-5,6-diphenylpyridazine-4-carbonitrile (6).
The structure of compound 6 was inferred from its IR spectrum that showed absorp-
tions characteristic for NH, NH , and CN groups.
2
1
H NMR spectrum was in accordance with the proposed structure as it displayed two
broad singlet signals for NH and NH protons which were exchanged on deuteration.
2

4
H. E. HASHEM ET AL.
Scheme 4. Synthesis of some new Schiff bases from hydrazinyl-pyridazine 6.
Further evidence was gained from its EIMS spectrum as it showed the correct
molecular ion peak and some other important peaks (cf. “Experimental” section).
Treatment of hydrazinyl-pyridazine 6 with different heterocyclic aldehydes namely
indole-3-carbaldehyde, 2-chloro-quinoline-3-carboxaldehyde and 1,3-diphenyl pyrazole-
4-carbaldehyde in refluxing ethanol and few drops of acetic acid glacial afforded new
Schiff base compounds 7, 8, and 9, respectively (cf. Scheme 4).
IR spectra of compounds 7–9 showed absorption bands correlated to NH, C¼N, and
1
CN groups. Further support for the assigned structures was gained from H NMR spec-
tra which exhibited extra exchangeable broad singlet signals for NH protons in com-
pounds 7, 9 as well as the imino methine CH¼N protons that suggest their existence as
mixtures of Syn/Anti stereoisomers in equal ratio.
Mass spectra of compounds 7–9 supported the suggested structures as they displayed
the molecular ion peaks and other some important peaks (cf. “Experimental” section).
Heating of the hydrazinyl derivative 6 with acetic anhydride yielded the fused pyra-
zolo-pyridazine derivative 10 (cf. Scheme 5). The structure of compound 10 was estab-
lished from its spectral data. Its IR spectrum revealed strong absorption bands at 1747,
ꢀ
1
1
1
732 cm characteristic for the coupling pattern for the carbonyl groups. The H NMR
spectrum didn’t show any signals corresponding to NH protons, instead, it showed
three singlet signals for CH groups.
3

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5
Scheme 5. Reactions of hydrazinyl derivative 6 with different carbon electrophiles.
The suggested structure got further support from its mass spectrum as it revealed its
molecular ion peak and other important peaks (cf. “Experimental” section).
Further synthesis of new heterocyclic compounds was achieved by the reactions of
hydrazinyl derivative 6 with different carbon electrophiles such as acetyl acetone or
diethyl malonate (cf. Scheme 5).
Refluxing an ethanolic solution of compound 6 with acetyl acetone in the presence of
few drops of glacial acetic acid gave the pyrazolyl pyridazine derivative 11 (cf.
Scheme 5).
The structure of compound 11 was established from its spectral data. Its IR spectrum
was devoid from any absorptions characteristic for NH groups, but it showed bands for
1
CN and C ¼ N groups. Moreover, the H NMR spectrum revealed two singlet signals
for protons of two CH groups, as well as multiplet signals correlated to the aromatic
3
and CH ¼ protons(cf. “Experimental” section).
Mass spectrum of compound 11 showed its molecular ion peak and other abundant
peaks corresponding with its structure.
Heating equimolar amounts of compound 6 and diethyl malonate in refluxing
dioxane afforded 3-(3,5-dioxopyrazolidin-1-yl)-5,6-diphenylpyridazine-4-carbonitrile
(12) in a good yield.
Infrared spectrum of compound 12 exhibited absorption bands correlated to CN,
NH, and CO groups. Further support for the structure of compound 12 was gained

6
H. E. HASHEM ET AL.
Scheme 6. Reaction of hydrazinyl derivative 6 with phenylisothiocyanate in different media
1
from its H NMR spectrum which showed one singlet signal for protons of CH group
2
and another broad singlet in the downfield region for NH proton which collapsed rap-
idly on deuteration. Moreover, EIMS spectrum of compound 12 displayed the correct
molecular ion peak together with some abundant peaks (cf. “Experimental” section).
Further synthesis was achieved by reacting of the hydrazinyl derivative 6 with phenyl
isothiocyanate in refluxing ethanol and a catalytic amount of sodium hydroxide that
furnished the carbamothioate derivative 13. However, on doing the same reaction in
refluxing dioxane, it gave the fused pyrazolopyridazine derivative 14 (cf. Scheme 7).
The structures of compounds 13 and 14 were evidenced by studying their analytical
as well as spectral data. Their IR spectra showed bands for NH and C¼S groups.
1
Moreover, their H NMR spectra were in accordance with the suggested structures
(cf. “Experimental” section). Their EIMS spectra supported their structures as they
displayed their correct molecular ion peaks beside other important peaks (cf.
“Experimental” section).
It is observed that the hydrazinyl pyridazine 6 has no role in the formation of com-
pound 13, however, phenylisothiocyanate underwent dimerization followed by concur-
rent ring opening by one molecule of ethanol (Scheme 6).
Pharmacology
Anti-microbial activity
The newly synthesized compounds were evaluated for antimicrobial activity against
gram-positive bacteria (Staphylococcus aureus) and Gram-negative bacteria (Escherichia
coli). The anti-fungal activities of the new compounds were tested against
(Candida albicans).

