Direct, Late‐Stage Mono‐N‐arylation of Pentamidine: Method Development, Mechanistic Insight, 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. Accessing antiparasitic amidines: A selective mono‐N‐arylation strategy of amidines under Chan‐Lam conditions was used 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. This work highlights the potential of Chan‐Lam mono‐N‐arylation to develop therapeutic leads against diamidine‐resistant trypanosomiasis and leishmaniasis.