Synthesis and antimycobacterial and antiprotozoal activities of some novel nitrobenzylated heterocycles

Article abstract of DOI:10.1515/znb-2006-0120

A series of N-, S-, and O-mononitro- and dinitrobenzyl derivatives of heterocycles was synthesized by alkylation of heterocyclic bases with the respective nitrobenzyl chlorides. Of the newly synthesized compounds, dinitrobenzylsulfanyl derivatives of 1-me

Full text of DOI:10.1515/znb-2006-0120

Synthesis and Antimycobacterial and Antiprotozoal Activities of
Some Novel Nitrobenzylated Heterocycles
a
b
b
c
˙
Agata Go´rska , Lidia Chomicz , Justyna Zebrowska , Przemysław Myjak ,
Ewa Augustynowicz-Kopec´d, Zofia Zwolskad, Janusz Piekarczyke, Henryk Rebandelf,
and Zygmunt Kazimierczuka,g
a Institute of Chemistry, Agricultural University, 159C Nowoursynowska St., 02-787 Warsaw, Poland
b Department of Medical Biology, Medical University of Warsaw, 73 Nowogrodzka St.,
02-018 Warsaw, Poland
c Department of Tropical Parasitology, Medical University of Gdansk, 9b Powstania
Styczniowego St. 81-106 Gdynia, Poland
d National Tuberculosis and Lung Diseases Research Institute, 26 Płocka St.,
01-138 Warsaw, Poland
e 2nd Department of Maxillofacial Surgery, Medical University of Warsaw, 4 Lindleya St.,
02-005 Warsaw, Poland
f
Department of Teaching and Effects of Education, Medical University of Warsaw, 4 Oczki St.,
02-007 Warsaw, Poland
g Laboratory of Experimental Pharmacology, Polish Academy of Sciences Medical Research Center,
5 Pawinskiego St., 02-106 Warsaw, Poland
Reprint requests to Prof. Z. Kazimierczuk. E-mail: kazimierczuk@delta.sggw.waw.pl
Z. Naturforsch. 61b, 101 – 107 (2006); received October 7, 2005
A series of N-, S-, and O-mononitro- and dinitrobenzyl derivatives of heterocycles was synthe-
sized by alkylation of heterocyclic bases with the respective nitrobenzyl chlorides. Of the newly syn-
thesized compounds, dinitrobenzylsulfanyl derivatives of 1-methyl-2-mercaptoimidazole (2c) and of
5-nitro- and 5,6-dichloro-2-mercaptobenzimidazole (8b and 8c, and 8e and 8f, respectively) showed
considerable antimycobacterial activity. On a molar basis, nine of the novel compounds showed also
a considerably higher antiprotozoal efficacy than metronidazole that reduced T. hominis viability
to 73.5% at 8 µg/ml.
Key words: Nitrobenzyl Derivatives, Antimycobacterial Activity, Antiprotozoal Activity,
Trichomonas hominis
Introduction
The standard treatment for TB as recommended
by WHO is a multidrug regimen that includes four
antibiotics: rifampicin, isoniazid (INH), pyrazinamid,
and either streptomycin or ethambutol. This treatment
scheme is usually effective against M. tuberculosis.
However, it may fail in settings with high frequency
of drug resistance, resulting in markedly lowered cure
rate [1]. For instance, if an M. tuberculosis strain is
resistant to rifampicin and INH, the effectiveness of
the standard treatment decreases by 15 to 77% [2].
Despite enormous work done in genetics and biology
of this bacterium, practically no new clinically useful
drug against this disease was developed over the last
40 years. Therefore, there is an urgent need for de-
signing, synthesis, and testing of new potential anti-TB
agents.
Tuberculosis (TB) is a growing global health prob-
lem in terms of both disease burden and resistance
to conventional chemotherapy. Nearly one–third of
the world population is infected with Mycobacterium
tuberculosis. This concerns both the developing and
well-developed countries. The World Health Organi-
zation estimated that over 8 million new cases ap-
peared in 2002, and the global incidence rate of TB
was growing by about 1.1% per year. An important
aspect of the epidemic is also the rise in the occur-
rence of multidrug-resistant strains of M. tuberculo-
sis. Infections due to mycobacteria other than tuber-
culosis (MOTT), ‘synergy’ of mycobacterial and HIV
infections, and mycobacterial infections in immuno-
compromised patients add to the complexity of the
issue.
