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Newport, WA, United States

Holla H.,Griffith University | Labaied M.,Seattle Biomedical | Pham N.,Griffith University | Jenkins I.D.,Griffith University | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

A short practical synthesis of a new natural product based scaffold (6), based on antitrypanosomal and antimalarial compounds isolated from different Plakortis species is described. The scaffold contains a peroxide unit that is surprisingly stable to chemical manipulation elsewhere in the molecule, enabling it to be elaborated into a small library of derivatives. It is stable to ozonolysis, reductive work-up with dimethylsulfide and the Wittig reaction with stabilized phosphorus ylides. The scaffold along with its Wittig analogues has displayed low to sub-micro molar (0.2-3.3 μM) antitrypanosomal activity. © 2011 Elsevier Ltd. All rights reserved. Source

Zhang Z.,Northern Illinois University | Jakkaraju S.,Northern Illinois University | Blain J.,Northern Illinois University | Gogol K.,Northern Illinois University | And 13 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

Published biological data suggest that the methyl erythritol phosphate (MEP) pathway, a non-mevalonate isoprenoid biosynthetic pathway, is essential for certain bacteria and other infectious disease organisms. One highly conserved enzyme in the MEP pathway is 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase (IspF). Fragment-bound complexes of IspF from Burkholderia pseudomallei were used to design and synthesize a series of molecules linking the cytidine moiety to different zinc pocket fragment binders. Testing by surface plasmon resonance (SPR) found one molecule in the series to possess binding affinity equal to that of cytidine diphosphate, despite lacking any metal-coordinating phosphate groups. Close inspection of the SPR data suggest different binding stoichiometries between IspF and test compounds. Crystallographic analysis shows important variations between the binding mode of one synthesized compound and the pose of the bound fragment from which it was designed. The binding modes of these molecules add to our structural knowledge base for IspF and suggest future refinements in this compound series. © 2013 Elsevier Ltd. All rights reserved. Source

Pham N.B.,Griffith University | Deydier S.,Griffith University | Labaied M.,Seattle Biomedical | Monnerat S.,Seattle Biomedical | And 2 more authors.
European Journal of Medicinal Chemistry | Year: 2014

The natural product, convolutamine I (1), has anti-trypanosomal activity however it has a high molecular weight of 473 due to a presence of 3 bromine atoms. The synthesis of the natural product convolutamine I (1) together with its analogues are presented. A SAR study against Trypanosoma brucei brucei led to compounds with improved physico-chemical properties: lower molecular weight and lower log P while maintaining potency (with a slight 2-fold improvement). © 2014 Elsevier B.V. Source

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