Synthesis of some pyridazine derivatives carrying urea, thiourea, and sulfonamide moieties and their antimicrobial activity

Article abstract of DOI:10.3906/kim-0904-27

Some pyridazine derivatives carrying urea, thiourea, and sulfonamide groups were synthesized and evaluated for their antimicrobial activity against gram-positive and gram-negative bacteria, and fungi by using broth microdilution. The structures of these new compounds were confirmed by ¹H-NMR, mass spectrum, and elemental analysis. The synthesized compounds exhibited generally promising inhibitory activity against S. aureus (MIC ranging from 2 to 4 μg/mL) and E. coli (MIC ranging from 4 to 16 μg/mL). Moreover, all compounds showed antifungal activity against both C. albicans and C. parapsilosis, with a MIC value of 8 μg/mL. TUeBITAK.

Full text of DOI:10.3906/kim-0904-27

Turk J Chem
34 (2010) , 57 – 65.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-0904-27
Synthesis of some pyridazine derivatives carrying urea,
thiourea, and sulfonamide moieties and their
antimicrobial activity
1,∗
1
1
˘
¨
1
Deniz S. DOGRUER , S¸¨olen URLU , Tijen ONKOL ,
2
¨
˙
˙
Berrin OZC¸ELIK , M. Fethi S¸AHIN
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University,
06330 Etiler, Ankara-TURKEY
e-mail: denizdogruer2002@yahoo.com
2Department of Microbiology, Faculty of Pharmacy, Gazi University,
06330 Etiler, Ankara-TURKEY
Received 16.04.2009
Some pyridazine derivatives carrying urea, thiourea, and sulfonamide groups were synthesized and
evaluated for their antimicrobial activity against gram-positive and gram-negative bacteria, and fungi by
using broth microdilution. The structures of these new compounds were confirmed by 1 H-NMR, mass
spectrum, and elemental analysis. The synthesized compounds exhibited generally promising inhibitory
activity against S. aureus (MIC ranging from 2 to 4 μg/mL) and E. coli (MIC ranging from 4 to 16
μg/mL). Moreover, all compounds showed antifungal activity against both C. albicans and C. parapsilosis,
with a MIC value of 8 μg/mL.
Key Words: Pyridazine derivatives, antibacterial activity, antifungal activity.
Introduction
Despite many significant progresses in antimicrobial therapy, infectious diseases caused by bacteria and fungi
remain a major worldwide health problem due to rapid development of resistance to the existing antimicrobial
drugs (antibacterial and antifungal). In other words, the increasing use and misuse of the existing antimicrobial
drugs have resulted in the development of resistant pathogens.
∗Corresponding author
57

˘
Synthesis of some pyridazine derivatives carrying..., D. S. DOGRUER, et al.,
In particular, the emergence of multidrug resistant gram-positive and gram-negative bacteria has caused
life-threatening infectious diseases in many countries around the world. For example, multidrug resistant
gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant S.
aureus (VRSA), and vancomycin-resistant Enterococci (VRE) are of major concern.1 Similarly, gram-negative
bacteria producing extended spectrum β-lactamase (ESβL) like Escherichia coli have also caused serious
health problems.1 In addition, systemic and dermal fungal infections have significantly increased, specifically
in individuals with suppressed immune systems such as cancer chemotherapy and AIDS patients.2 Although
there are different antifungal drugs used in the treatment of fungal infections, some of them have undesirable
side effects because of the biochemical similarity between human cell and fungi forms.3 Moreover, some of them
become less effective due to the development of resistance to these drugs.3 Therefore, a number of clinically
effective antibacterial and antifungal drugs have become less effective due to the development of resistance to
these drugs.
As a result, there is an increasing need to design new antibacterial and antifungal agents with better
activity profile and lower toxicity.
Many research groups as well as our group have been interested in pyridazine derivatives due to their
diverse biological activities, including antimicrobial,4−6 antioxidant,7 analgesic, and anti-inflammatory.8,9 On
the other hand, urea and thiourea derivatives have been reported to have antimicrobial,10 antiviral,11,12anti-
HIV,13,14 and antitumor15,16 properties apart from other biological activities. As for sulfonamide derivatives,
they are reported to possess different biological activities and some are used as drugs.3,17
On the basis of these findings, the aim of this study was to synthesize the hybrid molecules through the
combination of different pharmacophores in one structure with the hope of obtaining better antibacterial and
antifungal agents.
