Antiamoebic coumarins from the root bark of Adina cordifolia and their new thiosemicarbazone derivatives

In continuation of our search for potential antiamoebic agents from folklore Indian medicinal plants, we found that the benzene and ethyl acetate extracts from the root bark of Adina cordifolia exhibited strong antiamoebic activity with IC50 values of 2.92 and 2.50 μg/ml, respectively. Bioassay-guided fractionation of benzene and ethyl acetate extracts led to the isolation of 7-hydroxycoumarin (umbelliferone 1) and 7-β-D-glucosylcoumarin (skimmin 2), respectively. Umbelliferone 1 was converted into 7-acetoxycoumarin 1a, which on treatment with aluminium chloride afforded 7-hydroxy-8-acetylcoumarin 2a. A new series of thiosemicarbazones 3a–e of 7-hydroxy-8-acetylcoumarin with different thiosemicarbazides were synthesized. Umbelliferone was also converted into its methoxy derivative (7-methoxycoumarin 4). Subsequently, all the compounds were assessed for antiamoebic activity against HM1:IMMS strain of Entamoeba histolytica. Umbelliferone and skimmin were found to possess a very good activity with IC50 values of 6.38 and 4.35 μM/ml, respectively. The activity drastically increased on converting compound 2a into its thiosemicarbazone derivatives 3a–e with IC50 values ranging between 1.06 and 4.46 μM/ml. Compounds 3b,c and e with IC50 values of 1.49, 1.56 and 1.06 μM/ml, respectively, exhibited even higher antiamoebic activity than the standard drug metronidazole (IC50 = 2.62 μg/ml). The activity of 7-methoxycoumarin (IC50 = 8.92 μM/ml) was less than umbelliferone. Compounds 3b, c and e were tested for toxicity using H9c2 cardiac myoblasts cell line. The compounds exhibit >80% viability at 3.125–200 μg/ml. It is apparent from these results that umbelliferone and skimmin may be a useful lead for the development of new antiamoebic drugs.

Graphical abstractThe root bark of Adina cordifolia led to the isolation of 7-hydroxycoumarin 1 and 7-β-D-glucosylcoumarin 2. A new series of thiosemicarbazones 3a–e of 7-hydroxy-8-acetylcoumarin with different thiosemicarbazides were synthesized. Compounds 3b, c, and e with IC50 values 1.49, 1.56, 1,06 μM/ml exhibited higher antiamoebic activity than the standard drug metronidazole (IC50 = 2.63 μM/ml). All the active compounds were tested for toxicity using H9c2 cardiac myoblasts cell line and all were found to exhibit >80% viability at 3.125–200 μg/ml.Figure optionsDownload full-size imageDownload as PowerPoint slide