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

Robertson, Jack and Ungogo, Marzuq A. and Aldfer, Mustafa M. and Lemgruber, Leandro and McWhinnie, Fergus S. and Bode, Bela E. and Jones, Katherine L. and Watson, Allan J. B. and de Koning, Harry P. and Burley, Glenn A. (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. ISSN 1860-7179 (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 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.

ORCID iDs

Robertson, Jack, Ungogo, Marzuq A., Aldfer, Mustafa M., Lemgruber, Leandro, McWhinnie, Fergus S. ORCID logoORCID: https://orcid.org/0000-0002-2373-386X, Bode, Bela E., Jones, Katherine L., Watson, Allan J. B., de Koning, Harry P. and Burley, Glenn A.;
CORE (COnnecting REpositories)