Most recent studies of novel compounds of benz-
imidazole ‘ancestry’ revealed that the nitrobenzylsul-
c
0932–0776 / 06 / 0100–0101 $ 06.00 ꢀ 2006 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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102
A. Go´rska et al. · Nitrobenzyl Derivatives
fanyl substituent in position 2 of the benzimidazole ing candidate for the synthesis of modified derivatives
core especially enhanced antimycobacterial activity in as prospective drugs against M. tuberculosis and T. ho-
5-methylbenzimidazole and in benzimidazoles carry- minis. The results of the present study offer some hints
ing no substituent in the benzene ring [3 – 5]. It also for the search of novel candidate drugs among con-
has been found that 4,6-dichloro- and 4,6-dibromo- geners of the heterocyclic systems presented.
2-(p-nitrobenzylsulfanyl)benzimidazoles showed high
efficacy against some Gram-positive bacteria [6]. Hav-
ing this in mind we synthesized a number of hetero-
cycles carrying the most promising S-nitrobenzylated
substituents.
Results and Discussion
The S-substituted heterocyclic compounds studied
were obtained by the alkylation of compounds 1, 3,
5, 7 and 9 with the appropriate nitrobenzyl chlorides
(Scheme 1). While alkylation of 3 and 9 were per-
formed in a water-acetone or water-ethanol mixture, in
the presence of K2CO3 as base, to give 4a – b and 10a –
c, respectively, “phase transfer” conditions were em-
ployed to prepare compounds 2a– c, 6a – c and 8a– f.
The products were obtained in good or satisfactory
yields; however, flash chromatography was needed to
We decided to check as well the activity in vitro of
the newly synthesized nitrobenzyl derivatives against
the protozoan species Trichomonas hominis (also
called Pentatrichomonas hominis). The flagellate re-
sides as a trophozoite in the distal part of small intes-
tine and in large intestine in humans; no cyst stage is
known. While the parasite is cosmopolitan by nature, it
is more common in the subtropical and tropical zones.
Infections with T. hominis were reported in persons
of both sexes and all ages. However, because of pre-
vailingly fecal-oral transmission route, the flagellate is
found more often in children than in adults. T. hominis
is often identified in human diarrheic stools. Severe T.
hominis-associated diarrhea cases have been reported
in newborns and children up to 5 years of age, some
of which were caused by mixed infections with this
and other protozoa, including Entamoeba histolytica,
Giardia intestinalis and Blastocystis hominis [7 – 12].
A rare case was also described of a mixed infection
with T. hominis, oral bacteria, and an oral protozoan
Trichomonas tenax in pus from a subhepatic abscess
in a patient with perforated penetrating ventricular ul-
cer [13].
Whereas infections with T. hominis are even more
common than those with Giardia intestinalis in some
world regions, an optimal treatment for the former
has not been defined yet. The drug used widely
for many protozoan anaerobic parasites is metronida-
zole (chemical name: 1-(2-hydroxyethyl)-2-methyl-5-
nitroimidazole), which is also recommended to fight
intestinal trichomonosis. Due to increased use of
the agent, many metronidazole-resistant strains of
Clostridium, Helicobacter pylori, Entamoeba histolyt-
ica, Trichomonas vaginalis and Giardia intestinalis
emerge, which are reported more and more frequently
(see [14 – 18]). Therefore, there is a growing need for
new antiprotozoal agents.
In this study we tested numerous nitrobenzyl deriv-
atives of heterocyclic compounds to find a hetero-
cyclic core structure that would be the most promis- Scheme 1.
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A. Go´rska et al. · Nitrobenzyl Derivatives
103
ε
λ
δ
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104
A. Go´rska et al. · Nitrobenzyl Derivatives
Table 2. In vitro antimycobacterial activity of nitrobenzylated heterocycles expressed as the minimum inhibitory concentration
(µg/ml).
