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dc.contributor.authorRobertson, Jack
dc.contributor.authorUngogo, Marzuq
dc.contributor.authorAldfer, Mustafa
dc.contributor.authorde Koning, Harry
dc.contributor.authorLemgruber, Leandro
dc.contributor.authorMcWhinnie, Fergus
dc.contributor.authorBode, Bela
dc.contributor.authorJones, Katherine
dc.contributor.authorWatson, Allan J. B.
dc.contributor.authorBurley, Glenn
dc.identifier.citationRobertson , 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 .
dc.identifier.otherPURE: 275346976
dc.identifier.otherPURE UUID: b7b5bbf2-7201-4e18-9c3b-c103c91a6f6b
dc.identifier.otherRIS: urn:C8C9F579B34271CAE73C48D5D8A5A3D9
dc.identifier.otherORCID: /0000-0002-3384-271X/work/99466242
dc.identifier.otherORCID: /0000-0002-1582-4286/work/99466603
dc.identifier.otherScopus: 85114109191
dc.identifier.otherWOS: 000695315400001
dc.descriptionJ.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.abstractA 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.rightsCopyright © 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.subjectMedicinal chemistryen
dc.subjectQD Chemistryen
dc.titleDirect, late-stage mono-N-arylation of pentamidine : method development, mechanistic insights, and expedient access to novel antiparastitics against diamidine-resistant parasitesen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.School of Chemistryen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.contributor.institutionUniversity of St Andrews.Centre of Magnetic Resonanceen
dc.contributor.institutionUniversity of St Andrews.EaSTCHEMen
dc.contributor.institutionUniversity of St Andrews.Sir James Mackenzie Institute for Early Diagnosisen
dc.description.statusPeer revieweden

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