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Direct, late-stage mono-N-arylation of pentamidine : method development, mechanistic insights, and expedient access to novel antiparastitics against diamidine-resistant parasites
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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 | 275346976 | |
dc.identifier | b7b5bbf2-7201-4e18-9c3b-c103c91a6f6b | |
dc.identifier | 85114109191 | |
dc.identifier | 000695315400001 | |
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 | 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.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.format.extent | 6543042 | |
dc.language.iso | eng | |
dc.relation.ispartof | ChemMedChem | 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.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 | 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 |
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