Studies on pyrazine derivatives, XLIV: Synthesis and tuberculostatic activity of 4-substituted 3,4,5,6-tetrahydro-2H-[1,2′]-bis-pyrazine derivatives

Article abstract of DOI:10.1080/104265090930137

2-chloro-3-cyanopyrazine was a substrate in the syntheses of some potentially tuberculostatic pyrazine derivatives. This compound, upon action of secondary amines, pyrazine derivatives 1-phenyl-, 1-piperonyl-, 1-(4-fluorophenyl)-, 1-(2-pyridil)-, and 1-be

Full text of DOI:10.1080/104265090930137

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Phosphorus, Sulfur, and Silicon
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Studies on Pyrazine
Derivatives, XLIV: Synthesis
and Tuberculostatic Activity
of 4-Substituted 3,4,5,6-
Tetrahydro-2H-[1,2′]-Bis-
Pyrazine Derivatives
Henryk Foks a , Danuta Pancechowska-Ksepko a
, Mieczyslaw Janowiec b , Zofia Zwolska b & Ewa
Augustynowicz-Kopec b
a Department of Organic Chemistry , Medical
University of Gdańsk , Gdańsk, Poland
b Department of Microbiology , Institute of
Tuberculosis and Pulmonary Diseases , Warsaw,
Poland
Published online: 16 Aug 2006.
To cite this article: Henryk Foks , Danuta Pancechowska-Ksepko , Mieczyslaw
Janowiec , Zofia Zwolska & Ewa Augustynowicz-Kopec (2005) Studies on Pyrazine
Derivatives, XLIV: Synthesis and Tuberculostatic Activity of 4-Substituted 3,4,5,6-
Tetrahydro-2H-[1,2′]-Bis-Pyrazine Derivatives, Phosphorus, Sulfur, and Silicon and the
Related Elements, 180:11, 2543-2548, DOI: 10.1080/104265090930137
To link to this article: http://dx.doi.org/10.1080/104265090930137
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Phosphorus, Sulfur, and Silicon, 180:2543–2548, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090930137
Studies on Pyrazine Derivatives, XLIV: Synthesis
and Tuberculostatic Activity of 4-Substituted
3,4,5,6-Tetrahydro-2H-[1,2’]-Bis-Pyrazine Derivatives
Henryk Foks
Danuta Pancechowska-Ksepko
Department of Organic Chemistry, Medical University of Gdan´sk,
Gdan´sk, Poland
Mieczyslꢀaw Janowiec
Zofia Zwolska
Ewa Augustynowicz-Kopec
Department of Microbiology, Institute of Tuberculosis and Pulmonary
Diseases, Warsaw, Poland
2-chloro-3-cyanopyrazine was a substrate in the syntheses of some potentially tuber-
culostatic pyrazine derivatives. This compound, upon action of secondary amines,
pyrazine derivatives 1-phenyl-, 1-piperonyl-, 1-(4-fluorophenyl)-, 1-(2-pyridil)-, and
1-benzylpiperazine, gave the corresponding nitriles (1a–e). Compounds 1c, d, e were
changed into the amidoximes (2c, d, e) by hydroxylamine action. Derivatives 1a–e
were transformed into the corresponding thioamides (3a–e) when treated with am-
monium polysulphide. Two of these, thioamides, 3a and 3b, in the cyclization reac-
tions with ethylenediamine gave the imidazolines (4a, b) with phenacyl bromide—
the thiazole derivatives (5a, b). The compounds obtained were tested in vitro for
their tuberculostatic activity. The tuberculostatic activity of compound 5b was the
highest: MIC 3.1–7.8 µg/mL.
Keywords 1,4-disubstituted piperazine; 2,3-disubstituted pyrazine; thioamides; tuber-
culostatic
INTRODUCTION
The aim of this work was to obtain the new pyrazine derivatives
and check their tuberculostatic activity. The amide of pyrazinecar-
boxylic acid (pyrazinamide) has been used as the antituberculytic
drug since 1936, and its derivative, N-(4-morpholinomethyl)-amide,
Received November 16, 2004; accepted December 1, 2004.
Address correspondence to Henryk Foks, Al. Gen. J. Hallera 107, Gdan´sk 80416,
Poland. E-mail: hfoks@amg.gda.pl
2543

2544
H. Foks et al.
of the same acid (morinamide) appeared to be even stronger and a
less toxic chemotherapeutic agent.1,2,3 Ethylthioisonicotinic acid amide
(ethionamide) has been used in consumption treatment as well.4
Our earlier works showed that pharmacological activity used to
be increased by introducing the phenylpiperazine system into the
molecule. This system can be found in the molecules of some
potent chemotherapeutics such as ophlexacine, ciprofloxacine, and
sparfloxacine—the most powerful drug in the fight against Mycobac-
terium tuberculosis.5,6,7
INVESTIGATIONS AND RESULTS
Synthesis of the Derivatives
The substrate used in the syntheses was 2-chloro-3-cyanopyrazine,
which was obtained by cyanopyrazine chlorination with sulphuryl
chloride.8 The compound was treated with the secondary amines
1-phenyl-, 1-piperonyl-, 1-(4-fluorophenyl)-, 1-(2-pyridil)-, and 1-
benzylpiperazine, which resulted in the corresponding products of chlo-
rine substitution by the piperazine system (1a–e). The nitriles obtained
(1c, d, e) were changed into the amidoximes (2c, d, e) by hydroxylamine
action. The treatment with ammonium polysulphide transformed com-
pounds 1a–e into thioamide derivatives (3a–e). The thioamides 3a,
b underwent cyclization reactions with ethylenediamine to the corre-
sponding imidazolines (4a, b), and with phenacyl bromide to thiazole
derivatives (5a, b; Scheme 1).
The structure of new compounds (1–5) that were obtained was estab-
lished by the analysis of IR and 1H NMR spectra, and their character-
istics are given in Table I.
Pharmacological Tests
The compounds obtained (1–5) were tested for their tuberculostatic
activity towards the Mycobacterium tuberculosis H37Rv strains and
two strains that were isolated from the tuberculotic patients: (1) one
resistant to isonicotinic acid hydrazide, ethambutol, and rifampicine,
and (2) the other fully susceptible to the tuberculostatics adminis-
tered. Tuberculostatic activity was tested with the test tube method
on Youman’s liquid medium containing 10% of a bovine serum.9 Min-
imum growth inhibiting concentration (MIC) values were within the
limits of 3.1–500 µg/mL (Table I). The most active compound—thiazole