Therefore, we synthesized 16 new pyridazine derivatives carrying urea, thiourea, and sulfonamide groups
at position 3 in order to investigate their antibacterial and antifungal activities.
N
N
N
N
N
N
R'
NH
NH (CH2)n
NH
NH
NH
R
S
O
O
x
x
X = O, S
n = 1, 2
R and R' = H, Cl, CH3, OCH3
Figure. General structure of the synthesized compounds.
58

˘
Synthesis of some pyridazine derivatives carrying..., D. S. DOGRUER, et al.,
Experimental
Chemistry
3-Chloro-6-phenylpyridazine was purchased from Maybridge (England). All the other chemicals used for the
synthesis of the compounds were purchased from Aldrich (Germany) and Merck (Germany). Microwave irradi-
ation was carried out in a microwave oven (Milestone-MicroSYNTH-Italy). Melting points of the compounds
were recorded on an Electrothermal-9200 digital melting points apparatus and are uncorrected. The 1 H-NMR
spectra were recorded with a Varian Mercury-400 FT-NMR spectrometer (Varian Inc., Palo Alto, CA, USA) in
DMSO-d6 at the Faculty of Pharmacy, Ankara University, Ankara, Turkey. The mass spectra were obtained
on a Waters ZQ micromass LC-MS spectrometer (Waters Corporation, Milford, MA, USA) using the ESI(+)
method at the Faculty of Pharmacy, Ankara University. Elemental analysis was performed on a Leco 932 CHNS
instrument (St. Joseph, MI, USA) at the Faculty of Pharmacy, Ankara University, and the results were within
0.4% of the theoretical values. 3-Amino-6-phenylpyridazine (1) used to synthesize the title compounds was
prepared by Suzuki cross coupling reaction in our laboratory as described in the literature.18
General procedure for synthesis of (2a-2d)
The appropriate isocyanate derivatives (0.0022 mol) were added to a solution of the 3-amino-6-phenylpyridazine
(0.002 mol) in 15 mL of toluene. The resulting mixture was heated under microwave irradiation at 120 ◦ C
(450 W) for 15 min. At the end of this period, the reaction mixture was evaporated to dryness and all urea
derivatives were crystallized from acetic acid.
N -Phenyl-N’-(6-phenylpyridazin-3-yl)urea (2a)
Yield: 38%; m.p.: 307 ◦ C. 1 H-NMR (DMSO-d6) δ: 9.85 (s, 1H), 9.76 (s, 1H), 8.22 (d, J =9.2 Hz, 1H),
8.15-8.03 (m, 3H), 7.56-7.47 (m, 5H), 7.34 (t, J =7.6 Hz, 2H), 7.05 (t,J =7.6 Hz, 1H). MS ESI(+) m/e291
(M+H,100). Anal. (C17 H14 N4 O): C, H, N calc. 70.33, 4.86, 19.30 found 70.22, 4.58, 19.03.
N -(4-Chlorophenyl)-N’-(6-phenylpyridazin-3-yl)urea (2b)
Yield: 45%; m.p.: 298 ◦ C. 1 H-NMR (DMSO-d6) δ: 9.88 (s, 1H), 9.86 (s, 1H), 8.22 (d,J =9.2 Hz, 1H), 8.13-8.08
(m, 3H), 7.56-7.49 (m, 5H), 7.38 (d,J =8.8 Hz, 2H). MS ESI(+) m/e325 (M+H, 100). Anal. (C17 H13 ClN4 O):
C, H, N calc. 62.87, 4.03, 17.25 found 63.24, 4.16, 17.22.
N -(4-Methylphenyl)-N’-(6-phenylpyridazin-3-yl)urea (2c)
Yield: 33%; m.p.: 287 ◦ C. 1 H-NMR (DMSO-d6) δ: 9.83 (s, 1H), 9.70 (s, 1H), 8.22 (d, J =9.2 Hz, 1H),
8.12-8.08 (m, 3H), 7.56-7.49 (m, 3H), 7.40 (d, J =8 Hz, 2H), 7.14 (d, J =8 Hz, 2H), 2.27 (s, 3H). MS ESI(+)
m/e305 (M+H, 100). Anal. (C18 H16 N4 O): C, H, N calc. 71.04, 5.30, 18.41 found 71.31, 4.92, 18.19.
