Synthesis and Antibacterial Activity of 1,3-Diallyltrisulfane Derivatives Bull. Korean Chem. Soc. 2009, Vol. 30, No. 3 687 Synthesis and Antibacterial Activit y of 1,3-Diallyltrisulfane Derivatives Fang-Kui Ren, Xiao-Yan He, Li Deng, Bo-Heng Li, † Dong-Soo Shin, ‡,* and Zhu-Bo Li * College of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China † High School Attached to Southwest Normal University, Chongqing 400715, China ‡ Department of Chemistry, Changwon National University, Changwon, GN 641-733, Korea * E-mail: dsshin@changwon.ac.kr Received October 29, 2008, Accepted February 5, 2009 A series of novel 1,3-diallyltrisulfane analogues were synthesized and assayed in vitro for antimicrobial activity against Gram positive, Gram negative bacteria and fungi. The antimicrobial activity of the 1,3-diallyltrisulfane derivatives showed, on the whole, very potent towards all the tested Gram positive, Gram negative and fungi (MIC ranging from 4 to 256 µg/mL). 1,3-Di(pent-4-enyl)trisulfane 3b and 1,3-bis(3-methylbut-2-enyl)trisulfane 3e exhibited the strongest antibacterial activity among all the compounds, and both of them were more active than 1,3-diallyltrisulfane (DATS). Results indicated the relationship of either carbon number or lipophilicity with antimicrobial activity presented “V” shape. These observations provided some predictions in order to further design 1,3-diallyltrisulfane derivatives with antimicrobial activity. Key Words: Diallylsulfane, Diallyldisulfane, Diallyltrisulfane, Antimicrobial activity, Biological activity S S S 1,3-diallyltrisulfane (DATS) S diallylsulfane (DAS) S S 1,2-diallyldisulfane (DADS) Scheme 1. Diallylsulfanes in garlic Introduction Garlic (Allium sativum L.) has long been recognized to be nature plant medical. 1 Garlic contains abundance of organo- sulfur compounds, such as diallylsulfane (DAS), 1,2-diallyl- disulfane (DADS) and 1,3-diallyltrisulfane (DATS) (Scheme 1). On the other hand, thio ether and double bond has been indicated as an important pharmacophore and privileged structure in medicinal chemistry, 2-4 producing a diverse range of biological activities including antibacterical, 5 antiparasite, 6 antiviral, 7 anticancer, 8 antitumor, 9 antioxidation 10-11 and anticar- diovascular activities. 12 Usually, 1,3-diallyltrisulfane was synthesized by unsaturated alkyl halide, sodium thiosulfate and sodium sulfide in DMSO, THF or H 2 O-EtOH. Buffer solutions or expensive metal catalysts were used in some reactions. 13-16 Until now 1,3-diallyltrisulfane derivatives were not reported. Herein, we improved the method and synthe- sized novel 1,3-diallyltrisulfane derivatives 3a -3e, containing longer chain and branched allyl moieties in the structures. All the compounds were tested for in vitro antimicrobial pro- perties against Gram positive, Gram negative bacteria and fungi, and exhibited excellent activity. The structure-activity relationship of the 1,3-diallyltrisulfane derivatives was stu- died. Materials and Methods All chemicals and solvents used were of AR grade and DATS was purchased from Institute of Biology, the Chinese Academy of Sciences. Extracted solvents were dried over anhydrous Na2SO4, followed by evaporation under vacuum. 1 H NMR and 13 C NMR spectra were recorded in CDCl 3 (400 MHz for 1 H NMR and 100 MHz for 13 C NMR, respectively) with TMS as the internal reference on Bruker Advance 400 FT spectrometer. Chemicals shifts were reported in parts per million. Mass spectra (MS) were measured by EPCI method. IR spectra were recorded, as KBr pellets, on a Jasco FT-IR 300E spectrophotometer (Jasco Ltd., Japan) and the reported wave numbers were given in cm -1 . Silica gel (200-300 mesh) was used for flash column chromatography. All the reactions were monitored by TLC using 0.25 mm silica gel plates (Merck 60F-254) with UV indicator. The ClogP values were calculated using ChemDraw Ultra 8.0. General procedure for the synthesis. To the saturated aqueous solution of sodium thiosulfate (0.13 mol), was added the unsaturated alkyl bromide (0.1 mol) dropwise at 50-60 o C, kept stirring. When the solution turned clear, the reaction mixture was cooled to room temperature and standing for separation. To the under layer the sodium sulfide solution (30 mL, 0.001 mol/mL) was added, kept stirring at room tem- perature overnight. The upper layer of the reaction mixture was washed by water and dried over aqueous sodium sulfate. Crude products were purified by column chromatography, yielding 80-90% of the products. 1,3-Di(but-3-enyl)trisulfane(3a): light-yellow oil; IR (KBr) ν max 3078, 2978, 2922, 2844, 1835, 1639, 1435, 1415, 1273, 1215, 992, 914, 749, 634, 478 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 2.49-2.55 (m, 4H), 2.94 (t, J = 7.6 Hz, 4H), 5.05-5.14 (m, 4H), 5.79-5.89 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 33.0, 37.9, 116.5, 134.0; MS (APCI) m/z 206 [M + ].