Mycobacterium strain used
Compound
tested
M. tuberculosis
37Rv
M. tuberculosis
INH-resistant
strain
M. bovis
MOTT
M. kansasii
MOTT
M. xenopii
M. avium-inter-
cellulare com-
plex (MAIC)
H
Incubation time (days)
14
21
14
21
14
21
14
21
14
21
14
21
2a
2b
2c
4a
4b
6a
6b
6c
8a
8b
8c
8d
8e
> 16
> 100
8
> 16
> 16
> 100
> 100
> 100
16
16
16
> 16
16
16
> 16
> 100
8
> 16
> 16
> 100
> 100
> 100
> 16
16
> 16
> 100
> 16
> 16
16
> 100
> 100
> 100
> 16
16
> 16
> 100
> 16
> 16
16
> 100
> 100
> 100
> 16
16
> 16
> 100
16
> 16
> 100
16
> 100
> 100
16
> 100
> 100
> 100
> 100
> 100
16
> 100
> 100
16
> 100
> 100
> 100
> 100
> 100
16
> 100
> 100
16
> 100
> 100
16
> 16
> 100
> 100
> 16
> 16
> 100
> 100
> 100
> 16
> 16
> 16
> 16
> 16
> 16
> 100
> 100
> 100
10
> 16
> 100
> 100
> 16
> 16
> 100
> 100
> 100
> 16
> 16
> 16
> 16
> 16
> 16
> 100
> 100
> 100
10
> 16
> 16
> 100
> 100
> 100
> 16
> 16
16
> 16
16
8
> 100
> 100
> 16
10
> 16
> 16
> 100
> 100
> 100
> 16
> 16
16
> 16
16
8
> 100
> 100
> 16
10
> 100
> 16
> 100
> 100
> 100
> 16
> 16
> 16
> 16
> 16
> 16
> 100
> 100
16
> 100
> 16
> 100
> 100
> 100
> 16
> 16
> 16
> 16
> 16
> 16
> 100
> 100
16
> 16
16
> 16
16
16
> 16
16
16
16
> 16
> 16
16
> 100
> 100
16
> 16
> 16
16
> 100
> 100
16
> 100
> 16
> 16
> 100
> 100
> 16
> 100
> 100
> 16
> 16
> 100
> 100
> 16
> 100
8f
16
10a
10c
10c
INH
> 100
> 100
> 16
1
> 100
> 100
> 16
1
> 100
> 100
10
10
INH – isoniazid used as a reference compound.
remove some minor byproducts. One of the reported tested. Of the N1-O-substituted benzotriazole deriva-
compounds (4a) was described earlier [20]. Yet, the tives 10a – c only the 3,5-dinitrobenzylsulfanyl com-
reaction condictions used were different and the com- pound was considerably toxic to the INH-resistant M.
pound was not fully characterized in that report; there- tuberculosis strain and to M. xenopii. None of the com-
fore it was included in the present study.
pounds reported here was appreciably active against
the M. avium intercellulare complex.
As mentioned above, some (nitrobenzylthio)benz-
imidazoles, of which the 3,5-dinitrobenzyl derivatives
showed the highest activity in vitro, were found ear-
lier to be effective antimycobacterial agents [3 – 5].
In the present study, we attempted to assess the im-
portance of the structure of the heterocyclic portion
of the nitrobenzylated derivatives. Such experiments
may allow finding another leading structure to expand
the series of the most promising heterocyclic deriva-
tives. 4,6-Dimethylpyridine derivatives 6a – c were to-
tally inactive against all mycobacteria strains utilized.
Of the imidazoles substituted at the exocyclic sulfur
(2a– c) or N1-nitrogen (4a, 4b), only 3,5-dinitrobenzyl
derivatives exhibited a considerable antimycobacter-
ial activity; interestingly, 2c showed a wider activ-
ity than the N1-substituted compound 4b that was
only effective against the INH-resistant M. tuberculo-
sis strain. The 5-nitro- and 5,6-dichlorobenzimidazole
Results of the trichomonacidal activity of the newly
synthesized compounds are presented in Table 3. T. ho-
minis trophozoites showed great variation in suscepti-
bility to the tested chemicals. Our previous studies on
susceptibility in vitro of diverse protozoan species to
selected chemicals also showed marked differences in
antiprotozoal efficacy of currently used drugs or anti-
septic agents [21 – 23].
In the present study, antiprotozoal activity mani-
fested itself in higher concentration (8 – 9 µg/ml) of
most compounds examined. Metronidazole at 8 µg/ml
decreased the survival of T. hominis trophozoites
by 26.5%. Strikingly, the lower tested concentration of
this drug (4 µg/ml) increased the number of surviving
trophozoites. This paradoxical effect has also been ob-
served in our earlier studies [22].