59

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Synthesis of some pyridazine derivatives carrying..., D. S. DOGRUER, et al.,
N -(4-Methoxyphenyl)-N’-(6-phenylpyridazin-3-yl)urea (2d)
Yield: 30%; m.p.: 270 ◦ C. 1 H-NMR (DMSO-d6) δ: 9.79 (s, 1H), 9.65 (s, 1H), 8.22 (d, J =9.2 Hz, 1H),
8.10-8.08 (m, 3H), 7.55-7.49 (m, 3H), 7.42 (d, J =7.2 Hz, 2H), 6.92 (d, J =7.2 Hz, 2H), 3.74 (s, 3H). MS ESI(+)
m/e321 (M+H, 100). Anal. (C18 H16 N4 O2): C, H, N calc. 67.49, 5.03, 17.49 found 67.64, 4.70, 17.28.
N -Benzyl-N ’-(6-phenylpyridazin-3-yl)urea (2e)
Yield: 30%; m.p.: 268 ◦ C. 1 H-NMR (DMSO-d6) δ: 9.76 (s, 1H), 9.65 (s, 1H), 8.16 (d, J =9.2 Hz, 1H), 8.05
(d, J =7.2 Hz 2H), 7.94 (d, J =9.2 Hz, 1H), 7.54-7.25 (m, 8H), 4.43 (s, 2H). MS ESI(+) m/e305 (M+H, 100).
Anal. (C18 H16 N4 O): C, H, N calc. 71.04, 5.30, 18.41 found 71.19, 5.11, 18.24.
N -(2-Phenylethyl)-N’-(6-phenylpyridazin-3-yl)urea (2f)
Yield: 25%; m.p.: 216 ◦ C. 1 H-NMR (DMSO-d6) δ: 9.76 (s, 1H), 9.65 (s, 1H), 8.12 (d, J =9.2 Hz, 1H), 8.05
(d, J =7.2 Hz, 2H), 7.94 (d, J =9.2 Hz, 1H), 7.54-7.19 (m, 8H), 3.45 (t, J =7.2 Hz 2H), 2.81 (t, J =7.2 Hz, 2H).
MS ESI(+) m/e319 (M+H,100). Anal. (C19 H18 N4 O): C, H, N calc. 71.68, 5.70, 17.60 found 71.35, 5.90,
17.41.
General procedure for synthesis of (3a-3d)
The appropriate isothiocyanate derivatives (0.0022 mol) were added to a solution of the 3-amino-6-phenylpyridazine
(0.002 mol) in 15 mL of toluene. The resulting mixture was heated under microwave irradiation at 120 ◦ C
(450 W) for 20 min. At the end of this period, the reaction mixture was evaporated to dryness and all thiourea
derivatives were crystallized from butanol.
N -Phenyl-N’-(6-phenylpyridazin-3-yl)thiourea (3a)
Yield 35%; m.p.: 198 ◦ C. 1 H-NMR (DMSO-d6) δ: 13.52 (s, 1H), 11.19 (s, 1H), 8.34 (d, J =9.6 Hz, 1H), 8.10
(d, J =6.4 Hz, 2H), 7.71-7.52 (m, 6H), 7.44 (t,J =8 Hz, 2H), 7.28 (t, J =8 Hz, 1H). MS ESI(+) m/e307 (M+H,
100). Anal. (C17 H14 N4 S): C, H, N, S calc. 66.64, 4.61, 18.29, 10.47 found 66.76, 4.76, 18.12, 10.35.
N -(4-Chlorophenyl)-N’-(6-phenylpyridazin-3-yl)thiourea (3b)
Yield 38%; m.p.: 200 ◦ C. 1 H-NMR (DMSO-d6) δ: 13.53 (s, 1H), 11.25 (s, 1H), 8.33 (d, J =9.6 Hz, 1H), 8.10
(d, J =6.4 Hz, 2H), 7.75-7.48 (m, 8H). MS ESI(+) m/e341 (M+H, 100). Anal. (C17 H13 ClN4 S): C, H, N, S
calc. 59.91, 3.84, 16.44, 9.41 found 60.30, 3.94, 16.46, 9.25.
