Synthesis and Antimicrobial Activities of Containing Sulfur Heterocyclic Curcumin Derivatives

Eight novel containing sulfur heterocyclic curcumins were synthesized and characterized by 1 H-NMR, FTIR and MS spectroscopy. Their antimicrobial activities against Staphylococcus aureus , Bacillus subtilis , Escherichia coli and Aspergillus niger were also tested for MIC by using serial tube dilution method. The results showed that the antimicrobial activities of synthesized curcumin derivatives were better than curcumin. Especially, the compound 4-(1,3-dithiolan-2-ylidene)-1,7-di(thiophen-2-yl) hepta-1,6-diene-3,5-dione (2g) exhibited excellent the antimicrobial activities among these curcumin derivatives.

The curcumin derivatives (2a-2h) were synthesized via Claisen condensation of compound (1) with the required aldehyde in the presence of sodium ethoxide. Their structures were slao confirmed by FTIR, 1 H NMR and mass spectroscopy. Their 1 H NMR spectra revealed the double-double peaks at δ = 7.45-7.18ppm and δ = 6.97-6.81ppm, the single peaks at δ = 3.42-3.31ppm corresponding to the methylene protons in sulfur ring. Their IR spectra showed the absorption bands at 1571-1510cm -1 attributed to the C=C stretching vibration.

II Anti-Bacterial Activity
The screening results of antimicrobial activity of curcumin derivatives (2a-2h) are summarized in (Table 1). It is obvious from the data that these derivatives possess inhibitory activities to a certain degree against the tested microorganisms and display better antimicrobial activities than curcumin against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Aspergillus niger. It was also observed that the curcumin derivatives (2e-2h) exhibited much significant antimicrobial activities among these synthesized compounds, which was probably resulted from the introduction of modified substituents led to the increase of the hydrophobicity and the delocalization of the electron cloud. Especially, the derivative 2g displayed the highest activities in these synthesized compounds.

Conclusion
In conclusion, we designed and synthesized eight new curcumin derivatives. Their structures were confirmed by FT-IR, 1 H NMR and MS spectroscopy. The antimicrobial activities of these curcumin derivatives were evaluated by serial tube dilution method against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Aspergillus niger. The results showed that these derivatives showed certain degree of antimicrobial activities and their activities were much better than curcumin. In addition, curcumin derivatives (2e-2h) had much higher antimicrobial activities in these derivatives. Especially, the derivative 2g exhibited the highest antimicrobial activities against the tested microorganisms and all the MIC values were 8 µg/mL against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Aspergillus niger. Thus, these studies provide a lead for synthesis and evaluation of more curcumin derivatives for antimicrobial activity as the same could lead to the discovery of some potential agents.

Experimental
Melting points were determined using X-4 digital melting point apparatus and are corrected by benzoic acid. Infrared spectra were recorded on a Nicolet FTIR 5700 spectrophotometer with KBr pellets. The 1 H NMR spectra were measured on an advance IIITM 300 MHz NB Digital NMR spectrometer. Electrospray ionization mass spectra (ESI-MS) were performed with a Finnigan LCQ Advantage Max spectrometer. Reagents were of analytical grade and were used without further purification.

I Synthesis of Compound (1)
Potassium carbonate (5.5g, 40 mmol) and acetylacetone (2.1 mL, 20 mmol) were dissolved in 20 ml N, N-dimethylformamide and stirred for 0.5h at room temperature, CS2 (1.33 ml) was added and stirred for 1h under ice water. 1,2-dibromoethane (2.6 mL) was added dropwise and stirred for 14h at room temperature. The reaction mixture was poured into a beaker full of water (200mL), stirred until the yellow product precipitated. The precipitate was filtered off and washed with aqueous contain 95% ethanol. The crude products were recrystallized from ethanol to give the 3-

II Synthesis of Curcumin Derivatives 2a-2h
Sodium (10.0 mmol) was completely dissolved in ethanol (10 mL) and stirred at room temperature, a solution of compound (1) (2.5 mmol) in ethanol, the aromatic aldehyde (6.0 mmol) was added dropwise and stirred under ice water for 4h. Then the product precipitated. The precipitate was separated by suction filtration, purified by recrystallized from industrial alcohol and dichloromethane to give the curcumin derivatives (2a-2h).

III Procedure for Anti-Bacterial Activity
The synthesized curcumin derivatives (2a-2h) were screened for their in vitro antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Aspergillus niger. Their MICs were evaluated by using serial tube dilution methods at various concentration of 256, 128, 64, 32, 16, 8, 4, 2, 1 µg/mL [17]. The MIC, defined as the lowest concentration of the test derivative which inhibits the visible growth after 24 h, was determined visually after incubation at 37°C. Tests using DMSO as negative control were carried out in parallel. Curcumin was used as standard for antimicrobial activity.