One-pot synthesis of new triazole-sucrose derivatives via click chemistry and evaluation of their antitubercular activity

Introduction

Tuberculosis caused by Mycobacterium tuberculosis still remains the leading cause of worldwide deaths among infectious diseases. The World Health Organization reported that more than one-third of the world’s population was infected with tuberculosis, which resulted in an estimated 1.5 million deaths worldwide in 2013 [1]. The long duration of therapy generally is due to the nonconformity of the treatment and to the extensively drug-resistant tuberculosis, which is highly lethal, extremely expensive and complicated to treat, posing new challenges for the prevention, treatment and control of tuberculosis [2].

Ferreria and coworkers [3] have reported that 1,4-disubstituted 1,2,3-triazole derivatives A and B (Figure 1) exhibit good inhibitory activities against MTB H37Rv. Similarly, 1,2,3-triazoles C show inhibitory activities against H37Rv [4].

Figure 1

1,2,3-Triazoles A–C with antitubercular activity.

The catalyzed azide-alkyne cycloaddition reaction has found extensive application in the preparation of carbohydrate derivatives [5]. This method, developed by Meldal [6] and Sharpless [7], has became an important tool in organic synthesis due to a regioselective formation of 1,4-disubstituted 1,2,3-triazoles [8]. Moreover, the use of water as a solvent makes this reaction very attractive [9]. Recently, significant attention also has been paid to the use of copper nanoparticles (CuNPs) as catalysts in ‘CuAAC’ reactions in the synthesis of 1,2,3-triazoles. However, most of these reactions require organic solvents and high loading of CuNPs [10], [11], [12]. We wish to present herein the applicability of a copper nanoparticles for the click synthesis of new 1,2,3-triazole derivatives of carbohydrates in water.

Results and discussion

The cycloaddition of 1-prop-2-ynyl-pyrrolidine-2,5-dione 1a with carbohydrate azide 2 [13] in acetonitrile afforded the desired triazole 3a under copper catalysis conditions (Scheme 1). The CuNPs was prepared by reducing CuSO₄ with hydrazine according to literature procedures [14], [15]. The use of CuNPs and CuBr gave similar results. Then, the replacement of acetonitrile by water as a solvent substantially affected the yield (80%) of the reaction catalyzed by CuNPs which was completed (TLC) within 15 min, while the CuBr catalyzed reaction gave 3a in 60% yield under similar conditions. Encouraged by the efficiency of the reaction protocol described above, the scope of the reaction was examined with alkynes 1b–e. Corresponding triazoles 3b–e were obtained in good yields.

Scheme 1

All the target molecules 3b–e were screened against M. tuberculosis H37RV (ATCC27294) using agar dilution method [16]. Their antimycobacterial activity was evaluated in terms of minimum inhibitory concentration (MIC) values. The MIC values of these compounds are in the range of 3.125–25 mg/mL. As can be seen from Figure 2, compounds 3a–c show potent anti-tubercular activity with MIC of 3.125 μg/mL each. The MIC values of these three compounds are comparable with that of the standard drug, ethambutol. Compound 3e shows moderate inhibition activity with MIC of 12.5 mg/mL.

Figure 2

The antitubercular activity of 3a–e against M. tuberculosis H37RV (INH: isoniazid; EMB: ethambutol; PZA: pyrazinamide).

Experimental

Flash chromatography was performed using silica gel Merck 60 (particle size 0.040–0.063 mm). All anhydrous reactions were performed under nitrogen using anhydrous solvents. NMR spectra were obtained on a Bruker AC 300 spectrometer operating at 300 MHz for ¹H and at 75 MHz for ¹³C. Melting points were determined on a Buchi-510 capillary melting point apparatus. Chemical shifts are given in parts per million relative to tetramethylsilane (TMS). The spectra were recorded in CDCl₃ as solvent at room temperature. Elemental analysis was recorded on a Perkin-Elmer 240B microanalyzer. Mass spectra were recorded on a Finnigan LCQ DECA XP plus spectrometer.