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

Jack Robertson; Marzuq Ungogo; Mustafa Aldfer; Harry de Koning; Leandro Lemgruber; Fergus McWhinnie; Bela Bode; Katherine Jones; Allan J. B. Watson; Glenn Burley

doi:10.1002/cmdc.202100509

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

Jack Robertson, Marzuq Ungogo, Mustafa Aldfer, Harry de Koning, Leandro Lemgruber, Fergus McWhinnie, Bela Bode, Katherine Jones, Allan J. B. Watson, Glenn Burley

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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.

Original language	English
Number of pages	8
Journal	ChemMedChem
Volume	Early View
Early online date	2 Sept 2021
DOIs	https://doi.org/10.1002/cmdc.202100509
Publication status	E-pub ahead of print - 2 Sept 2021

Keywords

Antiparasitics
Amidine
Arylation
Copper
Medicinal chemistry

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10.1002/cmdc.202100509Licence: CC BY

Robertson_2021_Chemistry-Europe_Direct-late-stage_CC
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.
Final published version, 6.24 MBLicence: CC BY

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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, Early View. Advance online publication. https://doi.org/10.1002/cmdc.202100509

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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.",

keywords = "Antiparasitics, Amidine, Arylation, Copper, Medicinal chemistry",

author = "Jack Robertson and Marzuq Ungogo and Mustafa Aldfer and {de Koning}, Harry and Leandro Lemgruber and Fergus McWhinnie and Bela Bode and Katherine Jones and Watson, {Allan J. B.} and Glenn Burley",

note = "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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Robertson, J, Ungogo, M, Aldfer, M, de Koning, H, Lemgruber, L, McWhinnie, F, Bode, B, Jones, K, Watson, AJB & 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

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AU - Robertson, Jack

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AU - Aldfer, Mustafa

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AU - McWhinnie, Fergus

AU - Bode, Bela

AU - Jones, Katherine

AU - Watson, Allan J. B.

AU - Burley, Glenn

N1 - 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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N2 - 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.

AB - 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.

KW - Antiparasitics

KW - Amidine

KW - Arylation

KW - Copper

KW - Medicinal chemistry

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M3 - Article

SN - 1860-7179

VL - Early View

JO - ChemMedChem

JF - ChemMedChem

ER -

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

Abstract

Keywords

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CCDC 2101634 & 2101824: Experimental Crystal Structure Determination

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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

Abstract

Keywords

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Datasets

CCDC 2101634 & 2101824: Experimental Crystal Structure Determination

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