Fluorine walk: The impact of fluorine in quinolone amides on their activity against African sleeping sickness

被引：9

作者：

Berninger, Michael ^{[1
]}

Erk, Christine ^{[1
]}

Fuss, Antje ^{[2
]}

Skaf, Joseph ^{[1
]}

Al-Momani, Ehab ^{[3
]}

Israel, Ina ^{[3
]}

Raschig, Martina ^{[1
]}

Guentzel, Paul ^{[1
]}

Samnick, Samuel ^{[3
]}

Holzgrabe, Ulrike ^{[1
]}

机构：

[1] Univ Wurzburg, Inst Pharm & Food Chem, D-97074 Wurzburg, Germany

[2] Med Mission Inst Wurzburg, Hermann Schell Str 7, D-97074 Wurzburg, Germany

[3] Univ Hosp Wurzburg, Dept Nucl Med, Oberduerrbacher Str 6, D-97080 Wurzburg, Germany

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 152卷

关键词：

Quinolone amides; Trypanosoma brucei brucei; Structure-activity relationship; Fluorine walk; Metabolism; Blood-brain barrier; Autoradiography; TRYPANOSOMA-BRUCEI; MEDICINAL CHEMISTRY; DISCOVERY; DERIVATIVES; RHODESIENSE; CHALLENGES; GAMBIENSE; AGENT; ACIDS; ASSAY;

D O I：

10.1016/j.ejmech.2018.04.055

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Human African Trypanosomiasis, also known as African sleeping sickness, is caused by the parasitic protozoa of the genus Trypanosoma. If there is no pharmacological intervention, the parasites can cross the blood-brain barrier (BBB), inevitably leading to death of the patients. Previous investigation identified the quinolone amide GHQ168 as a promising lead compound having a nanomolar activity against T b. brucei. Here, the role of a fluorine substitution at different positions was investigated in regard to toxicity, pharmacokinetics, and antitrypanosomal activity. This 'fluorine walk' led to new compounds with improved metabolic stability and consistent activity against T. b. brucei. The ability of the new quinolone amides to cross the BBB was confirmed using an F-18-labelled quinolone amide derivative by means of ex vivo autoradiography of a murine brain. (C) 2018 Elsevier Masson SAS. All rights reserved.

引用

页码：377 / 391

页数：15

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