Liver disease is a leading cause of death in many countries and the causative factors are alcohol consumption, malnutrition, aneamia, hepatotoxic drugs and infections etc. The liver, a vital organ instrumental in metabolism, detoxification and elimination, is responsible for protection of human body against adverse effects of drugs, chemicals, toxins, bacteria, viruses and parasites etc., but in the process liver itself is under threat and obviously needs protection.

         So far no effective measures are available for the treatment of liver diseases. The different medical, surgical and therapeutic methods used at present are inadequate with generally poor results. Also some of the modern drugs which are given to treat liver diseases may themselves cause liver damage.

         It is therefore, imperative to search alternative drugs for the treatment of liver diseases to replace the existing currently used drugs of doubtful efficacy and safety.

Phytochemical investigation and antihepatotoxic activity of Silybum marianum:

         Silybum marianum Linn. (Carduus marianus), family: Asteraceae, a medicinal plant widely used in traditional European medicine for the treatment of various liver ailment, was selected for phytochemical and pharmacological investigation to establish the efficacy of plant extracts, and various isolated constituents as potent antihepatotoxic agent.

         50 Kg seeds of S. marianum were dried and crushed to coarse powder which was then exhaustively extracted with ethanol by cold percolation. The crude alcoholic extract was fractionated into Pet. Ether (900 gm), Ethyl acetate (800 gm) and Methanol (300 gm) soluble fraction respectively.

         The different compounds like silybin a1, silybina2, silybin b1, silybin b2, and various steroids were isolated and characterized on the basis of IR, UV, NMR and Mass spectral data.

         One of the isolated compound, silybin was treated with Boron trifluoride in diethyl ether and change in stereochemistry was studied. The studies suggested that proton of ring C of silybin became Trans from Cis, and orientation of proton at position 8’’ in 1, 4 dioxane ring also changed from b to a.

         The various extracts and isolated compounds were evaluated for antihepatotoxic activity in albino rats by using CCl4 as toxicant. The degree of protection was measured by performing histopathological studies and by estimating various biochemical parameters. Like SGOT, SGPT, ALKP, TP & TA. The methanolic extract showed good antihepatotoxic activity, which was comparable to effects produced by standard drug silybon- 70. The other two extracts, Pet. ether and ethyl acetate also showed moderate protection.

         All the isolated compounds showed better protection than standard drug, however among all the isolated compounds, SK –16 and SK-1 were found to be most potent antihepatotoxic compounds.

Synthesis and antihepatotoxic activity of compounds containing 1,4 dioxane ring system:

         Silymarin (silybon-70), a hepatoprotective drug is a mixture of three isomers namely silybin, silychristin and silydianin. Among the three isomers silybin is the most potent antihepatotoxic agent. On analyzing the chemical structure of 3 isomers, it was observed that silybin contains 1,4 dioxane ring system in its structure, however this ring is absent in other two isomers. Thus the hepatoprotective activity possessed by silybin can be attributed to the presence of 1,4 dioxane ring system in its strucuture.

         We therefore, thought worthwhile that 1,4 dioxane ring system might play an important role in exhibiting antihepatotoxic activity. Thus on the basis of above finding a number of heterocyclic compounds like flavones, xanthones, coumarins and chalcones etc. possessing 1,4 dioxane ring in their molecule were synthesized. The synthesized compounds were screened for antihepatotoxic activity against CCl4 intoxicated albino rats, by estimating biochemical parameters. The synthesized compounds were simple, low molecular weight and could be easily synthesized in lab. For incorporating 1,4 dioxane ring the free ortho dihydroxy compounds were condensed with either ethylene bromide to obtain unsubstituted benzo 1,4 dioxane derivatives or with epichlorohydrin to obtain 2- hydroxymethyl benzo 1,4 dioxane derivatives in presence of aq. Alkali.

         Among the synthesized compounds the flavono dioxins were found to be the most potent compounds as they decreased the elevated levels of SGOT, SGPT, ALKP and TA, and increased the decreased level of TP. The effects produced by flavono dioxins were comparable to standard drug silybon 70. The dioxino coumarins showed moderate results followed by dioxino xanthones and chalocone derivatives.

         The above studies suggested that both flavone moiety and 1,4 dioxane ring along with 2- hydroxy methyl group in the side chain could exhibit potent antihepatotoxic activity and in turn could be used for treatment of various ailments of liver. The synthesized compounds are low molecular weight and could be easily prepared. On the other hand silybin is a complex molecule and thus can not be prepared easily. Furthermore the synthesized compounds are expected to be easily metabolizable in comparison to silymarin, being simple and low molecular weight