N -(4-Methylphenyl)-N’-(6-phenylpyridazin-3-yl)thiourea (3c)
Yield 32%; m.p.: 199 ◦ C. 1 H-NMR (DMSO-d6) δ: 13.44 (s, 1H), 11.14 (s, 1H), 8.33 (d, J =9.6 Hz, 1H), 8.10
(d,J =6.4 Hz, 2H), 7.70 (d,J =9.6 Hz, 1H), 7.57-7.52 (m, 5H), 7.23 (d, J =8 Hz, 2H), 2.34 (s, 3H). MS ESI(+)
m/e321 (M+H, 100). Anal. (C18 H16 N4 S): C, H, N, S calc. 67.47, 5.03, 17.49, 10.01 found 67.36, 5.16, 17.44,
9.93.
60

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Synthesis of some pyridazine derivatives carrying..., D. S. DOGRUER, et al.,
N -(4-Methoxyphenyl)-N’-(6-phenylpyridazin-3-yl)thiourea (3d)
Yield 30%; m.p.: 208 ◦ C. 1 H-NMR (DMSO-d6) δ: 13.32 (s, 1H), 11.13 (s, 1H), 8.33 (d, J =9.6 Hz, 1H), 8.10
(d,J =6.4 Hz, 2H), 7.70 (d,J =9.6 Hz, 1H), 7.60-7.52 (m, 5H), 6.99 (d, J =8 Hz, 2H), 3.79 (s, 3H). MS ESI(+)
m/e337 (M+H, 100). Anal. (C18 H16 N4 OS): C, H, N, S calc. 64.26, 4.79, 16.65, 9.53 found 64.61, 4.73, 16.70,
9.43.
N -Benzyl-N ’-(6-phenylpyridazin-3-yl)thiourea (3e)
Yield 30%; m.p.: 217 ◦ C. 1 H-NMR (DMSO-d6) δ: 11.92 (s, 1H), 10.97 (s, 1H), 8.24 (d,J =9.6 Hz, 1H), 8.03
(d, J =6.4 Hz, 2H), 7.59-7.27 (m, 9H), 4.95 (s, 2H). MS ESI(+) m/e321 (M+H, 100). Anal. (C18 H16 N4 S):
C, H, N, S calc. 67.47, 5.03, 17.49, 10.01 found 67.65, 5.20, 17.36, 9.97.
N -(2-Phenylethyl)-N’-(6-phenylpyridazin-3-yl)thiourea (3f)
Yield: 25%; m.p.: 258 ◦ C. 1 H-NMR (DMSO-d6) δ: 11.62 (s, 1H), 10.80 (s, 1H), 8.24 (d, J =9.6 Hz, 1H), 8.03
(d, J =6.4 Hz, 2H), 7.59-7.20 (m, 9H), 3.90 (t, J =7.2 Hz, 2H), 2.99 (t, J =7.2 Hz, 2H). MS ESI(+) m/e335
(M+H, 100). Anal. (C19 H18 N4 S): C, H, N, S calc. 68.23, 5.42, 16.75, 9.59 found 62.22, 5.70, 16.59, 9.71.
General procedure for synthesis of (4a-4d)
Substituted benzenesulfonyl chlorides (0.003 mol) were added to the solution of 3-amino-6-phenylpyridazine
(0.003 mol) in 10 mL of pyridine at 0 o C. The resulting mixture was stirred at room temperature for 4 h. At
the end of this period, the reaction mixture was poured into ice water. The precipitate was filtered and dried.
After that, all sulfonamide derivatives were crystallized from isopropyl alcohol.
N -(6-Phenylpyridazin-3-yl)benzenesulfonamide (4a)
Yield 80%; m.p.: 204 ◦ C. 1 H-NMR (DMSO-d6) δ: 8.27 (d,J =10 Hz, 1H), 7.89-7.47 (m, 11H). MS ESI(+)
m/e312 (M+H, 100). Anal. (C16 H13 N3 O2 S): C, H, N, S calc. 61.72, 4.21, 13.50, 10.30 found 61.90, 4.19,
13.45, 10.30.
4-Chloro-N -(6-phenylpyridazin-3-yl)benzenesulfonamide (4b)
Yield 85%; m.p.: 209 ◦ C. 1 H-NMR (DMSO-d6) δ: 8.33 (d, J =10 Hz, 1H), 7.92-7.51 (m, 10H). MS ESI(+)
m/e346 (M+H, 100). Anal. (C16 H12 ClN3 O2 S): C, H, N, S calc. 55.57, 3.50, 12.15, 9.27 found 55.74, 3.60,
12.09, 9.24.
