Synthesis, characterization, and biological studies of some novel pyrazole carboxamide, pyridazine and thienopyridazine derivatives

Article abstract of DOI:10.1080/00397911.2019.1703002

The arylhydrazones 3a, b were prepared and reacted with various reagents to yield the target compounds pyrazoles 6a–f, 1,6-dihydropyridazine-3-carboxamide derivatives 9a,b and thieno[3,4-d]pyridazine-1-carboxamide derivatives 10a,b. The structures of the synthesized compounds were confirmed by various spectral data and elemental analyses. Furthermore, all target derivatives were tested for their antibacterial bioactivity against different types of Gram+?ve and Gram-ve strains and for antifungal activity against two fungi micro-organisms by well diffusion method. Thus, the observed results showed that the 5-cyano-6-imino-N-(4-methoxyphenyl)-4-methyl-1-phenyl-1,6-dihydropyridazine-3-carboxamide (9b) displayed the best antimicrobial activity (with MIC values ranged from 0.49 ± 0.2 to 3.9 ± 0.6 μg/mL).

Full text of DOI:10.1080/00397911.2019.1703002

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, characterization, and biological studies
of some novel pyrazole carboxamide, pyridazine
and thienopyridazine derivatives
Ismail M. M. Othman & Abdel Haleem M. Hussein
To cite this article: Ismail M. M. Othman & Abdel Haleem M. Hussein (2019): Synthesis,
characterization, and biological studies of some novel pyrazole carboxamide, pyridazine and
thienopyridazine derivatives, Synthetic Communications, DOI: 10.1080/00397911.2019.1703002
To link to this article: https://doi.org/10.1080/00397911.2019.1703002
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https://doi.org/10.1080/00397911.2019.1703002
Synthesis, characterization, and biological studies of some
novel pyrazole carboxamide, pyridazine and
thienopyridazine derivatives
Ismail M. M. Othman and Abdel Haleem M. Hussein
Department of Chemistry, Faculty of Science, Al-Azhar University, Assiut, Egypt
ABSTRACT
ARTICLE HISTORY
Received 23 August 2019
The arylhydrazones 3a, b were prepared and reacted with various
reagents to yield the target compounds pyrazoles 6a–f, 1,6-dihydro-
pyridazine-3-carboxamide derivatives 9a,b and thieno[3,4-d]pyrida-
zine-1-carboxamide derivatives 10a,b. The structures of the
synthesized compounds were confirmed by various spectral data
and elemental analyses. Furthermore, all target derivatives were
tested for their antibacterial bioactivity against different types of
Gramþve and Gram-ve strains and for antifungal activity against two
fungi micro-organisms by well diffusion method. Thus, the observed
results showed that the 5-cyano-6-imino-N-(4-methoxyphenyl)-4-
methyl-1-phenyl-1,6-dihydropyridazine-3-carboxamide (9b) displayed
the best antimicrobial activity (with MIC values ranged from
0.49 0.2 to 3.9 0.6 lg/mL).
KEYWORDS
Antimicrobial activities;
pyrazoles; pyridazines;
thieno[34-d]pyridazines
GRAPHICAL ABSTRACT
CONTACT Ismail M. M. Othman
ismail201179@yahoo.com
Department of Chemistry, Faculty of Science, Al-Azhar
University, Assiut, 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
I. M. M. OTHMAN AND A. H. M. HUSSEIN
Introduction
Heterocyclic compounds are important key features in synthetic medicines and natural
products due to their variation of possible substituents, less toxicity and large-effi-
ciency[1–3]. Pyrazole derivatives are significant kinds of heterocyclic nitrogen com-
pounds[4,5], which demonstrates a wide range of biological activities, such as
anticancer[6,7], antimicrobial[8], antifungal[9], antitumor[10] and anti-inflammatory[11]
.
Some pyrazole derivatives based drugs belonging to various classes with different thera-
peutic activities (Fig. 1) have been successfully developed by various companies. The
presence of the pyrazole moieties in varied compounds leads to different applications in
diversified areas such as medicine, agriculture and technology. They are revealed as an
antioxidant, inhibitors of protein glycation, anti-tuberculosis, antiviral and antibacterial
agents[12,13]. In addition, heterocycles with carboxamide groups are constitute of a kind
of compounds exhibiting extensive biological activities, such as antiproliferative[14], anti-
biofilm[15], plant growth regulation[16], They represent a valuable class of very numerous
constructing blocks for the synthesis of bioactive compounds in agrochemical
industry and pharmaceutical drug design. In the past few years, some succinate-
dehydrogenase-inhibitor (SDHI) fungicides are possible in the market for effective ther-
apy of vegetable crops and fruit, such as penflufen (which used for the therapy of a
wide area of diseases) and sedaxane (Fig. 1). Pyridazine-based structures are widely
found in biologically active compounds with anti-HAV agents[17], anticonvulsant[18]
,
anti-Alzheimer’s[19], anti-depressant[20], and so on. As an extension of our program in
respect of synthesizing heterocyclic compounds particularly those with expected anti-
microbial activity [21–24], we target to synthesize novel series of pyrazole, pyridazine,
and thienopyridazine derivatives with the expectation that new biological agents might
be discovered.
O
F3C
N
CH3
O
N
H
N
N
N
N
N
N
H
N
Cl
CH3
CN
Rimonabant
Anti-obesity
Cl
Cl
CDPPB
Anti-psychotic
SO2NH2
Celecoxib
Anti-inflammatory
F
O
N
O
O
CH3
N
N
N
N
N
CH3
H
N
N
H
H
F
CH3
N
N
F
Difenamizole
Analgesic
Penflufen
sedaxane
Figure 1. Pharmaceutical drugs containing pyrazole unit.

