Synthesis and tuberculostatic activity of some 2-piperazinmethylene derivatives 1,2,4-triazole-3-thiones

Article abstract of DOI:10.1080/104265090517280

The Mannich reaction's products of 1,2,4-triazole-3-thiones, substituted in position 4 (with ethyl, allyl, phenyl, Ph-4-Br) or 5 (with phenyl, Ph-4-OH, Ph-3,4,5-(OMe)₃, 2-phenyl) were obtained. Their amino-components were 1-phenylpiperazine, 1-

Full text of DOI:10.1080/104265090517280

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Phosphorus, Sulfur, and Silicon
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Synthesis and Tuberculostatic
Activity of Some 2-
Piperazinmethylene
Derivatives 1,2,4-Triazole-3-
Thiones
Henryk Foks a , Mieczyslaw Janowiec b , Zofia
b
Zwolska b & Ewa Augustynowicz-Kopeć
a Department of Organic Chemistry , Medical
University of Gdańsk , Al. Gen. J. Hallera 107,
80416 Gdansk, Poland
b Department of Microbiology , Institute of
Tuberculosis and Pulmonary , Diseases Warsaw,
Poland
Published online: 21 Dec 2010.
To cite this article: Henryk Foks , Mieczyslaw Janowiec , Zofia Zwolska & Ewa
Augustynowicz-Kopeć (2005) Synthesis and Tuberculostatic Activity of Some 2-
Piperazinmethylene Derivatives 1,2,4-Triazole-3-Thiones, Phosphorus, Sulfur, and
Silicon and the Related Elements, 180:2, 537-543, DOI: 10.1080/104265090517280
To link to this article: http://dx.doi.org/10.1080/104265090517280
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Phosphorus, Sulfur, and Silicon, 180:537–543, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090517280
Synthesis and Tuberculostatic Activity of Some
2-Piperazinmethylene Derivatives
1,2,4-Triazole-3-Thiones
Henryk Foks
Department of Organic Chemistry, Medical University of Gdan´sk,
Poland
Mieczyslꢀaw Janowiec
Zofia Zwolska
Ewa Augustynowicz-Kopec
´
Department of Microbiology, Institute of Tuberculosis and Pulmonary
Diseases Warsaw, Poland
The Mannich reaction’s products of 1,2,4-triazole-3-thiones, substituted in position
4 (with ethyl, allyl, phenyl, Ph-4-Br) or 5 (with phenyl, Ph-4-OH, Ph-3,4,5-(OMe)3,
2-phenyl) were obtained. Their amino-components were 1-phenylpiperazine, 1-
(4-fluorophenyl)-piperazine, 1-benzylpiperazine, 1-(2-pyridyl)-piperazine and 1-
piperonyl-piperazine. Tuberculostatic activity of the compounds obtained was tested
in vitro and their MIC values within 25–100 mcg/mL.
Keywords 1,2,4-Triazole-3-thiones; Mannich reactions; tuberculostatic
INTRODUCTION
Many examples of Mannich compounds’ officinal use may be found
in therapeutics. These compounds gave evidence of more advanta-
geous physiological effect, than the parent ones—disposessed of the
aminomethylene arrangement. The Mannich bases of tetracyclines1
medicinal use, as well as the morpholinomethylene-pyrazinamide
derivative (Morfazinamid) application to tuberculosis treatment could
be given for instance.
Some aminomethylation products of 1,2,4-triazole-3-thiones, already
reported, showed the antibacterial activity as well.2−6
Received July 6, 2004; in final form July 20, 2004.
Address correspondence to Henryk Foks, Department of Organic Chemistry, Medical
University of Gdan´sk, Al. Gen. J. Hallera 107, 80416 Gdan´sk, Poland. E-mail: hfoks@
farmacja.amg.gda.pl
537

538
H. Foks et al.
RESULTS AND DISCUSSION
With regard to the reasons, for 4,5-disubstituted-1,2,4-triazole-3-
thiones the aminomethylation products with the piperazine arrange-
ment were synthesised. Our previous works (unpublished) showed
that the presence of this arrangement in the compounds tested
often used to increase the tuberculostatic activity, while checked
in vitro.
In accordance with the methods commonly used, acid hydrazides
1–4 (benzoic, 4-hydroxy-benzoic, 3,4,5-trimethoxybenzoic and 2-
furylocarboxylic hydrazides) in the reactions with ethyl-, allyl-, phenyl-,
and p-bromophenyl isothiocyanates gave the corresponding thiosemi-
carbazide derivatives (5–12), which subsequently underwent the cy-
clization (in 10% NaOH) to triazolothiones (13–20). The last-mentioned
compounds were exposed to the Mannich reaction, in which for-
malin and the substituted piperazines [1-phenyl-, 1-benzyl-, 1-(4-
fluorophenyl)-, 1-piperonyl- and 1-(2-pyridyl)-piperazine] were used
(Scheme 1).
SCHEME 1
MICROBIOLOGY
The compounds obtained were tested for their tuberculostatic activity
towards the Mycobacterium tuberculosis H37Rv strain and two wild
strains isolated from the tuberculotic patients: one—resistant to p-
aminosalicylic acid (PAS), isonicotinic acid hydrazide (INH), etham-
butol (ETB) and rifampycine (RFP)—and the other fully susceptible to
the drugs administered.

Triazole-Thiones
539
Tuberculostatic activity was tested in vitro by classical test tube
method with Youman’s liquid medium containing 10% of bovine serum.6
On the ground of the minimum inhibiting concentration (MIC) values
obtained it may be concluded, that the group of the compounds tested
exhibited low tuberculostatic activity. MIC values for the most of the
compounds was within 25—100 mcg/mL.12
EXPERIMENTAL
Melting points were determined with a Boetius apparatus and are un-
corrected. The IR spectra were taken with Satellite spectrophotometer.
The 1H NMR spectra were taken with Varian Gemini (200 MHz) spec-
trometer at the NMR Laboratory, Technical University of Gdansk.
The results of the elemental analyses (% C, H, N) for all the com-
pounds obtained were in good agreement with the data calculated.
Thiosemicarbazides (5–12)
Acid hydrazided (benzoic, p-hydroxybenzoic, 3,4,5-trimethoxybenzoic,
or 2-furylcarboxylic (10 mmole), ethanol (30 mL) and the correspond-
ing isothiocyanate (ethyl-, allyl-, or p-bromo-phenyl (10 mmole)) were
refluxed for 0.5 h. On cooling the precipitated thiosemicarbazides were
filtered off and crystallized.
4,5-Disubstituted-1,2,4-triazole-3-thiones (13–20)
The corresponding thiosemicarbazide (5–12) (10 mmole) was refluxed
in 10% aqueous NaOH solution (30 mL) for 2 h. On cooling, the mixture
was acidified with diluted (1:1) HCl. The precipitates were washed with
water, dried, and purified by crystallization.
Mannich Compounds (21–49)
Triazolothione (13–20) (5 mmole) dissolved in methanol or dioxane
(20 mL) was treated with the corresponding piperazine (1-phenyl-, 1-
benzyl-, 1-(4-fluorophenyl)-, 1-piperonyl-, or 1-(2-pyridyl)-piperazine (6
mmole)) and then with 40% formalin (1 mL). The mixture was refluxed
for 1 h. On cooling with ice the precipitates were filtered off, dried, and
purified by crystallization. When oils were obtained the solvent was
distilled under reduced pressure and the residue allowed to stand for
crystallization.
The physical characteristics of the compounds obtained are given in
Table I.

540

541

542

Triazole-Thiones
543
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