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7
Scheme 7. The proposed mechanism for the reactivity of compounds 6, 12, and 14 towards
ABTS radical.
All compounds dissolved in DMSO (1 mg/ml), paper discs of Whatman filter paper
were prepared with standard size (5 cm), cut and sterilized in an autoclave. The paper
discs soaked in the desired concentration of the complex solution were placed aseptic-
ally in the petri dishes containing nutrient agar media (agar 20 g þ beef extract
3
g þ peptone 5 g) seeded with S. aureus, E. coli, and C. albicans. The petri dishes were
[27]
ꢁ
incubated at 36 C and the inhibition zones were recorded after 24 h of incubation.
Each treatment was replicated three times. The antibacterial activity of a common
standard Ciprofloxacin as high antibiotic drugs and antifungal Clotrimazole was also
recorded using the same procedure as above at the same concentration and solvents.

8
H. E. HASHEM ET AL.
Table 1. Diameter of inhibition zone (mm) and percentage activity index results for the newly syn-
thesized compounds as antibacterial and antifungal activity.
E. coli (mg/ml)
S. aureus (mg/ml)
C. albicans (mg/ml)
Diameter of
Diameter of
Diameter of
inhibition
Percentage
inhibition
Percentage
inhibition
Percentage
No. Compound
zone (mm)
activity index
zone (mm)
activity index
zone (mm)
activity index
1
2
3
4
5
6
7
8
2
4
5
6
7
8
9
10
11
12
14
NA
NA
2
12
7
5
9
4
NA
10
7
26
NA
–
–
7.7
8
NA
7
33.3
–
10
3
7
17
12
8
14
5
NA
17
15
NA
27
37.0
11.1
25.9
63.0
44.4
29.6
51.8
18.5
–
29.2
79.2
54.2
41.7
66.7
20.8
–
75.0
45.8
100
–
46.1
26.9
19.2
34.6
15.4
–
38.5
26.9
100
–
19
13
10
16
5
NA
18
11
24
NA
–
1
1
0
1
63.0
55.5
–
Ciprofloxacin
Colitrimazole
100
The percentage activity index for the complex was calculated by the formula:
zone of inhibition by test compound ðdiameterÞ
Percentage activity index ¼
ꢂ100
zone of inhibition by standard ðdiameterÞ
The result of the study showed that compounds 6, 9, and 12 have highest activity
against bacteria and fungi. Compounds 7 and 8 exhibit moderate activity against gram-
negative bacteria and fungi, and low activity against gram-positive activity. Compound
1
4 has high activity against fungi and moderate antibacterial activity. Compound 2 has
no activity against gram-positive bacteria. However it exhibits moderate activity against
fungi and gram-negative bacteria. Compounds 4, 5, and 10 showed low antimicrobial
activity (cf. Table 1).
Antioxidant activity
Antioxidant chemical compounds have significant importance for inhibition of oxida-
tion process for therapeutic process “in activating the immune response, in preventing
[
28–30]
the clotting of blood vessels, and in many other metabolic processes.”
Antioxidant activity can be detected by different mechanisms, such as hydrogen atom
transfer (HAT), single electron transfer (ET), or others.
In our present work, the newly synthesized compounds were tested as antioxidant
[
31]
activity by using the ABTS method.
, 7, 9, 12, and 14 exhibit high antioxidant activity comparable with the standard anti-
oxidant Ascorbic acid. Compounds 2 and 8 have moderate activity, while compounds 3,
, 10, and 11 have low antioxidant activity (cf. Table 2 and Figure 1).
The results of the study showed that compounds
6
5
Structure-activity relationship (SAR)
The results obtained from antimicrobial and antioxidant activity of the newly prepared
heterocyclic compounds can explicate the structure-activity relationships as follow:

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9
Table 2. Antioxidant activity using ABTS method for the newly synthesized compounds.
ABTS Abs (control) – Abs (test)/Abs (control) ꢂ 100
Method
No.
Compounds
Absorbance of samples
% inhibition
Control of ABTS
Ascorbic acid
0.518
0.058
0.316
0.384
0.353
0.201
0.250
0.328
0.232
0.372
0.407
0.193
0.229
0
ꢄ
88.8
39.0
25.9
31.8
61.2
51.7
36.7
55.2
28.2
21.4
62.7
55.8
1
2
3
4
5
6
7
8
9
2
4
5
6
7
8
9
10
11
12
14
1
1
0
1
Anꢀoxidant Acꢀvity (ABTS)
100.00%
9
8
7
6
5
4
3
2
1
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
%
Inhibiꢀon
0.00%
Figure 1. Antioxidant activity (% inhibition) for tested compound against standard ascorbic acid.
ꢃ
ꢃ
The basic moiety of pyridazine responsible for the broad activity against different
bacteria and fungi.
Hydrazinyl derivative 6 is the most potent active compound as antimicrobial due
to the presence of free amino group with high electron density that increases the
reactivity towards the enzyme.
ꢃ
ꢃ
The presence of hydrazinyl, dioxypyrazolidine, and thioamide moieties, in com-
pounds 6, 12, and 14, respectively revealed their highest antioxidant activity that
detects the stabilization of free radicals of nitrogen or oxygen atoms as shown in
(Scheme 7).
The prepared Schiff base 9 showed the highest antimicrobial and antioxidant
activity comparable to the other two Schiff bases 7 and 8. This result affirms that
the pyrazole moiety is more active than quinolone and indole rings.
Conclusion
New pyridazine, fused pyridazine, and Schiff bases were synthesized starting from benzil
and cyanoacetohydrazide under green chemistry using microwave irradiation. Most of