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3
Results and discussion
Chemistry
The structures of the prepared derivatives were showed in Schemes 1–3. Based on the
synthetic strategies, it has been found that the coupling of N-(4-methoxyphenyl)-3-oxo-
butanamide (1)[25], with diazotized aromatic amines 2a,b in ethanol/AcONa yielded the
1
hydrazono derivatives 3a,b based on their spectral data, (Scheme 1). For instance, H
NMR spectrum of (3a in DMSO-d6) displayed the presence of multiple signals at
d ¼ 6.95–7.42 ppm corresponding to aromatic protons and signals at d ¼ 9.11 and
11.14 ppm corresponding to 2NH groups. The arylhydrazone derivatives 3 seem to be
an interesting candidate for further chemical transformations. Thus, the arylhydrazones
O
O
O
O
O
1
O
N
CH3
ArN=NCl
EtOH
2 a, b
2 and 3 a , Ar = C6H5
b, Ar = C6H4SO2NH2
H
N
CH3
N
H
NH
Ar
3 a, b
4a; R = CN
b; R = COCH3
c; R = COOH
DMF/ NaOH
Reflux
Cl-CH2-R
4a-c
O
O
O
O
O
CH3
R
-H2O
N
H
CH3
N
H
N
N
N
Ar
N
R
Ar
5a-f
6a-f
5 and 6 a; Ar = C6H5 , R = CN
b; Ar = C6H5 , R = COCH3
c; Ar = C6H5, R = COOH
d; Ar = C6H4SO2NH2 , R = CN
e; Ar = C6H4SO2NH2, R = COCH3
f; Ar = C6H4SO2NH2 , R = COOH
Scheme 1. Synthesis of hydrazone and pyrazole derivatives
O
O
O
CH3
N
O
H3C OH
CN
X
H
N
H
CN
7
a,b
N
H
NCCH2X
N
3a
..
X
N
EtOH / pip.
NH
9 a,b
9 a, X= S
b, X= NH
a,b
8
7 and 8 a, X= CSNH2
b, X= CN
Scheme 2. Synthesis of pyridazine derivatives

4
I. M. M. OTHMAN AND A. H. M. HUSSEIN
O
S
O
NH2
N
S / EtOH / TEA
a, X= S
H
N
N
S
10 a
9 a,b
O
S
O
NH2
N
S / EtOH / TEA
b, X= NH
H
N
N
NH
10 b
Scheme 3. Synthesis of thienopyridazine derivatives
3a,b were treated with halo compounds 4a–c to yield pyrazole carboxamide products.
So, structures 3a,b were reacted with equimolecular amount of chloroacetonitrile (4a),
chloroacetone (4 b) and chloroacetic acid (4c) in the presence of few plates of sodium
hydroxide and dimethylformamide (DMF) under reflux for 6 hours to yield the pyrazole
derivatives 6a–f. Confirmations of compounds 6a–f were based on its compatible spec-
1
troscopic data (IR, H NMR and 13C NMR). The IR spectrum of compound 6a exhib-
ited the appearance of absorption bands due to the NH, CN and CO functional groups
1
at t 3372, 2207 and 1663 cmꢀ1, respectively. While its H NMR spectrum indicated
singlet signal at d 10.65 ppm assigned to NH amidic group and the disappearance of any
signal corresponding to NH proton of hydrazo group at high downfield beside the other
protons in their proper positions (Scheme 1 and Experimental part). Moreover, 13C
NMR of the pyrazole carboxamide 6a illustrated signal at d 114.1 ppm characterized to
the carbon of CN group, in addition, to signal at d 163.8 ppm attributed to the carbon
of CO group.
Construction of 6 was carried via the nucleophilic attack of NH hydrazo group of 3
to the halogen compound 4 to give the intermediate 5 which cyclized through the
nucleophilic attack of active methylene moiety in 5 to the carbon of the acetyl group to
yield the reaction products 6a–f via removal of H2O molecule. Furthermore, the
obtained arylhydrazones were utilized as starting materials for the synthesis of some
novel pyridazine and thienopyridazine derivatives. Thus, the reaction of arylhydrazone
3a with cyanothioacetamide (7a) or malononitrile (7b) in ethanol/piperidine under
reflux yielded the corresponding compounds dihydropyridazine-3-carboxamide deriva-
tives 9a,b. (Scheme 2).
The structures of 9a,b were confirmed via analysis of their spectral studies. The IR
spectra of 9a, taken as a typical example, illustrate absorption bands at 3343, 2203, and

