Chemical modification of monensin as a source of potent antiplasmodial agents

This research was financially supported by an OPUS 21 grant (2021/41/B/ST4/00088) funded to A.H. by the National Science Center in Poland (NCN). For the purpose of Open Access, the authors have applied public copyright license to any Author Accepted Manuscript (AAM) version arising from this submission.

Malaria remains a significant public health issue and one of the leading causes of child mortality worldwide. Due to the growing problem of drug resistance, new modes of fighting the disease are searched for. In this context, ionophore antibiotics, natural compounds with high potential for combating parasitic diseases, deserve special attention. The primary representative of such compounds, monensin (MON), demonstrates exceptionally high antiplasmodial activity. In this work, the C26-amino derivative of MON was used as a convenient substrate for the synthesis of its acyl analogues, such as amides and urea. All derivatives exhibited strong activity against the hepatic stage of Plasmodium berghei infection in vitro, which exceeded that shown by the reference drug primaquine. The IC50 value for MON O-phenyl urethane (8) was less than 1 nM.