Synthesis and tuberculostatic activity of 1,3-thiazacycloalkyl[3,2-b]-1,2, 4-triazoles

Article abstract of DOI:10.1080/104265090968244

The 4-hydroxyalkyl-1,2,4-triazole-3-thiones cyclization allowed us to work out the effective method of 1,3-thiazacycloalkyl[3,2-b]-1,2,4-triazoles synthesis. Some of the compounds that were obtained were tested for their tuberculostatic activity. Copyrigh

Full text of DOI:10.1080/104265090968244

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Phosphorus, Sulfur, and Silicon
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Synthesis and Tuberculostatic
Activity of 1,3-
Thiazacycloalkyl[3,2-b]-1,2,4-
triazoles
Barbara Milczarska a , Henryk Foks a , Urszula
Dobrzycka a , Zofia Zwolska b & Ewa Augustynowicz-
b
Kopeć
a Department of Organic Chemistry , Medical
University of Gdańsk , Poland
b Department of Microbiology , Institute of
Tuberculosis and Pulmonary Diseases , Warsaw,
Poland
Published online: 19 Aug 2006.
To cite this article: Barbara Milczarska , Henryk Foks , Urszula Dobrzycka , Zofia
Zwolska & Ewa Augustynowicz-Kopeć (2005) Synthesis and Tuberculostatic Activity of
1,3-Thiazacycloalkyl[3,2-b]-1,2,4-triazoles, Phosphorus, Sulfur, and Silicon and the
Related Elements, 180:12, 2793-2799, DOI: 10.1080/104265090968244
To link to this article: http://dx.doi.org/10.1080/104265090968244
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Phosphorus, Sulfur, and Silicon, 180:2793–2799, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090968244
Synthesis and Tuberculostatic Activity
of 1,3-Thiazacycloalkyl[3,2-b]-1,2,4-triazoles
Barbara Milczarska
Henryk Foks
Urszula Dobrzycka
Department of Organic Chemistry, Medical University
of Gdan´sk, Poland
Zofia Zwolska
Ewa Augustynowicz-Kopec
´
Department of Microbiology, Institute of Tuberculosis
and Pulmonary Diseases, Warsaw, Poland
The 4-hydroxyalkyl-1,2,4-triazole-3-thiones cyclization allowed us to work out the
effective method of 1,3-thiazacycloalkyl[3,2-b]-1,2,4-triazoles synthesis. Some of the
compounds that were obtained were tested for their tuberculostatic activity.
Keywords 1,3-Thiazacycloalkyl[3,2-b]-1,2,4-triazoles; 4-hydroxyalkyl-1,2,4-triazole-3-
thiones; methyl 2-acylodithiocarbazates; tuberculostatic
INTRODUCTION
The heterocyclic derivatives of 1,2,4-triazole-3-thiones were repor-
ted2−4,11 to have large bactericidal activity and some influence on the
circulatory system. These compounds exhibited antiphlogistic, antimy-
cotic and antidepressive activity5−7 as well.
The most often used methods for the preparation of the 1,2,4-
triazole derivatives containing the cyclic dihydrothiazole or dihydro-
1,3-triazine system are the following: reactions of the corres-
ponding hydrazides with halogeno-alkanoisothiocyanates;8 reactions
of 1,2,4-triazolo-3-thione derivatives with dihalogeno compounds;9,10,12
reactions of dihalogenoalkanes with aryloylthiosemicarbazide
Received February 15, 2005; in final form March 8, 2005.
Address correspondence to H. Foks, Department of Organic Chemistry, Medical Uni-
versity of Gdan´sk, Al. Gen. J. Hallera 107, 80-416 Gdan´sk, Poland. E-mail: hfoks@
amg.gda.pl
2793

2794
B. Milczarska et al.
derivatives;12 and reactions of 3-aryldithiocarbazaic acid methyl
ester with halogenoamines.10,11
All these reactions used to give the previously mentioned cyclic com-
pounds; their yields, however, were often below 10–20%.
RESULTS AND DISCUSSION
In continuation of our works on the syntheses of biologically ac-
tive 1,2,4-triazolo-3-thione derivatives, the compounds with hydrox-
yalkyl substituents in position 4 were obtained.1 The transformation
of these compounds into the derivatives containing the condensed 1,3-
thiazacycloalkyl[3,2-b]-1,2,4-triazole systems is reported below.
The synthesis presented, unlike the till now described ones, is the
method of high yield (on the average of above 70%).
The cyclization of 4-hydroxyalkyl-1,2,4-triazolo-3-thiones took place
in concentrated hydrochloric acid, or polyphosphoric acid surroundings.
Under these circumstances the compounds 1a–c, 2a–e and 3a–e gave
4a–e, 5a–e, and 6a–e, respectively. The products of 1c, 2e, and 3e cy-
clization (i.e., 4c, 5e, and 6e) were obtained in higher yields, while in a
concentrated HCl medium.
The reactions realized are shown in Scheme 1.
SCHEME 1
The reaction paths of 2e and 3e cyclization had to be considered: one,
with the participation of primary alcoholic group in the ring closure, or
two with secondary group participation.