1
0
H. E. HASHEM ET AL.
the new compounds possess significant biological activity when tested as antimicrobial
and antioxidant.
Experimental
All melting points are uncorrected and were measured on a Gallenkamp electric melting
point apparatus. The IR spectra were recorded using potassium bromide disks on an
FTIR Thermo Electron Nicolet 7600 (USA) IR spectrometer at the Central Laboratory
1
of Faculty of Science, Ain Shams University. H NMR spectra were run at 300 MHz on
a GEMINI 300 BB NMR spectrometer using tetramethylsilane as internal standard in
deuterated dimethyl sulfoxide (DMSO-d ) at Faculty of Pharmacy, Ain Shams
6
University. The mass spectra were recorded on Shimadzu GCMSQP 1000EX mass spec-
trometer operating at 70 eV and the elemental analyses at the Micro Analytical Center
of Al-Azhar University. TLC was performed on Merck Kiesel gel 60 F254 aluminum-
backed plates. The spots were detected by UV irradiation at 254–365 nm.
3
-Oxo-5,6-diphenyl-2,3-dihydropyridazine-4-carbonitrile (1)
Method [A]: Microwave radiation
Equimolar amounts of benzil and cyanoacetohydrazide in ethanol and drops of piperi-
dine were irradiated in microwave oven for 2 min. The reaction mixture was cooled at
room temperature and then treated with water. The solid product formed was filtered
off, dried and recrystallized from ethanol to give compound (1) (Yield: 94%).
Method [B]: Thermal reflux
A mixture of benzil (0.01 mol) and cyanoacetohydrazide (0.01 mol) in boiling ethanol
(20 ml) and drops of piperidine was refluxed for 3 h, the solvent was distilled off and
then poured onto water and HCl. The solid formed was filtered off and recrystallized
ꢁ
ꢁ
from ethanol (Yield: 85%); off-white crystals; m.p. 264–266 C (lit. m.p. 260–261 C)
[
ꢀ
1
25]; IR (KBr) (t, cm ): 3194 (NH), 3064 (CHarom), 2230 (CN), 1665 (CO).
5
-Amino-7-oxo-3, 4-diphenyl-7,8-dihydropyrido [2, 3-c] pyridazine-6-
carbonitrile (2)
A mixture of pyridazinone 1 (0.01 mol) and malononitrile (0.01 mol) was refluxed in
boiling ethanol (25 ml) and drops of trimethylamine for 6 h. The solid product formed
while cooling at room temperature was filtered off and recrystallized from ethanol to
ꢁ
ꢀ1
give compound 2 (Yield 71%); brown crystals; m.p. 240–242 C; IR (KBr) (t, cm ):
1
3
333 (NH), 3245, 3194 (NH ), 3063 (CHarom), 2215 (CN), 1659 (CO); H NMR
2
(
1
DMSO-d ) d: 4.10 (br.s, 2H, NH , exchangeable), 7.08–7.48 (m, 10H, ArH), 14.00 (br.s,
H, NH, exchangeable); MS (70 eV) m/z (%): 339 (M , 6), 323 (3), 315 (4), 296 (4), 273
6 2
þ
(68), 262 (4), 245 (12), 94 (16), 77 (36).
Anal. calcd. for C H N O (339.11): C, 70.79; H, 3.86; N, 20.64. Found: C, 70.48; H,
2
0
13 5
4.06; N, 20.28.

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11
3
-Chloro-5,6-diphenylpyridazine-4-carbonitrile (3)
A mixture of pyridazinone 1 (0.5 g) and phosphurs oxychloride (10 ml) in dioxane
20 ml) was heated under reflux for 8 h. The reaction mixture cooled at room tempera-
(
ture and poured gradually onto ice/water. The solid formed was filtered off and recrys-
tallized from diluted ethanol to give compound 3 (Yield 59%); off-white crystals; m.p.
ꢁ ꢁ
95–196 C (lit. m.p. 201 C).
[25]
1
1
Full experimental detail, H NMR spectra, Mass, IR and elemental analysis. This
material can be found via the “Supplementary Content” section of this
article’s webpage.
ORCID
David S. A. Haneen
http://orcid.org/0000-0002-8085-2910
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