Of the novel nitrobenzyl derivatives tested, 4a,
derivatives 8a – f, including both 2,4-dinitro- (8b and 4b and 10a (two N-imidazoles and a single N1-O-
8e) and 3,5-dinitrobenzylsulfanyl compounds (8c and hydroxybenzotriazole derivative) were the most effec-
8f) were toxic to four out of six mycobacterial strains tive in reducing the number of viable protozoa (by up
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A. Go´rska et al. · Nitrobenzyl Derivatives
105
Table 3. Percentage of sur-
viving Trichomonas hominis
trophozoites after 24 h in-
cubaction with the compounds
shown.
Compound
Concentration
[µg/ml]
4
Survivors∗
[%]
76 2.9
95.5 5.5
79.0 1.0
62.0 1.0
70.5 4.5
74 1.0
Compound
Concentration
[µg/ml]
Survivors∗
[%]
2a
8a
8b
4
8
4
8
4
8
4
8
4
8
4
8
4.3
8.6
4.3
8.6
4.5
9
81.5 4.5
82.5 2.5
84.0 2.0
66.5 6.5
105.5 1.5
51.5 3.5
87.5 3.5
51.5 0.5
81.0 1.0
71.0 1.0
77.5 1.5
98.5 1.5
90 1.0
8
2b
4.2
8.2
4
8.2
4
∗
2c
8c
Values shown are mean SD of
four counts performed using a sin-
gle 1 ml culture sample;
4a
76 1.0
8d
∗∗
8
35.5 1.5
89.0 0.8
38.0 2.0
76.5 3.5
79.5 1.5
79 1.0
73.5 2.5
74 1.0
97 2.0
the value is the mean for con-
4b
4.4
8.8
4.1
8.2
4.1
8.2
4.1
8.2
4
8e
trol culture and culture with only
DMSO added.
6a
6b
8f
10a
10b
10c
45.0 1.0
88.5 1.5
59.7 2.4
76.0 1.0
66.5 3.5
6c
Metronidazole
Control**
186.2 9.2
73.5 4.2
100 2.5
8
to 64, 62 and 55%, respectively). A slightly weaker tives may be similar to that of metronidazole; however,
effect, comparable with that observed in our previous the biochemistry of T. hominis has not been investi-
study at high chlorhexidine concentration [22], was ob- gated thoroughly. The results presented warrant further
served for compounds 8c and 8d. Derivatives 2b, 8b, studies on the nitrosubstituted heterocycles as prospec-
10b and 10c also showed a higher anti-protozoan effi- tive agents against this protozoan.
cacy than metronidazole.
Experimental Section
Metronidazole is favored in some countries for the
treatment of a wide variety of infections caused by bac-
teria and protists living in low-aerobic environments,
e.g. by Helicobacter, Clostridium, Trichomonas, Gi-
ardia, and Entamoeba. In most protozoans studied,
metronidazole’s cytotoxicity relies on the reduction
of its nitro group by ferredoxin [15]. It is a com-
mon belief that, in Trichomonas, this drug undergoes
activation to an active catabolite in specialized or-
ganelles called hydrogenosomes. Although the treat-
ment with metronidazole is generally effective, resis-
tance in vitro and in vivo has been described both in
bacteria and protists [14– 16, 24]. An increasing occur-
rence of metronidazole-resistant clinical cases shows
that the problem will need more attention in the near
future.
Instrumentation: All chemicals and solvents were pur-
chased from Sigma-Aldrich. Melting points (uncorr.) were
measured in open capillary tubes on a Gallenkamp-5 melting
point apparatus. Ultraviolet absorption spectra were recorded
in a Kontron Uvikon 940 spectrophotometer. 1H NMR spec-
tra (in ppm) were measured on a model Varian Gemini
200 MHz (or Varian UNITY plus 500 MHz) spectrometer
at 298 K in [D6]-DMSO using tetramethylsilane as internal
standard. Flash chromatography was performed with Merck
silica gel 60 (200 – 400 mesh). Analytical TLC was carried
out on precoated silica gel F254 (Merck) plates (0.25 mm
thickness). Analyses of the new compounds, indicated by the
symbols of the elements, were within 0.4% of the respec-
tive theoretical values.
Synthesis: All the chemicals used were analytical grade
commercial products and were used with no further purifica-
tion.
The search for antiprotozoal drugs that would be
useful against Giardia, Enthamoeba or Trichomonas
vaginalis was the subject of numerous studies. T. ho- Synthesis of 2-S-substituted heterocycles 2a – c, 6a – c,
8a – f
minis was given much less attention, probably due to a
doubtful opinion that it is a “mild” pathogen. The re-
sults of this study reveal that this intestinal parasite is
clearly susceptible in vitro to many of the novel com-
pounds examined, and particularly to 4a, 4b and 10a.