Thiazacycloalkyl-Triazoles
2795
While analyzing the registered 1H NMR spectra, taken in DMSO at
500 MHz, a doublet for the 1H secondary alkoholic group CH OH at
5.62 ppm and a multiplet for the 1H CH at 4.35 ppm were observed.
Furthermore, with the use of the Distortionless Enhancement by
Polarisation Transfer method, the positive signals of two methylene
groups and negative signals of methine groups (aromatic system me-
thine groups at 7.5–7.7 ppm and CH OH at 4.35 ppm) were observed.
The spectrum at the simultaneous decoupling of protons (Spin De-
coupling method) was registered as well. The singlet of the alcoholic
group’s protons and the simplification of the methine group signal were
registered. These observations proved unequivocally the participation
of the primary alcoholic group in the cyclization process.
MICROBIOLOGY
The major part of 4-(hydroxyalkyl)-1,2,4-triazolo-3-thione1 derivatives
and of the cyclic compounds obtained was tested in vitro for the tuber-
culostatic activity with the classical method described elsewhere.13
Some of the compounds were tested for their tuberculostatic activity
towards the standard Mycobacterium tuberculosis H37Rv strain and
two “wild” strains, isolated from the tuberculotic patients (Table I): one,
Myc. species 210, resistant to P-aminosalicylic Acid (PAS), Isonicotinic
Acid Hydrazide (INH), Etambutol (EMB) and Rifampycine (RFP); the
other, Myc. species 192, fully susceptible to the drugs administered.
The results showed that the major part of the compounds tested
was active towards Myc. spec. 210 strain—resistant to the drugs
TABLE I Tuberculostatic Activity (µg/mL)
Myc.spec. Myc.spec.
192 210
H37Rv (susceptible) (resistant) number
Myc.spec. Myc.spec.
192 210
H37Rv (susceptible) (resistant)
Compound Myc.tbc.
number
Compound Myc.tbc.
1a
50
100
100
50
100
100
100
100
100
100
50
50
100
100
100
100
100
100
100
100
100
100
100
50
100
50
50
100
50
50
50
50
50
4a
4c
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
50
50
100
100
100
6.2
50
50
100
100
100
100
100
25
50
25
50
50
50
100
100
100
25
50
50
50
50
1b
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
100
50
25
100
100
100
50
50
50
50
100
50

2796

2797

2798
B. Milczarska et al.
commonly used PAS, INH, EMB, and RFP—with Minimum Growth
Inhibiting Concentration (MIC) value of 50 µg/mL. The bicyclic com-
pounds were even more active. The MIC for the compound 5d was 6.2–
25 µg/mL, and for the compounds 6a, c, d, e, from 25–50 µg/mL.
EXPERIMENTAL
All melting points were obtained with a Boe¨tius apparatus and are un-
corrected. The IR spectra were taken with a Satellite spectrophotome-
ter. The 1H NMR spectra were taken with a Tesla BS-487 spectrometer
at 80 MHz in CDCl3 and DMSO-d6, or with Varian Gemini 200 and Var-
ian Unity 500 MHz spectrometers at 200 MHz in CDCl3 and DMSO-d6.
The results of elemental analyses (% C, H, and N) for all the com-
pounds obtained were in good agreement with the data calculated.
The reaction yields and the physical constants of the new com-
pounds were given in Table II. Methyl 2-acylodithiocarbazates 1–3 and
4,5-disubstituted s-triazole-3-thiones 1a–c, 2a–e, and 3a–e were ob-
tained according to the method described elsewhere.1
1,3-Thiazacycloalkyl[3,2-b]-1,2,4-triazoles (4a–c, 5a–e, and
6a–e)
Method A
The corresponding 4-hydroxyalkyl-5-aryl-1,2,4-triazole-3-thiones
1a–b, 2a–d, or 3a–d (2.5 mmole) were heated to 100◦C in polyphos-
phoric acid (6–7 g) for 2 h. After cooling, water (25 mL) was added and
alkalified with ammonia to pH 6.5–7.0. The products precipitated were
filtered and crystallized.
Method B
The reaction was carried out in a similar way: compounds 1c, 2e,
and 3e were refluxed with concentrated HCl (6 mL) for 2 h.
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A. Rodwanska, J. Petrusewicz, H. Trzeciak, B. Okopien, M. Jarowiec, and Z.
Zwaska-Kweik, Pharmazie, 47, 770 (1992).
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ꢀ
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Thiazacycloalkyl-Triazoles
2799
[8] L. G. Payne, M. T. Wu, and A. A. Patehett. Heterocycles, 12, 1171 (1979).
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