4-Methyl-N-(6-phenylpyridazin-3-yl)benzenesulfonamide (4c)
Yield 75%; m.p.: 194 ◦ C. 1 H-NMR (DMSO-d6) δ: 8.28 (d, J =10 Hz, 1H), 7.91-7.50 (m, 8H), 7.35 (d,J =8
Hz, 2H), 2.35 (s, 3H). MS ESI(+) m/e326 (M+H, 100). Anal. (C17 H15 N3 O2 S): C, H, N, S calc 62.75, 4.65,
12.91, 9.85 found 62.95, 4.60, 12.91, 9.88.
61

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Synthesis of some pyridazine derivatives carrying..., D. S. DOGRUER, et al.,
4-Methoxy-N-(6-phenylpyridazin-3-yl)benzenesulfonamide (4d)
Yield 75%; m.p.: 165 ◦ C. 1 H-NMR (DMSO-d6) δ: 8.24 (d,J =10 Hz, 1H), 7.89-7.47 (m, 8H), 7.04 (d, J =8.6
Hz, 2H), 3.78 (s, 3H). MS ESI(+) m/e342 (M+H, 100). Anal. (C17 H15 N3 O3 S): C, H, N, S calc 59.81, 4.43,
12.31, 9.39 found 59.88, 4.34, 12.25, 9.45.
Antimicrobial activity19,20
Minimum inhibitory concentration (MIC) values for the synthesized compounds were determined by using broth
microdilution. Standard and the isolated strains of the bacteria;. coli ATCC 25922, E. coli producing extended
spectrum β-lactamase (ESβL), P. aeruginosa ATCC 27853, P. aeruginosa isolate S. aureus ATCC 29213,
methicillin-resistant S. aureus (MRSA), Enterococcus faecalis ATCC 29212, and E. faecalis isolate were used to
determine antibacterial activity. As for antifungal activity, standard strains of Candida albicans ATCC 10231
and Candida parapsilosis ATCC 90018 were used. Ampicillin and fluconazole were used as references. All
bacteria were cultivated in Mueller–Hinton Agar and were diluted with Mueller–Hinton Broth (Oxoid). All
fungi were cultivated in Sabouraud Dextrose Agar. The fungi inoculums were prepared in Sabouraud liquid
medium (Oxoid), which had been kept at 36 ◦ C overnight, and were diluted with RPMI-1640 medium with
L-glutamine buffered with 3-[N-morpholino]-propansulfonic acid (MOPS) at pH 7. The synthesized compounds
and references were dissolved in DMSO/H2 O (50%), at a concentration of 1024 μg/mL. Two-fold dilutions
of the synthesized compounds and reference compounds were added to the wells (512, 256. . . . . . . .
..0.25 μg/mL). After that, suspension of the microorganisms was inoculated into all the wells. Final inoculum
concentrations were 104 cfu/mL for bacteria and 2.5 × 103 cfu/mL for fungi in the wells. The sealed microplates
were incubated at 36 ◦ C for 24 h for antibacterial activity and at 36 ◦ C for 48 h for antifungal activity in a
humid chamber. At the end of the incubation period, MIC values were recorded as the lowest concentrations
of the substances that had no visible turbidity.
Results and discussion
Chemistry
3-Amino-6-phenylpyridazine (1) used to synthesize the title compounds was prepared by Suzuki cross coupling
reaction in our laboratory as described in the literature.18 The urea (2a-2f) and thiourea derivatives (3a-3f)
were obtained by the reaction of 3-amino-6-phenylpyridazine with the appropriate isocyanates and isothio-
cyanates respectively by microwave synthesis in toluene. The sulfonamide derivatives (4a-4d) were synthesized
by the reaction of 3-amino-6-phenylpyridazine with the appropriate benzenesulfonyl chlorides in pyridine.
Synthetic route of the compounds is given in the Scheme. The chemical structures of the title compounds
were elucidated by 1 H-NMR, mass spectrum, and elemental analysis. The 1 H-NMR, mass spectra, and
elemental analysis data are in agreement with the proposed structures. In the 1 H-NMR spectra, the N-H
protons of the urea (2a-2f) and thiourea (3a-3f) derivatives were observed as 2 separate singlets at 9.88-9.65
and 13.53-10.80 ppm, respectively. However, the N-H protons of the sulfonamide derivatives (4a-4d) were not
seen in the 1 H-NMR spectrum; this may be attributed to the deuterium exchange.