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SYNTHETIC COMMUNICATIONSV
5
1
1661 cmꢀ1 corresponding to NH, CN, and CO groups, respectively. While its H NMR
spectrum indicated signals at d 2.71, 3.83 and 10,15 corresponding to 2CH3 and NH
protons in addition to aromatic protons at d 7.07–8.19. Also, 13C NMR of the structure
revealed signals at 113.1 ppm (CN), 163.5 ppm (C¼O), 182.3 ppm (C¼S), in addition to
all signals assigned to carbons of sp2 in the molecule. Formation of the iminopyridazine
derivative 9b was proposed to proceed by condensation of the methylene group in com-
pound 7b with carbonyl of acetyl group in 3a to yield the non-isolated intermediate 8b
which cyclized through nucleophilic attack of NH group to CN group affording the imi-
nopyidazine derivative 9 b, (Scheme 2). The pyridazine carboxamide derivatives 9a,b
were utilized as starting material to obtain some fused azines[26]. Thus, the pyridazines
9a,b were reacted with elemental sulfur in boiling ethanol/triethylamine to afford the
dihydrothieno[3,4-d]pyridazine carboxamide derivatives 10a,b. The spectral and elemen-
tal analysis data are in accordance with the assigned compounds 10a,b. For instance,
the IR spectra of 10a displayed the absence of the absorption band assigned to the CN
function group and the appearance of an absorption band corresponding to the NH2
1
groups at t 3375, 3229 cmꢀ1. H NMR spectrum (DMSO-d6) displayed signals that is in
accordance with the expected structure at d 3.82, 5.12 ppm attributed to the OCH3 and
NH2 protons and multiple signals in the region of d 6.97–7.52 ppm attributed to aro-
matic protons in addition to NH proton at d 10.21. 13C NMR spectra of the dihydro-
thieno[3,4-d]pyridazine derivative 10a displayed two signals at 163.3 and 172.1 ppm due
to CONH and CS groups, (Scheme 3 and Experimental part).
Antimicrobial testing
As clarified in Table 1, the newly targeted structures examined exhibited in vitro
antibacterial against Streptococcus pneumonia, Bacillus subtilis, Pseudomonas aerugi-
nosa, Escherichia coli, and antifungal against Aspergillus fumigatus and Candida
Table 1. Diameter of inhibition zone (mm) of the synthesized compounds at 1 mg/mL.
Mean diameter of inhibition
zone (Mean SEM) (mm)
Gram-positive bacteria
Gram-negative bacteria
Fungi
A. fumigatus
S. pneumoniae
B. subtilis
P. aeruginosa
E. coli
C. albicans
Compounds
RCMB 010010
RCMB 010067
RCMB 010043
RCMB 010052
RCMB 002568
RCMB 005036
3a
3b
6a
6b
12.8 0.4
18.5 0.7
NA
NA
20.3 0.5
20.1 0.6
NA
NA
NA
11.8 0.5
NA
10.3 1.5
16.4 1.5
17.7 0.5
NA
NA
14.2 1.2
NA
26.3 0.1
15.1 0.7
NA
NA
NA
NA
6c
6d
6e
6f
9a
9b
10a
NA
NA
NA
NA
NA
NA
26.4 0.5
23.1 0.8
27.2 0.4
13.4 0.6
28.6 0.5
NA
23.8 1.3
18.1 0.6
24.1 0.5
NA
25.7 0.2
NA
19.2 0.5
17.2 1.5
22.6 0.5
12.3 0.4
23.5 1.2
NA
15.3 1.3
14.8 0.1
21.2 1.3
16.1 0.5
24.1 0.1
NA
22.6 0.5
21.2 0.4
18.7 1.5
14.6 1.3
20.2 1.2
NA
17.5 0.2
11.4 0.3
15.5 0.2
NA
26.3 0.5
NA
10b
Ketoconazole
Gentamycin
23.5 0.7
27.7 0.3
20.2 1.5
19.7 0.7
12.2 1.3
23.7 1.1
–
13.1 0.7
25.4 0.1
–
–
–
–
–
23.8 0.7
26.4 0.5
19.7 0.6
24.9 1.5
NA: No activity under the screening conditions; –: Not tested; SEM: standard error mean; each value is the mean of
3 values.

