Design and Synthesis of Metabolically Stable tRNA Synthetase Inhibitors Derived from Cladosporin.

Autor: Rusch M; NIBR-Novartis Institute for Biomedical Research, Fabrikstrasse 22-1.051.17, 4054, Basel, Switzerland., Thevenon A; NIBR-Novartis Institute for Biomedical Research, Fabrikstrasse 22-1.051.17, 4054, Basel, Switzerland.; Department of Chemistry, Imperial College, London, SW7 2AZ, UK., Hoepfner D; NIBR-Novartis Institute for Biomedical Research, Fabrikstrasse 22-1.051.17, 4054, Basel, Switzerland., Aust T; NIBR-Novartis Institute for Biomedical Research, Fabrikstrasse 22-1.051.17, 4054, Basel, Switzerland., Studer C; NIBR-Novartis Institute for Biomedical Research, Fabrikstrasse 22-1.051.17, 4054, Basel, Switzerland., Patoor M; NIBR-Novartis Institute for Biomedical Research, Fabrikstrasse 22-1.051.17, 4054, Basel, Switzerland., Rollin P; Institut de Chimie Organique et Analytique (ICOA), UMR7311, Université d'Orléans, 45100, Orléans, France., Livendahl M; NIBR-Novartis Institute for Biomedical Research, Fabrikstrasse 22-1.051.17, 4054, Basel, Switzerland., Ranieri B; NIBR-Novartis Institute for Biomedical Research, Fabrikstrasse 22-1.051.17, 4054, Basel, Switzerland., Schmitt E; NIBR-Novartis Institute for Biomedical Research, Fabrikstrasse 22-1.051.17, 4054, Basel, Switzerland., Spanka C; NIBR-Novartis Institute for Biomedical Research, Fabrikstrasse 22-1.051.17, 4054, Basel, Switzerland., Gademann K; University of Zürich, Department of Chemistry, Winterthurerstrasse 190, 8057, Zürich, Switzerland., Bouchez LC; NIBR-Novartis Institute for Biomedical Research, Fabrikstrasse 22-1.051.17, 4054, Basel, Switzerland.
Jazyk: angličtina
Zdroj: Chembiochem : a European journal of chemical biology [Chembiochem] 2019 Mar 01; Vol. 20 (5), pp. 644-649. Date of Electronic Publication: 2019 Feb 04.
DOI: 10.1002/cbic.201800587
Abstrakt: Selective and specific inhibitors of Plasmodium falciparum lysyl-tRNA synthetase represent promising therapeutic antimalarial avenues. Cladosporin was identified as a potent P. falciparum lysyl-tRNA synthetase inhibitor, with an activity against parasite lysyl-tRNA synthetase >100-fold more potent than that of the activity registered against the human enzyme. Despite its compelling activity, cladosporin exhibits poor oral bioavailability; a critical requirement for antimalarial drugs. Thus, the quest to develop metabolically stable cladosporin-derived analogues, while retaining similar selectivity and potency to that of the natural compound, has begun. Chemogenomic profiling of a designed library allowed an entirely innovative structure-activity relationship study to be initiated; this shed light on structural evidence of a privileged scaffold with a unique activity against tRNA synthetases.
(© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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