To a vigorously stirred suspension of the mercapto-
substituted heterocycle 1, 5, or 7 (7 mmol) in a biphasic
mixture of water (25 ml) and CH2Cl2 (25 ml), contain-
ing K2CO3 (1.5 g) and benzyltrimethylammonium chloride
The mechanism of action of these nitrobenzyl deriva- (0.1 g, 1 mmol), the respective nitrobenzyl chloride (6 mmol)
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106
A. Go´rska et al. · Nitrobenzyl Derivatives
was added. The solution was stirred overnight at room tem- INH-resistant or -sensitive MOTT strains: M. kansasii, M.
perature. The lower phase was separated, washed twice with xenopii and M. avium-intercellulare complex.
water (50 ml), and adsorbed on silica gel that was placed
In vitro microbiological studies of the newly synthesized
on the top of a silica gel column (3 × 15 cm) and chro- compounds were carried out by a classical test tube method
matographed with petroleum ether (200 ml) followed by of serial dilutions. Minimum inhibitory concentrations were
petroleum ether/ethyl acetate (1:1, v/v). Product-containing determined in liquid Youman’s medium containing 10%
fractions were evaporated to dryness, and the residue was bovine serum. The results presented are means of three in-
crystallized from EtOH/water. The yields, melting points, dependent measurements.
Rf values, 1H NMR and UV data are listed in Table 1.
Antiprotozoal activity studies: Trichomonas hominis
trophozoites derived from diarrheic stool of an adult patient
◦
were cultured at 37 C in 15 ml tubes containing the liq-
Synthesis of N-nitrobenzyl imidazoles 4a and 4b
uid Pahm medium [19], and were subcultured twice a week.
One-ml samples of the cultures were used to test susceptibil-
ity to both the reference drug (metronidazole) and novel com-
pounds. The addition of 10 µl of dimethyl sulfoxide (DMSO)
to 1 ml of T. hominis cultures exerted no effect on the num-
ber and status of the protozoan. Therefore the same DMSO
concentration was used for negative controls and when test-
ing the compounds of interest. Two concentrations of each
agent were used. After 24 h exposure at 37 ◦C to the tested
compounds, the cultures were vortexed and 20 µl samples
were taken for trophozoite counting; means of four counts
were calculated. Bu¨rker chamber was used to determine the
quantity of the trichomonads; only motile protozoans were
counted. For microscopic assessment of the status and num-
ber of the surviving flagellates, 100× and 400× magnifica-
tions were used. The percentage of surviving trophozoites
was determined in relation to the respective negative con-
trol cultures. Because of specific reaction of this protozoan
species to some of the tested compounds (see below), we de-
cided to present surviving trophozoites’ percentages at two
concentrations rather than minimum inhibitory concentra-
tions that we considered less representative.
To a solution of 2-methyl-5-nitrobenzimidazole (3, 0.22 g,
1.75 mmol) in acetone (35 ml), anh. K2CO3 (0.5 g) and
4-nitro- (0.275 g, 1.6 mmol) or 3,5-dinitro benzyl chloride
(0.354 g, 1.6 mmol) were added. The mixture was stirred
overnight at r. t., and the solids were separated by filtration.
The filtrate was adsorbed on silica gel that was placed on the
top of a silica gel column (3 ×15 cm) and chromatographed
with CHCl3 (150 ml) followed by CHCl3/MeOH (95:5, v/v).
The product-containing fractions were evaporated to dry-
ness and the residue was crystallized from EtOH/water. The
yields, melting points, Rf values, and 1H NMR and UV data
are listed in Table 1.
Synthesis of 1-O-nitrobenzyloxybenzotriazoles 10a – c
To the stirred solution of 1-hydroxybenzotriazole (9,
4.5 mmol) in a mixture of water (25 ml) and EtOH (15 ml),
containing K2CO3 (900 mg), the respective nitrobenzyl chlo-
ride (4.5 mmol) was added portionwise over three hours. The
stirring was continued overnight. The precipitate formed was
filtered off and crystallized from EtOH/water. The yields,
1
melting points, Rf values, H NMR and UV data are listed
Acknowledgements
in Table 1.
The study was supported by the Foundation for the De-
velopment of Diagnostics and Therapy, Warsaw, Poland. The
authors thank Dr. S. J. Chrapusta of the Department of Exper-
imental Pharmacology, Polish Academy of Sciences Medical
Research Center, for his critical reading of the manuscript.