62

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Synthesis of some pyridazine derivatives carrying..., D. S. DOGRUER, et al.,
Cl
N
N
PhB(OH)2 , Pd(PPh3)4
2M Na2CO3 , Toluene
N
N
NH2
NH2
O O
Cl
R'
S
R
N C X
1
(CH2
)
n
N
C X
N
N
N
N
N
R'
N
HN
NH
R
HN
HN
NH
(CH2)
n
S
O
O
X
X
4
2, 3
2, 3
X = O, n =1 ; (2e)
X = O, n =2 ; (2f )
X = O
X = S R = H (3a), Cl (3b), CH3 (3c),
R = H (2a), Cl (2b), CH3 (2c),
OCH3 (2d)
OCH3 (3d)
R' = H (4a), Cl (4b),
CH (4c),
OCH3 (4d)
3
X = S, n =1 ; (3e)
X = S, n =2 ; (3f )
Scheme. Synthetic route of the synthesized compounds.
Antimicrobial Activity
The synthesized compounds were tested for antibacterial activity against gram-negative E. coli, E. coli producing
extended spectrum β-lactamase, P. aeruginosa, P. aeruginosa isolate, gram-positive S. aureus, methicillin-
resistant S. aureus (MRSA, isolate), E. faecalis, and E. faecalis isolate bacteria, and for antifungal activity
against C. albicans and C. parapsilosis by using broth microdilution. Ampicillin and fluconazole were used as
antibacterial and antifungal references, respectively.
As shown in the Table, the synthesized compounds exhibited a broad spectrum of activity with MIC
values 2-128 μg/mL against both gram-positive and gram-negative bacteria. Generally, synthesized compounds
were more active against gram-positive bacteria rather than gram-negative bacteria. Apart from E. coli isolate,
the title compounds were not active against the other bacteria isolates. Among the gram-positive bacteria
tested, S. aureus showed relative high sensitivity towards the title compounds. Compounds 2a, 2d, and 2e,
63

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Synthesis of some pyridazine derivatives carrying..., D. S. DOGRUER, et al.,
which are urea derivatives, and compounds 3b and 3e, which are thiourea derivatives, gave the best inhibitory
activity against S. aureus with a MIC value of 2 μg/mL; that is, their antibacterial activity was 50% of that
of ampicillin against S. aureus. Compounds 2a, 2d, 2e, 3b, and 3e may be worth studying further to develop
better antibacterial agents against S. aureus. Further substitution on the pyridazine ring can be studied for
these compounds. Antibacterial activity for the rest of the compounds was observed against S. aureus at 4
μg/mL concentration. The compounds showed activity against E. faecalis with MIC values of 4 and 8 μg/mL.
Regarding the antibacterial activity of the target compounds against gram-negative bacteria, they exerted a
relatively good inhibitory profile against E. coli, with MIC values ranging from 4 to 16 μg/mL. The antibacterial
activity of compounds 2a-2c, 3b-3d, and 4a-4c was 50% of that of ampicillin against E. coli. Therefore, it can
be suggested that these compounds show promise as antibacterial against E. coli. With respect to antifungal
activity of the synthesized compounds, all compounds displayed antifungal activity against both C. albicans
and C. parapsilosis, with a MIC value of 8 μg/mL. In other words, their antibacterial activity was 25% and 50%
of that of fluconazole against C. albicans and C. parapsilosis, respectively. According to the obtained results,
one can say that structural differences do not play a critical role in antifungal activity.
Table. Antimicrobial activity of the synthesized compounds (MICs, μg/mL).
Comp.
2a
A
2
4
4
2
2
4
4
2
4
4
2
4
4
4
4
4
1
-
B
C
4
8
8
4
4
8
8
8
8
8
8
4
8
4
4
4
D
E
4
F
G
H
I
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
-
J
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
-
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
128
32 128 128
32 128 128
32 128 128
2b
4
2c
4
2d
128 16 64 128 128
128 16 64 128 128
128 16 64 128 128
2e
2f
3a
128
128
128
128
8
4
4
4
32 128 128
32 128 128
32 128 128
32 128 128
3b
3c
3d
3e
128 16 64 128 128
128 16 32 128 128
3f
4a
128
128
128
4
4
4
32 128 128
32 128 128
32 128 128
4b
4c
4d
128 16 64 128 128
AMP
FLU
128 0.5 128
2
-
128 128 128
-
-
-
-
-
-
2
4
AMP: ampicillin, FLU: fluconazole
A: S. aureus ATCC 29213, B: MRSA, C: E. faecalis ATCC 29212, D: E. faecalis isolate, E: E.coli ATCC 25922,
F: E. coli isolate, G: P. aeruginosa ATCC 27853,
H: P. aeruginosa isolate, I: C. albicans ATCC 10231, J: C. parapsilosis ATCC 90018
64

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Synthesis of some pyridazine derivatives carrying..., D. S. DOGRUER, et al.,
Acknowledgments
This study was supported by Gazi University BAP (Project Number 02/2008-12).
