Direct, Late-Stage Mono-N-arylation of Pentamidine: Method Development, Mechanistic Insight, and Expedient Access to Novel Antiparastitics against Diamidine-Resistant Parasites.

Jack Robertson,Harry P De Koning,Allan J B Watson,Mustafa M Aldfer,Marzuq A Ungogo,Bela E Bode,Leandro Lemgruber,Fergus S Mcwhinnie,Glenn A Burley,Katherine L Jones

doi:10.1002/cmdc.202100509

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.

Highlights

A selective mono-N-arylation strategy of amidines under ChanLam conditions is described
Amidines are essential functional groups used throughout medicinal chemistry.[1]
A prominent exemplar of this approach is the development of the DNA-binding antiparasitic pentamidine for the treatment of early-stage Trypanosoma brucei gambiense-related human African trypanosomiasis (HAT) or sleeping sickness,[4] AIDS-related pneumocystis pneumonia, and leishmaniasis (Scheme 1a).[5]

Summary

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Binding analogues (Scheme 1a).[7]. Modification of the essential amidine moiety is a nascent strategy to by-pass resistance mechanisms in these parasites by modulating the affinity of diamidines for key drug transporters in T. brucei[8] [e. g., TbAT1/ P2 aminopurine transporters,[9] High Affinity Pentamidine Transporter (HAPT)[10]].[11]. The observation of a pronounced base effect led to a focused screen and identification of K2CO3 as the optimal additive (Entries 5–9) This screen provided selective mono-N-arylation set of conditions using 20 mol% Cu(OAc) giving 2 in 81 % isolated yield and without any observable generation of 3 (Entry 10). A paramagnetic species was observed upon addition of 1 (Figure S2) This suggests that 1 is responsible for paddlewheel denucleation, consistent with mechanistic proposals for the Chan-Lam amination.[22,25] Complex 4 could form after paddlewheel denucleation via ligand exchange processes at, for example, putative Cu(II) complexes 5 and 6 (Scheme 2b). Both mono- and bisamidines are known Cu-chelators,[26] which could hamper the wider utility of this approach to mono-

Entry Conditions

Conflict of Interest