5-Substituted 3-chlorokenpaullone derivatives are potent inhibitors of Trypanosoma brucei bloodstream forms. Issue 16 (15th August 2016)

• Record Type: Journal Article
• Authors: Orban, Oliver C.F.; Korn, Ricarda S.; Benítez, Diego; Medeiros, Andrea; Preu, Lutz; Loaëc, Nadège; Meijer, Laurent; Koch, Oliver; Comini, Marcelo A.; Kunick, Conrad
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 16(2016)
• Page Start: 3790
• Page End: 3800
• Publication Date: 2016-08-15
• Subjects: ACN acetonitrile -- CDK cyclin-dependent kinase -- CLK cdc2-like kinase -- CK casein kinase -- DIPEA diisopropylethylamine -- DMEM Dulbecco's modified Eagle'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′, N′-tetraacetic acid -- FCS fetal calf serum -- FSC forward scatter -- GSK-3 glycogen synthase kinase-3 -- HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid -- PyBOP benzotriazol-1-yl-oxytripyrrolidinophosphonium-hexafluorophosphate -- SSC side scatter -- SD standard deviation -- THF tetrahydrofuran -- TryS trypanothione synthetase; Leishmaniasis -- Neglected tropical diseases -- Paullone -- Trypanosomiasis -- Trypanothione synthetase -- Trypanosoma brucei; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.06.023
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 congener3a showed antitrypanosomal activity in double digit nanomolar concentrations and a selectivity index of three orders of magnitude versus murine macrophage cells.