Synthesis and antihepatotoxic activity of some heterocyclic compounds containing the 1,4-dioxane ring system

Silymarin isolated from Silybum marianum is a mixture of three isomers, silybin (1), silydianin (2) and silychristin (3). Silybin is the most active antihepatotoxic agent, and contains a 1,4-dioxane ring in addition to a flavonoid moiety. Based on the skeleton of silybin, we prepared some flavones and coumarins containing the 1,4-dioxane ring system and evaluated them for antihepatotoxic activity against carbon tetrachloride induced hepatotoxicity in albino rats. The degree of protection was determined by measuring biochemical parameters such as serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT), alkaline phosphatase (ALKP), total protein (TP) and total albumin (TA). The compounds namely 3′,4′(1″,4″-dioxino) flavone (4f), and 3′,4′(2-hydroxy methyl, 1″,4″-dioxino) flavone (4g) were found to exhibit a significant activity comparable to standard drug silymarin (silybon-70). Other compounds also exhibited good activity. The structure activity relationship (SAR) was also studied, and where the flavonoid analogues containing a hydroxy methyl group at position-2″ in the dioxane ring exhibited superior antihepatotoxic activity in comparison to coumarin derivatives.