6
I. M. M. OTHMAN AND A. H. M. HUSSEIN
Figure 2. Comparison of the biological activity of the newly target compounds.
albicans. A solution of the target derivatives in concentration 1 mg/mL were tested
against the various organisms and reported as inhibition zone diameter in mm (agar
well diffusion procedure) (Table 1 and Fig. 2). Derivatives 3a, 3b, 6a, 6d, 6e, 6f, 9a,
9b and 10b illustrated bioactivity ranging from reasonable to excellent against all
organisms strains. However, compound 9b showed the highest activity against all
microorganism’s strains used in this investigation. In addition, structure 9b displayed
nearly equipotent inhibition region as the standard drugs used for against organisms,
followed by compounds, 6f, 10b, 6d, 6e, 3b, 9a, 6a and 3a, respectively. On the
other hand, the 3-oxo-2-(2-phenylhydrazono)butanamide derivative 3a displayed
weak bioactivity on both of S. pneumonia and A. fumigates, whereas both of com-
pounds 6b,c and 10a had no pathogens activities. Moreover, the most bioactive
structures 3b, 6d, 6e, 6f, 9b and 10b were inspected for the determination of the
minimum inhibitory concentration (MIC). Compound 9b illustrated the best MIC
values ranged from 0.49 0.2 to 3.9 0.6 lg/mL, followed by 6f, 10b, 6d, 6e and 3b
(MIC 0.98 0.1–250 0.6 lg/mL) (Table 2).
Antimicrobial activity
All biological strains were received from the culture collection of the Regional Center for
Mycology and Biotechnology (RCMB), Al-Azhar University, Cairo, Egypt. All target deriva-
tives were tested in-vitro against to various kinds of bacteria, Gram-positive bacteria
(Streptococcus pneumoniae and Bacillus subtilis) and Gram-ve bacteria (Pseudomonas aerugi-
nosa strain and Escherichia coli strain) and against Aspergillus fumigatus strain, Candida
albicans strain for their antifungal activity, respectively. The standard drugs of gentamycin
and ketoconazole were used as examples of antibacterial and antifungal activity. The diam-
eter of the inhibition zone (mm) was measured for the antimicrobial bioactivity using the
diffusion technique[27]. The proper target structures were further tested to estimate their

