Synthesis, antimycobacterial activity and influence on mycobacterial InhA and PknB of 12-membered cyclodepsipeptides.

Autor: Laqua K; Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany., Klemm M; Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany., Richard-Greenblatt M; Division of Infectious Diseases, Department of Medicine, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada., Richter A; Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany., Liebe L; Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany., Huang T; State Key Laboratory of Microbial Metabolism, Joint International Laboratory on Metabolic & Developmental Sciences, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200030, PR China., Lin S; State Key Laboratory of Microbial Metabolism, Joint International Laboratory on Metabolic & Developmental Sciences, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200030, PR China., Guardia A; Diseases of the Developing World, Alternative Discovery & Development, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain., Pérez-Herran E; Diseases of the Developing World, Alternative Discovery & Development, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain., Ballell L; Diseases of the Developing World, Alternative Discovery & Development, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain., Av-Gay Y; Division of Infectious Diseases, Department of Medicine, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada., Imming P; Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany. Electronic address: peter.imming@pharmazie.uni-halle.de.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2018 Jul 23; Vol. 26 (12), pp. 3166-3190. Date of Electronic Publication: 2018 Apr 22.
DOI: 10.1016/j.bmc.2018.04.045
Abstrakt: In recent years, several small natural cyclopeptides and cyclodepsipeptides were reported to have antimycobacterial activity. Following this lead, a synthetic pathway was developed for a small series of 12-membered ring compounds with one amide and two ester bonds (cyclotridepsipeptides). Within the series, the ring system proved to be necessary for growth inhibition of Mycobacterium smegmatis and Mycobacterium tuberculosis in the low micromolar range. Open-chain precursors and analogues were inactive. The compounds modulated autophosphorylation of the mycobacterial protein kinase B (PknB). PknB inhibitors were active at µM concentration against mycobacteria while inducers were inactive. PknB regulates the activity of the mycobacterial reductase InhA, the target of isoniazid. The activity of the series against Mycobacterium bovis BCG InhA overexpressing strains was indistinguishable from that of the parental strain suggesting that they do not inhibit InhA. All substances were not cytotoxic (HeLa > 5 µg/ml) and did not show any significant antiproliferative effect (HUVEC > 5 µg/ml; K-562 > 5 µg/ml). Within the scope of this study, the molecular target of this new type of small cyclodepsipeptide was not identified, but the data suggest interaction with PknB or other kinases may partly cause the activity.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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