| Matrine is one of chief active components of Sophora flavescens Ait (Kushen), Traditional Chinese Herb. Basic and clinical researches have shown that they possess variety of pharmacological effects such as anti-tumor, antivirus, anti-arhythmia, antibiosis and immunity-regulation. They are used for chronic hepatitis, allergic dermatitis, gynecological disease and cardiovascular disease in clinical practice. However, it was reported that these components have a certain central system toxicity, poisoning caused by irregular breathing and even seizures, and severe case can lead to death. This led to the limited clinical applications of matrine. Herein, in order to decrease the toxicity and increase the pharmaco-activity, the structural modification of matrine-type alkaloids plays an important roll for its application and development.A novel hypotoxicity matrine derivative,13a-sodium sulfonate-matrine, was designed by Quantitative Structure-Activitity Relationship (QSAR). A 3D-QSAR model between toxicity and electrochem parameters was established, used LD50 of some matrine-type alkaloids as Activity parameters, Electron cloud density of C13, N4 and C12 as electrochem parameters. The regression equation was lg(1/LD50) = 13.617xE(C13)-16.282xE(N4)-43.210xE(C12)-11.321, (n=5, R=0.921, R2=0.848, F=1.855). The LD50 of novel compound was calculated by the regression equation and calculated value was 222024.714mg/kg.A novel matrine derivative was synthesized starting from sophocarpine and addition reaction by NaHSO3, with the yield of 82.6% and purity over 98%. Compared with matrine and sophocarpine, the sulfonic group was added in the 13a-sodium sulfonate-matrine indentified by UV, IR, NMR and MS. The QSAR model was validation by acute toxicity-test of mice. The results show that the MTD (maximum tolerated dose) of 13a-sodium sulfonate-matrine was greater than 10000 mg/kg by i.g. administration and greater than 5000 mg/kg by i.v. administration. It was conclude that 13a-sodium sulfonate-matrine is safe, and was conformity with calculated value from QSAR model.Micro-dilution method was used in the antibacterial experiment of matrine, sophocarpine and 13a-sodium sulfonate-matrine.13a-sodium sulfonate-matrine showed higher anti-microbial activity of bacillus proteus compared to matrine and sophocarpine with the MIC of 0.25μg/mL. Matrine and sophocarpine was 128,μg/mL and 32μg/mL, respectively. While no significant difference among these three compounds on anti-bacillus coli activity, the MIC of sophocarpine was 8μg/mL and 4μg/mL of matrine and 13a-sodium sulfonate-matrine. All of them showed no anti-microbial activity of Bacillus proteus and Saccharomyces cerevisiae.The HPLC was used to determine the plasma concentration of 13a-sodium sulfonate-matrine in rat plasma after intramuscular injection. Shim-pack VP-ODS C18 column, (150Lx6.0 mm,5μm,5 cm precolumn), mobile phase:methanol-0.02 M ammonium acetate in water-triethylamine (30:70:0.04, v/v/v); Flow rate:1 mL/min; Injection volume:20μL; Column temperature at 40℃; Absorbance was detected at 220nm using a UV detector (SPD-20A, Japan). The pharmacokinetic parameters were determined by DAS 2.1.1. The date were as follows:Cmax was 54.8479 mg-L-1, Tmax was 0.475 h, t1/2a was 0.4408 h, t1/2βwas 0.371 h,AUC0～t was 63.029 mg·h·L-1,AUC0～8 was 78.1069 mg·h·U1. V1/F was 0.5691L/kg, CL/F was 0.8365 L·h-1·kg-1, MRT0～t, was 1.1382 h-1 and MR.T0～8 was 28.4075 h-1. Compared with matrine, it was demonstrated that the absorption rate, disposition and clearance were increased, but the metabolism, bioavailability and volume of distribution in the central compartments was decreased.
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