5-Substituted 3-chlorokenpaullone derivatives are potent inhibitors of Trypanosoma brucei bloodstream forms

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• 作者：Oliver C.F. Orban^a ; ^&dagger ; ; Ricarda S. Korn^a ; ^&dagger ; ; Diego Bení ; tez^b ; Andrea Medeiros^b ; ^c ; Lutz Preu^a ; Nadè ; ge Loaë ; c^d ; Laurent Meijer^d ; Oliver Koch^e ; Marcelo A. Comini^b ; ^{mcomini@pasteur.edu.uy" class="auth_mail" title="E-mail the corresponding author} ; Conrad Kunick^a ; ^f ; ^{c.kunick@tu-braunschweig.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ACN ; acetonitrile ; CDK ; cyclin-dependent kinase ; CLK ; cdc2-like kinase ; CK ; casein kinase ; DIPEA ; diisopropylethylamine ; DMEM ; Dulbecco&rsquo ; s modified Eagle&rsquo ; s medium ; DMF ; N ; N-dimethylformamide ; DMSO ; dimethyl sulfoxide ; DYRK1A ; dual specificity tyrosine phosphorylation-regulated protein kinase 1A ; DTT ; dithiothreitol ; EDTA ; ethylenediaminetetraacetic acid ; EGTA ; ethylene glycol-bis(β-aminoethyl ether)-N ; N ; N&prime ; N&prime ; -tetraacetic acid ; FCS ; fetal calf serum ; FSC ; forward scatter ; G
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 August 2016
• 年：2016
• 卷：24
• 期：16
• 页码：3790-3800
• 全文大小：1000 K

文摘

Trypanothione synthetase is an essential enzyme for kinetoplastid parasites which cause highly disabling and fatal diseases in humans and animals. Inspired by the observation that N(5)-substituted paullones inhibit the trypanothione synthetase from the related parasite Leishmania infantum, we designed and synthesized a series of new derivatives. Although none of the new compounds displayed strong inhibition of Trypanosoma brucei trypanothione synthetase, several of them caused a remarkable growth inhibition of cultivated Trypanosoma brucei bloodstream forms. The most potent congener 3a showed antitrypanosomal activity in double digit nanomolar concentrations and a selectivity index of three orders of magnitude versus murine macrophage cells.