Direct, late‐stage mono‐N‐arylation of pentamidine: method development, mechanistic insights, and expedient access to novel antiparastitics against diamidine‐resistant parasites

Burley, G., Watson, A. J. B., de Koning, H. , Jones, K., Robertson, J., Bode, B., McWhinnie, F., Ungogo, M., Aldfer, M. and Lemgruber Soares, L. (2021) Direct, late‐stage mono‐N‐arylation of pentamidine: method development, mechanistic insights, and expedient access to novel antiparastitics against diamidine‐resistant parasites. ChemMedChem, 16(22), pp. 3396-3401. (doi: 10.1002/cmdc.202100509) (PMID:34357687)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:De Koning, Professor Harry and Ungogo, Marzuq and Aldfer, Mustafa Mohamed and Watson, Dr Allan and Burley, Dr Glenn and Lemgruber Soares, Dr Leandro and McWhinnie, Mr Fergus
Authors: Burley, G., Watson, A. J. B., de Koning, H., Jones, K., Robertson, J., Bode, B., McWhinnie, F., Ungogo, M., Aldfer, M., and Lemgruber Soares, L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Science and Engineering > School of Chemistry
Journal Name:ChemMedChem
Publisher:Wiley
ISSN:1860-7179
ISSN (Online):1860-7187
Published Online:06 August 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in ChemMedChem 2021
Publisher Policy:Reproduced under a Creative Commons License

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