Short communicationNew triazole and triazolothiadiazine derivatives as possible antimicrobial agents
Graphical abstract
Introduction
The treatment of infectious diseases still remains an important and challenging problem because of a combination of factors including emerging infectious diseases and the increasing number of multi-drug resistant microbial pathogens. In spite of a large number of antibiotics and chemotherapeutics available for medical use, at the same time the emergence of old and new antibiotic resistance created in the last decades revealed a substantial medical need for new classes of antimicrobial agents. There is real perceived need for the discovery of new compounds endowed with antimicrobial activity, possibly acting through mechanisms of action, which are distinct from those of well-known classes of antibacterial agents to which many clinically relevant pathogens are now resistant. Through the various molecules designed and synthesized for this aim, it was demonstrated that 1,2,4-triazoles and their derivatives could be considered as possible antimicrobial agents [1], [2], [3], [4], [5], [6], [7].
The biological activities of various 1,2,4-triazole derivatives and their N-bridged heterocyclic analogs have also been extensively studied. Triazole fused six-membered ring system is also found to possess diverse applications in the field of medicine [8], [9], [10], [11]. The commonly known systems are triazole fused with pyridines [8], pyridazines [9], pyrimidines [10], pyrazines [11] and triazines [10]. The literature survey reveals that there are not many examples of triazoles fused with thiadiazines. Those incorporating the N–C–S linkage as in the skeleton of 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine exhibit a broad spectrum of antimicrobial activity [12], [13], [14], [15], [16], [17], [18].
4-Amino-1,2,4-triazol-3-thiones can be considered as useful tools in fusing to triazolothiadiazines. The amino and mercapto groups are ready-made nucleophilic centers for the synthesis of condensed heterocyclic rings [3], [19], [20]. Besides, the amino group of this structure is of importance for obtaining various Schiff base derivatives with well-known antimicrobial properties [21], [22], [23], [24], [25].
On the other hand, antimicrobial properties have also been reported to be associated with the indolic nucleus [5], [26].
In the design of new drugs, the development of hybrid molecules through the combination of different pharmacophores in one frame may lead to compounds with interesting biological profiles.
In the present study, prompted by these observations, the synthesis and antimicrobial screening of new Schiff bases of 1,2,4-triazole derivatives and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines as hybrid molecules including different pharmacophores are aimed at.
Section snippets
Chemistry
In the present work, 4-amino-3-mercapto-5-[(1H-indol-3-yl)methyl]-1,2,4-triazole has been synthesized [27] by heating thiocarbohydrazide with 1H-indol-3-acetic acid. The reaction of triazole with arylaldehyde in presence of concentrated sulfuric acid in ethanol gave the Schiff bases (5-[(1H-indol-3-yl)methyl]-4-arylideneamino-3-mercapto-1,2,4-triazoles) (Ia–e). 3-[(1H-Indol-3-yl)methyl]-6-aryl-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (IIa–e) were obtained by condensing triazole with phenacyl
Antimicrobial activity
Antimicrobial activities of compounds were tested using microbroth dilution method [28], [29]. Tested microorganism strains were; Micrococcus luteus (NRLL B-4375), Bacillus cereus (NRRL B-3711), Proteus vulgaris (NRRL B-123), Salmonella typhimurium (NRRL B-4420), Staphylococcus aureus (NRRL B-767), Escherichia coli (NRRL B-3704), Candida albicans and Candida glabrata (isolates obtained from Osmangazi University, Faculty of Medicine). The observed data on the antimicrobial activity of the
Results, discussion and conclusion
In this present work, a series of 10 new compounds were synthesized. Scheme 1 illustrates the way used for the preparation of target compounds. As a starting material, thiocarbohydrazide and 1H-indol-3-acetic acid were used to produce triazole. The structure of the compounds was elucidated by IR, 1H NMR, mass spectral data and elemental analysis. In the IR spectra of all compounds C
N and CC bands were observed at about 1630–1430 cm−1 region. According to the IR spectroscopic data of the
Experimental
All reagents were used as purchased from commercial suppliers without further purification. Melting points were determined by using a Gallenkamp apparatus and are uncorrected. Thin-layer chromatography (TLC) was performed with glass plates (0.25 mm) precoated with Merck silica gel 60 F254, and flash chromatography separations (FC) were carried out with Merck silica gel 60 (200e 450 mesh), using 40:60 EtOAc/petroleum benzine as eluents. Spectroscopic data were recorded by the following
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