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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 diminazeneresistant 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 |
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Pages (from-to) | 3396-3401 |
Number of pages | 6 |
Journal | ChemMedChem |
Volume | 16 |
Issue number | 22 |
Early online date | 6 Aug 2021 |
DOIs | |
Publication status | Published - 19 Nov 2021 |
Keywords
- antiparasitics
- amidine
- arylation
- copper
- medicinal chemistry
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Dive into the research topics of 'Direct, late-stage mono-N-arylation of pentamidine: method development, mechanistic insights, and expedient access to novel antiparastitics against diamidine-resistant parasites'. Together they form a unique fingerprint.Projects
- 1 Finished
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Industrial Case Account 2016 | Robertson, Jack
Burley, G., Zagnoni, M. & Robertson, J.
EPSRC (Engineering and Physical Sciences Research Council)
1/10/16 → 1/04/21
Project: Research Studentship Case - Internally allocated