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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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Date
02/09/2021
Author
Robertson, Jack
Ungogo, Marzuq
Aldfer, Mustafa
de Koning, Harry
Lemgruber, Leandro
McWhinnie, Fergus
Bode, Bela
Jones, Katherine
Watson, Allan J. B.
Burley, Glenn
Keywords
Antiparasitics
Amidine
Arylation
Copper
Medicinal chemistry
QD Chemistry
3rd-DAS
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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.
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
Publication
ChemMedChem
Status
Peer reviewed
DOI
https://doi.org/10.1002/cmdc.202100509
ISSN
1860-7179
Type
Journal article
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.
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.
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  • University of St Andrews Research
URL
https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202100509#support-information-section
URI
http://hdl.handle.net/10023/23900

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