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

详细信息    查看全文

• 作者：Vanessa Silva Gontijo^a ; Wagner A.S. Judice^b ; Barbara Codonho^c ; Ivan Oliveira Pereira^c ; ^d ; Diego Magno Assis^e ; Jaqueline Pereira Januá ; rio^a ; Elide E. Caroselli^e ; Maria Aparecida Juliano^e ; Amanda de Carvalho Dosatti^b ; Marcos José ; Marques^c ; Claudio Viegas Junior^a ; Marcelo Henrique dos Santos^a ; ^{marcelohsantos@unifal.com.br}
• 关键词：Garcinia brasiliensis ; Biflavonoids ; Natural products ; Semisynthesis ; Antioxidants ; Antiproteolytic ; Leishmania amazonensis
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December, 2012
• 年：2012
• 卷：58
• 期：Complete
• 页码：613-623
• 全文大小：392 K

文摘

The natural biflavonoids morelloflavone-4?-O-¦Â-d-glycosyl (1), (¡À)-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¡ä,7¡å,3?,4?-penta-O-acetyl (4), morelloflavone-7,4¡ä,7¡å,3?,4?-penta-O-methyl (5) and morelloflavone-7,4¡ä,7¡å,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 IC₅₀ values of 0.0147, 0.0403 and 0.0189?¦ÌM, respectively. Compounds 4, 5 and 6 were also highly active against amastigote forms with IC₅₀ values of 0.042, 0.0603 and 0.059?¦ÌM, 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 IC₅₀ values of 0.4200 and 0.6744?¦ÌM, respectively. Compounds 5 and 6 also showed significant inhibitory activities with very similar IC₅₀ 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 EC₅₀ 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.