Abstract:
Malaria elimination requires multipronged approaches, including
the application of antimalarial drugs able to block humanto-
mosquito transmission of malaria parasites. The transmissible
gametocytes of Plasmodium falciparum seem to be highly
sensitive towards epidrugs, particularly those targeting demethylation
of histone post-translational marks. Here, we report
exploration of compounds from a chemical library generated
during hit-to-lead optimization of inhibitors of the human
histone lysine demethylase, KDM4B. Derivatives of 2-([1,1’-
biphenyl]-4-carboxamido) benzoic acid, around either the
amide or a sulfonamide linker backbone (2-(arylcarboxamido)
benzoic acid, 2-carboxamide (arylsulfonamido)benzoic
acid and N-(2-(1H-tetrazol-5-yl)phenyl)-arylcarboxamide),
showed potent activity towards late-stage gametocytes (stage
IV/V) of P. falciparum, with the most potent compound reaching
single digit nanomolar activity. Structure-activity relationship
trends were evident and frontrunner compounds also displayed
microsomal stability and favourable solubility profiles. Simplified
synthetic routes support further derivatization of these
compounds for further development of these series as malaria
transmission-blocking agents.