Antimycobacterial activity studies: The newly obtained
compounds were tested for tuberculostatic activity in vitro
using strains of both the M. tuberculosis complex and MOTT:
a standard strain of M. tuberculosis H37Rv, an INH-resistant
M. tuberculosis strain (clinical isolate), M. bovis, and a few
[1] A. Bloch, P. Simone, M. McRay, JAMA 275, 487
(1996).
llo-Rivera, A. E. Laudy, B. J. Staros´ciak, Z. Kazimier-
czuk, Eur. J. Pharm. Sci. 21, 323 (2004).
[2] S. J. Heymann, T. F. Brewer, M. E. Wilson, JAMA 281,
2138 (1999).
[3] V. Klimesova, J. Koci, K. Waisser, J. Kaustova, Far-
maco 57, 259 (2002).
[4] V. Klimesova, J. Koci, M. Pour, J. Stachem, K. Waisser,
J. Kaustova, Eur. J. Med. Chem. 37, 409 (2002).
[5] Z. Kazimierczuk, M. Andrzejewska, J. Kaustova,
V. Klimesova, Eur. J. Med. Chem. 40, 203 (2005).
[6] M. Andrzejewska, L. Yepez-Mulia, A. Tapia, R. Cedi-
[7] E. O. Ogunba, J. Trop. Med. Hyg. 80, 187 (1977).
[8] R. N. Chunge, I. A. Wamola, S. N. Kinoti, J. Muttunga,
L. N. Mutanda, N. Nagelkerke, L. Muthami, E. Muniu,
J. M. Simwa, P. N. Karumba, East Afr. Med. J. 66, 715
(1989).
[9] R. N. Chunge, J. M. Simwa, P. N. Karumba, P. R.
Kenya, S. N. Kinoti, J. Muttunga, N. Nagelkerke, East
Afr. Med. J. 69, 437 (1992).
Unauthenticated
Download Date | 4/16/17 6:49 PM

A. Go´rska et al. · Nitrobenzyl Derivatives
107
[10] J. Mancilla-Ramirez, R. Gonzalez-Yunes, Bol. Med.
Hosp. Infanti de Mexico 46, 623 (1989).
[11] C. N. Okafor, C. N. Azubike, West Afr. J. Med. 11, 106
(1992).
[12] L. S. Garcia, Diagnostic Medical Parasitology, ASM
Press, Washington, D.C. (2001).
[18] M. Malagoli, T. Rossi, A. Baggio, G. Zandomeneghi,
A. Zanca, C. Casolari, M. Castelli, Pharmacol. Res. 46,
469 (2002).
[19] P. Myjak, Biul. Inst. Med. Mor. Trop. 25, 113 (1974).
[20] J. D. Albright, D. B. Moran, J. Het. Chem. 23, 913
(1986).
˙
[13] E. B. Jacobsen, A. Friis-Moller, J. Friis, Eur. J. Clin.
Microbiol. 6, 296 (1987).
[21] K. Kopan´ska, A. Najda, J. Zebrowska, L. Chomicz,
J. Piekarczyk, P. Myjak, M. Bretner, Bioorg. Med.
[14] K. M. Land, J. P. Johnson, Drug Resist. Updat. 2, 289
(1999).
Chem. 12, 2617 (2004).
[22] L. Chomicz, J. Zebrowska, P. Zawadzki, P. Myjak,
˙
[15] J. A. Upcroft, P. Upcroft, Clin. Microbiol. Rev. 14, 150
(2001).
[16] J. A. Upcroft, P. Upcroft, Antimicrob. Agents Chemo-
ther. 45, 1810 (2001).
[17] N. Bharti, K. Husain, M. T. Gonzalez Garza, D. E.
Cruz-Vega, J. Castro-Garza, B. D. Mata-Cardenas,
F. Naqvi, A. Azam, Bioorg. Med. Chem. Lett. 12, 3475
(2002).
K. Perkowski, H. Rebandel, Z. Kazimierczuk, Z. Wiad.
Parazytol. 50, 405 (2004).
˙
[23] L. Chomicz, J. Zebrowska, J. Piekarczyk, B. J.
Staros´ciak, P. Myjak, M. Walski, Z. Kazimierczuk,
Acta Parasitol. 50, 25 (2005).
[24] C. Wassmann, I. Bruchhaus, Arch. Biochem. Biophys.
376, 236 (2000).
Unauthenticated
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