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SYNTHETIC COMMUNICATIONSV
7
Table 2. Minimum inhibitory concentration (MIC) (lg/mL) of the most bioactivity derivatives.
MIC (Mean SEM) (lg/mL)
Gram þ ve bacteria
Gram-ve bacteria
Fungi
S. pneumoniae
B. subtilis
P. aeruginosa
E. coli
A. fumigatus
C. albicans
Compd.
RCMB 010010
RCMB 010067
RCMB 010043
RCMB 010052
RCMB 002568
RCMB 005036
3b
6d
6e
6f
7.81 0.2
0.98 0.2
0.98 0.03
0.49 0.4
0.49 0.2
0.98 0.1
–
3.9 0.03
1.95 0.5
7.81 0.2
0.98 0.1
0.98 0.01
0.49 0.3
–
0.98 0.1
3.9 0.2
15.63 0.4
3.9 0.3
1.95 0.01
3.9 0.01
–
250 0.6
62.5 0.1
125 0.3
3.9 0.1
0.98 0.5
3.9 0.3
–
15.63 0.2
1.95 0.3
3.9 0.2
7.81 0.3
3.9 0.6
250 0.1
1.95 0.3
–
125 0.05
15.63 0.3
250 0.05
62.5 0. 5
0.98 0.6
125 0.2
0.98 0.1
–
9b
10b
Ketoconazole
Gentamycin
–
–
3.9 0.6
0.98 1.03
–: Not tested; NA: No activity under the screening conditions; SEM: mean of the standard error; each value is the mean
of 3 values.
antimicrobial activity expressed in terms of minimum inhibitory concentration (MIC) using
the modified agar well diffusion method[27]
.
Conclusion
3-Oxobutanamide derivative 1 was used to synthesize new valuable heterocycles target-
ing to excess their synthetic potential. Moreover, arylhydrazones 3a,b were used as a
valuable scaffold to build different heterocyclic rings through simple and synthetic strat-
egies reactions. Finally, on the inspection of newly-synthesized structures for their anti-
microbial bioactivity against selected pathogens strains, we noted that pyridazine
carboxamide derivative 9b displayed an excellent activity among all microorganism’s
strains used in this investigation.
Experimental
Melting points were determined with a Stuart melting point apparatus and are uncor-
rected. The IR spectra were recorded on a Pye-Unicam Sp-100 spectrophotometer using
KBr wafer technique. 1H-NMR (300 MHz) and 13C-NMR (100 MHz) measurements
were executed using Varian-400 MHz spectrometer, and chemical shifts were expressed
in d (ppm) relative to TMS (in DMSO-d6 as solvent) as the internal standard at the
Microanalytical center, Cairo and Assiut University. The elemental analyses were exe-
cuted on Perkin-Elmer 2400 elemental analyzer, and the values found were within
0.3% of the theoretical. Preparative and analytical TLC were executed on silica gel
plates (Fluka 70643-50EA. Sigma-Aldrich, Germany) using UV light. All reactions were
carried out under an air atmosphere.
General procedure for preparation of compounds 3a,b
To a cold solution of N-(4-methoxyphenyl)-3-oxobutanamide (1) (2.07 g, 10 mmol) and
sodium acetate (2 g) in ethanol (40 mL), the appropriate diazonium chlorides 2a,b (pre-
pared from (0.91 mL and 1.72 g, 10 mmol) of amines and the appropriate quantities of

8
I. M. M. OTHMAN AND A. H. M. HUSSEIN
HCl 4.00 mL and NaNO2 (0.69 g, 10 mmol)) were added. The addition was carried out
portion-wise with stirring at 0–58C over a period of 15 min. After complete addition,
the reaction mixture was stirred further for 1 h. The precipitated solid was collected by
filtration, washed with water, dried, and finally recrystallized from the proper solvent to
afford the corresponding coupling products 3a,b.
N-(4-Methoxyphenyl)-3-oxo-2-(2-phenylhydrazono)butanamide (3a)
It was obtained as red crystals from ethanol; yield (2.7 g, 90%), mp. 180–181˚C; IR
(KBr) m cmꢀ1 3247, 3185 (2NH), 3051 (CH-arom.), 2980 (CH-aliph.), 1686, 1662
1
(2C¼O); H NMR (300 MHz, DMSO-d6): d ¼ 2.48 (s, 3H, CH3), 3.81 (s, 3H, OCH3),
6.95–7.42 (m, 9H, Ar–H), 9.11 (s, 1H, NH), 11.14 (s, 1H, NH); 13C NMR (100 MHz,
DMSO-d6): 25.8, 55.2, 113.1, 114.0, 122.6, 123.7, 127.1, 129.7, 132.3, 143.0, 157.2, 164.3,
190.5. Anal. Calc. For C17H17N3O3 (311.34): C, 65.58; H, 5.50; N, 13.50%.Found: C,
65.80; H, 5.71; N, 13.73%.
N-(4-Methoxyphenyl)-3-oxo-2-(2-(4-sulfamoylphenyl)hydrazono)butanamide (3b)
It was obtained as yellow crystals from ethanol; yield (3.3 g, 89%), mp. 193–194ꢁC; IR
(KBr) m cmꢀ1 3433, 3325 (NH2), 3252, 3147 (2NH), 3058 (CH-arom.), 2974 (CH-
1
aliph.), 1691, 1665 (2C¼O); H NMR (300 MHz, DMSO-d6): d ¼ 2.42 (s, 3H, CH3), 3.78
(s, 3H, OCH3), 7.31–7.89 (m, 10H, Ar–H þ NH2), 10.17 (s, 1H, NH), 11.62 (s, 1H,
NH); 13C NMR (100 MHz, DMSO-d6): 27.1, 54.6, 114.5, 117.0, 122.2, 128.3, 129.7,
130.1, 132.3, 145.4, 157.5, 164.8, 191.11. Anal. Calc. for C17H18N4O5S (390.41): C, 52.30;
H, 4.65; N, 14.35; S, 8.21%.Found: C, 52.54; H, 4.86; N, 14.57; S, 8.43%.
Full experimental section and spectral data can be presented in the Supplementary
Information.
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