Inhibition of parasite protein kinase C by new antileishmanial imidazolidin-2-one compounds

被引：18

作者：

Alvarez, N ^{[1
]}

Robledo, S ^{[1
]}

Velez, ID ^{[1
]}

Robert, JM ^{[1
]}

Le Baut, G ^{[1
]}

Le Pape, P ^{[1
]}

机构：

[1] Fac Pharm Nantes, Serv Chim Therapeut, Nantes, France

来源：

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY | 2002年 / 17卷 / 06期

关键词：

Leishmania; imidazolidin-2-one compounds; invasion process; protein kinase C;

D O I：

10.1080/1475636021000005749

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The protein kinase C (PKC) family of isoenzymes mediate a wide range of signal transduction pathways in many different cells lines. Little is known regarding the presence and functional roles of PKC in Leishmania spp. Here we report the inhibition of parasite PKC by new imidazolidinone compounds. The most active derivative 7 showed an important activity (IC50 =9.9 muM) against the clinical relevant stage of parasites in comparison with Glucantime (R) (IC50 =464.5 muM), without inducing toxicity on human fibroblast cells (IC50 =102 muM). Pretreatment of intact parasites with 10 muM of compound 7 inhibited 80% of PKC activity. At the same concentration, this compound inhibited 70% of the parasite-host cell invasion process. An in vivo model showed that compound 7 reduced the liver parasite burden by 25% and spleen parasite burden by 44%. These results provide the first evidence that PKC plays a critical role in the invasion process. Thus Leishmania PKC activity could be a relevant therapeutic target and the imidazolidinones novel antileishmanial candidates.

引用

页码：443 / 447

页数：5

共 19 条

[1]

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[2]

ALVAREZ NF, 2001, UNPUB PARASITE

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