Leishmanicidal, antiproteolytic and antioxidant evaluation of natural biflavonoids isolated from Garcinia brasiliensis and their semisynthetic derivatives

Eur J Med Chem. 2012 Dec;58:613-23. doi: 10.1016/j.ejmech.2012.06.021. Epub 2012 Jun 28.

Abstract

The natural biflavonoids morelloflavone-4‴-O-β-D-glycosyl (1), (±)-fukugiside (2) and morelloflavone (3) were isolated from the ethyl acetate extract (EAEE) of dried and powdered fruit epicarps of Garcinia brasiliensis and derivatives of morelloflavone were semi-synthesised. Morelloflavone-7,4',7″,3‴,4‴-penta-O-acetyl (4), morelloflavone-7,4',7″,3‴,4‴-penta-O-methyl (5) and morelloflavone-7,4',7″,3‴,4‴-penta-O-butanoyl (6) were prepared by acylation and alkylation reactions. All compounds showed leishmanicidal, antiproteolytic and antioxidant activities in addition to exhibiting low cytotoxicity. Compounds 4, 5 and 6 were highly active against Leishmania amazonensis promastigote forms compared to natural compounds of low lipophilicity, exhibiting IC(50) values of 0.0147, 0.0403 and 0.0189 μM, respectively. Compounds 4, 5 and 6 were also highly active against amastigote forms with IC(50) values of 0.042, 0.0603 and 0.059 μM, respectively. In addition, highly inhibitory activity against r-CPB2.8 and r-CPB3 isoforms was observed with these compounds. Notably, compounds 3 and 4 were the most active against r-CPB2.8 with IC(50) values of 0.4200 and 0.6744 μM, respectively. Compounds 5 and 6 also showed significant inhibitory activities with very similar IC(50) values of 1.2663 and 1.0122, respectively. However, compounds 1 and 2 exhibited the lowest inhibitory activity against r-CPB2.8, almost 6 and 11-fold less active than the natural compound 3. In L. (L.) amazonensis lysates, and compounds 3 and 6 were the most active inhibitors of amastigote lysates at pH 5, which is near the pH environment of the parasitophorous vacuole within the macrophage. Finally, compounds 1, 2 and 3 exhibited effective antioxidant activity compared to the reference antioxidant ascorbic acid. However, the activity was lower than that of butylhydroxytoluene (BHT), which may be related to the reduced number of phenolic hydroxyl groups that were replaced by more lipophilic substituents in derivatives 4-6. Compounds 4-6 exhibited reduced antioxidant activity as evidenced by their higher EC(50) values. These results provide new perspectives on drug development for the treatment of leishmaniasis and inhibitory enzyme activity on Leishmania (L.) mexicana cysteine proteases and other isoforms.

MeSH terms

  • Animals
  • Antioxidants / isolation & purification
  • Antioxidants / metabolism
  • Antioxidants / pharmacology*
  • Antiprotozoal Agents / isolation & purification
  • Antiprotozoal Agents / metabolism
  • Antiprotozoal Agents / pharmacology*
  • Biflavonoids / isolation & purification
  • Biflavonoids / metabolism
  • Biflavonoids / pharmacology*
  • Biological Products / isolation & purification
  • Biological Products / metabolism
  • Biological Products / pharmacology*
  • Cysteine Proteases / metabolism*
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / isolation & purification
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Garcinia / chemistry
  • Leishmania / drug effects
  • Mice
  • Molecular Conformation
  • Parasitic Sensitivity Tests
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • Antioxidants
  • Antiprotozoal Agents
  • Biflavonoids
  • Biological Products
  • Cysteine Proteinase Inhibitors
  • Recombinant Proteins
  • Cysteine Proteases