Sep-Oct 2003
905
Synthesis of 1-Nonanoyl/octadecanoyl-4-substituted
Thiosemicarbazides and substituted 1,2,4-Trizoles as
biological active compounds
1
1
2
Katica Colanceska-Ragenovic , Vesna Dimova , Vlado Kakurinov ,
3
and Dora Molnar Gabor
1
Faculty of Technology and Metallurgy, The “Sv. Kiril & Metodij” University, R. Boskovic 16,
1000 Skopje, Macedonia
Faculty of Agriculture, Department of microbiology, The “Sv. Kiril & Metodij” University,
2
bul. Aleksandar Makedonski, bb, 1000 Skopje, Macedonia
Institute of Chemistry, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovica 3,
21000 Novi Sad, Yugoslavia
3
Received December 6, 2002
4-Alkyl/aryl-5-nonanoyl/octadecanoyl-2,4-dihydro-3H-1,2,4-triazoline-3-thiones were synthesized as
potential antimicrobial agents. The course of synthesis included the reaction of nonanoyl/octadecanoyl
hydrazines with selected alkyl/aryl isothiocyanates. The prepared thiosemicarbazides gave by cyclization
the required 1,2,4-triazoles. A number of synthesized compounds were subjected to in vitro testing against
two gram-positive, two gram-negative bacteria and two fungi.
J. Heterocyclic Chem., 40, 905 (2003).
Various 1-acyl/aroyl-4-substituted thiosemicarbazides
Ethyl esters of nonanoic and octadecanoic acids (1a-b)
were prepared following the standard method [18] by reflux-
ing the acids and the alcohol in presence of sulfuric acid.
Further, the desired nonanoyl/octadecanoylhydrazines
(2a-b) were obtained treating compounds (1) with
hydrazine in ethanol for 12 hours [19,20]. This period of
reflux leads to hydrazides with excellent purity and yield.
The same hydrazides (2a-b) were converted into 1-
nonanoyl/octadecanoyl-4-alkyl/aryl-thiosemicarbazides
(3a-b) by refluxing with suitable alkyl/aryl isothiocyanates
in ethanolic solution [21,22,23].
are known to exhibit significant tuberculostatic [1,2], anti-
fungal [3,4], antiviral [5] and anticonvulsant [6] activities.
Certain 1,2,4-triazole derivatives have also been reported
to have the similar effects [7-11].
The literature reports that the antiviral [12] and the
antibacterial [13-14] activities of thiourea derivatives were
due to the –NH-C(S)-NH- function in the molecule and
that the positive/negative changes in the biological activity
depended on the nature of its substituents. It is also known
that N-substituted fatty acid amides exhibit biological
activity [15,16]. A large number of N, O and N, S-hetero-
cyclic compounds prepared by condensation of fatty acids
alkyl amides with carbonyl compounds and phosphorous
penta sulfide, respectively, have shown excellent bactero-
static and fungistatic action [17].
Those observations prompted us to combine the fatty
acid amides moiety with thiosemicarbazide structure, to
synthesize substituted 1,2,4-triazoline-3-thiones with the
same pharmacophoric group and investigate their antibac-
terial and antifungal activities.
The reaction of cyclization [24,25] of the thiosemicar-
bazides with 2 M NaOH solution under reflux for about 4
hours produced 4,5-disubstituted-2,4-dihydro-3H-1,2,4-
triazoline-3-thiones (4a-g) in a pure state and in good
yield. The new compounds (3a-g, 4a-g) were character-
1
ized using ir and H nmr spectroscopy together with ele-
mental analysis.
Antibacterial Activites.
The filter paper disc method [26,27] was employed for
the in vitro study of antibacterial and antifungal effects
against Escherichia coli, Bacillus subtilis, Salmonela
enteritidis, Staphylococcus aureus, Aspergillus niger and
Candida albicans of the compounds (3d-g, 4d-g).
Chemistry.
The synthetic route to thiosemicarbazides and triazole
derivatives is presented in Scheme 1.
This method was performed using Sabouraud dextrose
broth and Mueller Hinton broth. These agar media were
inoculated with 0.5 ml of the 24 h liquid cultures contain-
Scheme 1
7
ing 10 microorganisms/mL. Standard 5 mm diameter
paper discs impregnated with solutions of each compound
(concentrations: 1mg/mL; 5mg/mL and 10mg/mL of
DMSO) were placed on the indicated agar mediums. The
incubation time was 24 h at 37 °C for bacterial and 48 h at
30 °C for Candida species. Inhibitory activity was mea-
sured (in mm) as the diameter of the observed inhibition
zones. The screening results given in Table 3 indicate that