References
1. Grare, M.; Mourer, M.; Fontanay, S.; Regnouf-de-Vains, J. B. Finance, C.; Duval, R. E. J. Antimicrob. Chemother.
2007, 60, 575-581.
2. Ghannoum, M.A.; Rice L. B. Clinical Microbiology Reviews 1999, 12, 501-517.
3. Williams DA, Lemke TL. Foye’s Principles of Medicinal Chemistry, 5th ed. Lippincott Williams and Wilkins,
2002.
4. El-Mariah F.; Nassar, E.; Hosny, M.; Deeb, A. Phosphorus, Sulfur, and Silicon, 2009, 184, 92-102.
5. Kandile, N. G.; Mohamed, M. I.; Zaky, H.; Mohamed, H. M. Eur. J. Med. Chem. 2009, 44, 1989-1996.
6. Butnariu, R. M.; Caprosu, M. D.; Bejan, V.; Ungureanu, M.; Poiata, A.; Tuchilus, C.; Florescu, M.; Mangalagiu,
I. I. J. Heterocyclic Chem. 2007, 44, 1149-1152.
7. Caliskan, E. B.; Sukuroglu, M.; Coban, T.; Banoglu, E.; Suzen, S. J. Enz. Inhib. Med. Chem. 2008, 23, 225-229.
8. Dogruer, D. S.; Unlu, S.; Kupeli, E.; Banoglu, E.; Sahin, M. F. Turkish J. Pharm. Sci. 2007, 4, 57-70.
9. Dog˘ruer, D. S.; S¸ahin M. F.; Ku¨peli, E.; Ye¸silada, E. Turk. J. Chem. 2003, 27, 727-738.
10. Abdel-Rahman, H. M.; Morsy, M. A. J. Enz. Inhib. Med. Chem. 2007, 22, 57-64.
11. Dzimbeg, G.; Zorc, B.; Kralj, M.; Ester, K.; Pavelic, K.; Andrei, G.; Snoeck, R.; Balzarini, J.; De Clercq, E.;
Mintas, M. Eur. J. Med. Chem. 2008, 43, 1180-1187.
12. Sun, C.; Zhang, X.; Huanga, H.; Zhoua, P. Bioorg. Med. Chem. 2006, 14, 8574-8581.
13. Rubinstein, A. Current Pharmaceutical Design, 2005, 11, 3769-3778.
14. Venkatachalam, T. K.; Sudbeck, E. A.; Mao, C.; Uckun, F. M. Bioorg. Med. Chem. 2001, 11, 523-528.
15. Sharma, B. K.; Sharma, S. K.; Singh, P.; Sharma, S. J. Enz. Inhib. Med. Chem. 2008, 23, 168-173.
16. Shusheng, Z.; Tianrong, Z.; Kun, C.; Youfeng, X.; Bo, Y. Eur. J. Med. Chem. 2008, 43, 2778-2783.
17. Scozzafava, A.; Owa, T.; Mastrolorenzo, A.; Supuran, C. T. Curr. Med. Chem.;003, 10, 925-953.
18. Maes, B. U. W.; Lemiere G. L. F.; Dommisse, R.; Augustyns, K.; Haemers, Tetrahedron 2000, 56, 1777-1781.
19. Clinical and Laboratory Standards Institute (CLSI; formerly NCCLS) Method for dilution antimicrobial suscepti-
bility tests for bacteria that grow aerobically, 3rd ed., Approved standard. NCCLS document M100-S12, Wayne,
PA, USA, 2002.
20. Clinical and Laboratory Standards Institute (CLSI; formerly NCCLS) Method for broth dilution antifungal
susceptibility testing yeast; approved standard. M27-A, 15, 10, NCCLS, VA Medical Center, Tucson, 1996.
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