Studies on Pyrazine Derivatives, XLIV
2545
SCHEME 1
derivative (5b)—was tested on a broad basis with use of the following
standard strains (MIC values are given in parentheses): Myc. H37Rv—
human strain (3.1), Myc. An5—cattle strain (12.5), Myc. kansasii—
photochromogenic strain (50), Myc. scrofulaceum—scotochromogenic
strain (100), Myc. intracellulare—non chromogenic strain (50), Myc.
fortuitum—quick-growing strain from IV group according to Runyn
(100), Myc. kirchberg—bird strain (50), Myc. wells—rodent’s strain (25),
and from quick-growing saprophytic strains Myc. smegmatic (100) and
Myc. phlei (50).
EXPERIMENTAL
Melting points were determined with a Reichert apparatus and are un-
corrected. The IR spectra were taken with a Varian Gemini 200 spec-
trometer BS-487c. Reaction yields and the physical constants of the
compounds obtained are given in Table I. The results of elemental anal-
yses (C and H) for all of the compounds that were obtained are in good
agreement with the data calculated.

2546

Studies on Pyrazine Derivatives, XLIV
2547
4-Phenyl-, 4-benzo[1,3]dioxol-5-ylmethyl-, 4-(4-fluorophenyl)-,
4-pyridin-2-yl-, 4-benzyl-3,4,5,6-tetrahydro-2H-
[1,2ꢀ]bispyrazinyl-3ꢀ-carbonitrile (1a–e)
2-chloro-3-cyanopyrazine (5 mmole) was dissolved in benzene (10
mL), treated with corresponding amine: 1-phenyl-, 1-piperonyl-, 1-(4-
fluorophenyl)-, 1-(2-pyridyl)-, or 1-benzylpiperazine, and refluxed for
1 h. On cooling, water (20 mL) was added, the benzene phase was sepa-
rated, and the aqueous phase was extracted twice with benzene (10 mL).
Combined benzene extracts were dried over anhydrous Na2SO4. Upon
benzene evaporation, the liquids that were obtained were allowed to
stand for crystallization (1a–e).
4-(4-Fluorophenyl)-, 4-pyridyn-2-yl-, 4-benzyl-N-hydroxy-
3,4,5,6-tetrahydro-2H-[1,2ꢀ]-bis-pyrazinyl-3ꢀ-carboxamidine
(2c, d, e)
Two solutions were prepared NH2OH × HCl (1.2 g) dissolved in
methanol (10 mL), and KOH (1.15 g) dissolved in methanol (10 mL) were
joined, the precipitated KCl was filtered, and the filtrate was treated
with the corresponding nitrile 1c, d, e (2.5 mmole). The mixture was
refluxed for 1 h. On cooling, the products were precipitated (2c, d, e).
4-Phenyl-, 4-benzo[1,3]dioxol-5-ylmethyl-, 4-(4-fluorophenyl)-,
4-pyridin-2-yl-, 4-benzyl-3,4,5,6-tetrahydro-2H-[1,2ꢀ]-
bipyrazinyl-3ꢀ-carbothioic acid amide (3a–e)
Corresponding nitrile (2.5 mmole) was added to concentrated NH4OH
(20 mL) that was saturated with H2S and stood for 2 days at ambient
temperature. The precipitates were filtered, washed with water, and
recrystallized (3a–e).
3ꢀ-(4,5-Dihydro-1H-imidazol-2-yl)-4-phenyl-3,4,5,6-tetrahydro-
2H-[1,2ꢀ]-bipyrazinyl (4a), 4-benzo[1,3]dioxol-5-ylmethyl-3ꢀ-
(4,5-dihydro-1H-imidazol-2-yl)-3,4,5,6-tetrahydro-2H-[1,2ꢀ]-
bipyrazinyl (4b)
Compound 3a or 3b (5 mmole) was refluxed with ethylenediamine
(2 mL) for 2 h. On cooling, water (10 mL) was added, and the precipitates
were filtered and washed with water (4a, b).

2548
H. Foks et al.
4-Phenyl-, 4-benzo[1,3]dioxol-5-ylmethyl-3ꢀ-(4-phenyl-thiazol-
2-yl)-3,4,5,6-tetrahydro-2H-[1,2ꢀ]-bipyrazinyl (5a, b)
Phenacyl bromide (5 mmole) was dissolved in hot absolute ethanol
(20 mL). The solution was cooled a little and treated with compound
3a or 3b, then refluxed for 1 h. On cooling, the precipitated compounds
5a or 5b were filtered.
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