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

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.