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New heterocyclic compounds from 1,2,4-triazole and 1,3,4-thiadiazole class bearing diphenylsulfone moieties. Synthesis, characterization and antimicrobial activity evaluation

https://doi.org/10.1016/j.ejmech.2012.01.031Get rights and content

Abstract

Some new 5-(4-(4-X-phenylsulfonyl)phenyl)-4-(R)-2H-1,2,4-triazol-3(4H)-thiones 4a,b; 5a,b and 5-(4-(4-X-phenylsulfonyl)phenyl)-N-(R)-1,3,4-thiadiazol-2-amines 6a,b; 7a,b were obtained by cyclization of new N1-[4-(4-X-phenylsulfonyl)benzoyl]-N4-(R)-thiosemicarbazides 2a,b; 3a,b (X = H, Br). The 1,2,4-triazoles were synthesized by intramolecular cyclization of acylthiosemicarbazides, in basic media. On the other hand, 1,3,4-thiadiazoles were obtained from same acylthiosemicarbazides, in acidic media. These new intermediates from thiosemicarbazide class were afforded by the reaction of 4-(4-X-phenylsulfonyl)benzoic acids hydrazides (X = H, Br) 1a,b with 4-trifluoromethoxyphenyl or 3,4,5-trimethoxyphenyl isothiocyanate. The newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR, MS and elemental analysis. All the new compounds were screened for their antimicrobial activity against some bacteria (Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 13061, Escherichia coli ATCC 25922, Enterobacter cloacae ATCC 49141, Acinetobacter baumannii ATCC 19606 and Pseudomonas aeruginosa ATCC 27853) and yeasts (Candida albicans ATCC 90028 and Candida parapsilosis ATCC 22019).

Graphical abstract

New 1,2,4-triazoles and 1,3,4-thiadiazoles were obtained by cyclization of corresponding acylthiosemicarbazides. The structures of compounds were confirmed by spectral techniques and elemental analysis. The compounds were screened for antimicrobial activity.

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Highlights

► New 1,2,4-triazol-3(4H)-thiones and 1,3,4-thiadiazol-2-amines were synthesized. ► The new structures were confirmed by elemental analysis and spectral methods. ► The potential antimicrobial effects of new compounds were investigated. ► The compounds which containing 3,4,5-trimethoxyphenyl showed the best results.

Introduction

During the past decades, the incidence of microbial infection has increased to alarming levels all over the world as a result of antimicrobial resistance. Thus, in recent years, much attention has been focused on addressing the problem of multi-drug resistant (MDR) bacteria and fungi resulting from the widespread use and misuse of classical antimicrobial agents. Due to this reason, discovering of new classes of antimicrobial agents with novel mechanisms is crucial to combat multi-drug resistant infections.

Organic compounds incorporating heterocyclic ring systems continue to attract considerable interest due to their wide range of biological activities. Among different five-membered heterocyclic systems 1,2,4-triazoles and 1,3,4-thiadiazoles and their derivatives have gained importance as they constitute the structural features of many bioactive compounds. It is known that triazole and thiadiazole rings are included in the structure of various drugs [1], [2], [3], [4]. From these classes of heterocyclic compounds, the synthesis of new derivatives of 1,2,4-triazole-3-thiones and 2-amino-1,3,4-thiadiazoles has been attracting considerable attention because of various biological properties such as: antibacterial [5], [6], [7], [8], [9], [10], antifungal [5], [11], [12], anti-tubercular [5], [8], [13], antiviral [6], [7], [13], antioxidant [14], [15], antitumoral [16], [17], [18], anti-inflammatory [19], [20], [21], anticonvulsant [22], [23], [24] etc.

On the other hand, literature survey revealed that diphenylsulfone derivatives have antibacterial activity [25], [26].

Motivated by these findings and in continuation of our ongoing efforts on the synthesis of heterocycles with potential antimicrobial activities [27], [28], [29], [30], [31], [32], we are purposed to synthesize and investigate the antimicrobial activity of a new series from 1,2,4-triazole and 1,3,4-thiadiazole class having diarylsulfone moiety as pharmacophore centre in 5 position and different radicals linked in 4 position of triazole or to amino group from 2 position of thiadiazole nucleus.

Section snippets

Chemistry

The synthetic route for the newly synthesized compounds, 1,2,4-triazoles, 1,3,4-thiadiazoles and their acylthiosemicarbazides intermediary, is illustrated and outlined in Scheme 1.

The precursors, 4-(4-X-phenylsulfonyl)benzoic acid hydrazides 1a,b (X = H, Br), were prepared, in several stages, according to the literature method [33]. Thus, diarylsulfones (X = H, Br), obtained by tosylation of benzene or bromobenzene with 4-methylbenzene-1-sulfonyl chloride, by oxidation with chromic anhydride and

Antimicrobial activity

The new synthesized compounds were tested for their in vitro antimicrobial activity against the Gram-positive bacteria: Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 13061, the Gram-negative bacteria: Escherichia coli ATCC 25922, Enterobacter cloacae ATCC 49141, Acinetobacter baumannii ATCC 19606, Pseudomonas aeruginosa ATCC 27853 and the yeasts Candida albicans ATCC 90028 and Candida parapsilosis ATCC 22019, by using the broth microdilution method for determination of MIC.

Chemistry

The structural assignments of new compounds were based on their elemental analysis and spectral data (IR, 1H NMR, 13C NMR and MS). The elemental analysis data and some physical properties of these new compounds are reported in Table 1.

The structure of thiosemicarbazides 2 and 3 was confirmed by their IR spectra which displayed absorption peaks at 3150–3438 cm−1 for NH, 1673–1686 cm−1 for Cdouble bondO and 1209–1236 cm−1 corresponding to Cdouble bondS stretching vibrations. In the 1H NMR spectra of these new compounds,

Conclusions

In this study we report the synthesis, characterization and antimicrobial activity evaluation of new compounds from 1,2,4-triazole and 1,3,4-thiadiazole class and their acylthiosemicarbazide intermediates bearing diphenylsulfone moiety. The target compounds from 1,2,4-triazole and 1,3,4-thiadiazole class were obtained from intramolecular cyclization of some new acylthiosemicarbazides in basic/acidic media. The intermediates from thiosemicarbazide class were synthesized by reaction of

Chemistry

Melting points were determined with Boetius apparatus and are uncorrected. The IR spectra (KBr pellets) were recorded on a Vertex 70 Bruker spectrometer. The NMR spectra were recorded on a Varian Gemini 300 BB spectrometer working at 300 MHz for a 1H and 75 MHz for 13C in DMSO-d6 solutions using TMS as an internal standard. The mass spectra of the new compounds were registered on a triple quadrupole mass spectrometer Varian 1200 L/MS/MS with electrospray interface (ESI), coupled with a high

Acknowledgements

This paper is supported by the Sectoral Operational Programme Human Resources Development, financed from the European Social Fund and by the Romanian Government under the contract number POSDRU/89/1.5/S/64109.

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    A part of this work was presented as poster presentation at 4th European Conference on Chemistry for Life Sciences (4ECCLS), Budapest, Hungary, August 31–September 3, 2011.

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