Files in this item
Direct, late-stage mono-N-arylation of pentamidine : method development, mechanistic insights, and expedient access to novel antiparastitics against diamidine-resistant parasites
Item metadata
dc.contributor.author | Robertson, Jack | |
dc.contributor.author | Ungogo, Marzuq | |
dc.contributor.author | Aldfer, Mustafa | |
dc.contributor.author | de Koning, Harry | |
dc.contributor.author | Lemgruber, Leandro | |
dc.contributor.author | McWhinnie, Fergus | |
dc.contributor.author | Bode, Bela | |
dc.contributor.author | Jones, Katherine | |
dc.contributor.author | Watson, Allan J. B. | |
dc.contributor.author | Burley, Glenn | |
dc.date.accessioned | 2021-09-06T08:30:13Z | |
dc.date.available | 2021-09-06T08:30:13Z | |
dc.date.issued | 2021-09-02 | |
dc.identifier.citation | Robertson , J , Ungogo , M , Aldfer , M , de Koning , H , Lemgruber , L , McWhinnie , F , Bode , B , Jones , K , Watson , A J B & Burley , G 2021 , ' Direct, late-stage mono- N -arylation of pentamidine : method development, mechanistic insights, and expedient access to novel antiparastitics against diamidine-resistant parasites ' , ChemMedChem , vol. Early View . https://doi.org/10.1002/cmdc.202100509 | en |
dc.identifier.issn | 1860-7179 | |
dc.identifier.other | PURE: 275346976 | |
dc.identifier.other | PURE UUID: b7b5bbf2-7201-4e18-9c3b-c103c91a6f6b | |
dc.identifier.other | RIS: urn:C8C9F579B34271CAE73C48D5D8A5A3D9 | |
dc.identifier.other | ORCID: /0000-0002-3384-271X/work/99466242 | |
dc.identifier.other | ORCID: /0000-0002-1582-4286/work/99466603 | |
dc.identifier.other | Scopus: 85114109191 | |
dc.identifier.other | WOS: 000695315400001 | |
dc.identifier.uri | https://hdl.handle.net/10023/23900 | |
dc.description | J.R. and G.A.B. thank GlaxoSmithKline (GSK) and the Engineering and Physical Sciences Research Council (EPSRC) for an industrial CASE studentship. MMA is supported by a studentship from the government of Libya, and MAU by a studentship from the Petroleum Technology Development Fund (PTDF), Abuja, Nigeria. | en |
dc.description.abstract | A selective mono-N-arylation strategy of amidines under Chan-Lam conditions is described. During the reaction optimization phase, the isolation of a mononuclear Cu(II) complex provided unique mechanistic insight into the operation of Chan-Lam mono-N-arylation. The scope of the process is demonstrated, and then applied to access the first mono-N-arylated analogues of pentamidine. Sub-micromolar activity against kinetoplastid parasites was observed for several analogues with no cross-resistance in pentamidine and diminazene-resistant trypanosome strains and against Leishmania mexicana. A fluorescent mono-N-arylated pentamidine analogue revealed rapid cellular uptake, accumulating in parasite nuclei and the kinetoplasts. The DNA binding capability of the mono-N-arylated pentamidine series was confirmed by UV-melt measurements using AT-rich DNA. This work highlights the potential to use Chan-Lam mono-N-arylation to develop therapeutic leads against diamidine-resistant trypanosomiasis and leishmaniasis. | |
dc.format.extent | 8 | |
dc.language.iso | eng | |
dc.relation.ispartof | ChemMedChem | en |
dc.rights | Copyright © 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. | en |
dc.subject | Antiparasitics | en |
dc.subject | Amidine | en |
dc.subject | Arylation | en |
dc.subject | Copper | en |
dc.subject | Medicinal chemistry | en |
dc.subject | QD Chemistry | en |
dc.subject | DAS | en |
dc.subject.lcc | QD | en |
dc.title | Direct, late-stage mono-N-arylation of pentamidine : method development, mechanistic insights, and expedient access to novel antiparastitics against diamidine-resistant parasites | en |
dc.type | Journal article | en |
dc.description.version | Publisher PDF | en |
dc.contributor.institution | University of St Andrews. School of Chemistry | en |
dc.contributor.institution | University of St Andrews. Biomedical Sciences Research Complex | en |
dc.contributor.institution | University of St Andrews. Centre of Magnetic Resonance | en |
dc.contributor.institution | University of St Andrews. EaSTCHEM | en |
dc.contributor.institution | University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis | en |
dc.identifier.doi | https://doi.org/10.1002/cmdc.202100509 | |
dc.description.status | Peer reviewed | en |
dc.identifier.url | https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202100509#support-information-section | en |
This item appears in the following Collection(s)
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.