A non-cytotoxic N-dehydroabietylamine derivative with potent antimalarial activity

• Dehydroabietylamine (DHA) has antimalarial activity, but is toxic to human cells.
• Abietic acid (AA) has neither antimalarial activity nor toxicity to human cells.
• Several DHA and AA derivatives are toxic to parasites but not to human cells.
• N-Dehydroabietylbezamide has potent antimalarial activity; nontoxic to human cells.

Malaria caused by the Plasmodium parasites continues to be an enormous global health problem owing to wide spread drug resistance of parasites to many of the available antimalarial drugs. Therefore, development of new classes of antimalarial agents is essential to effectively treat malaria. In this study, the efficacy of naturally occurring diterpenoids, dehydroabietylamine and abietic acid, and their synthetic derivatives was assessed for antimalarial activity. Dehydroabietylamine and its N-trifluoroacetyl, N-tribromoacetyl, N-benzoyl, and N-benzyl derivatives showed excellent activity against P. falciparum parasites with IC50 values of 0.36 to 2.6 µM. Interestingly, N-dehydroabietylbenzamide showed potent antimalarial activity (IC50 0.36), and negligible cytotoxicity (IC50 >100 µM) to mammalian cells; thus, this compound can be an important antimalarial drug. In contrast, abietic acid was only marginally effective, exhibiting an IC50 value of ~82 µM. Several carboxylic group-derivatives of abietic acid were moderately active with IC50 values of ~8.2 to ~13.3 µM. These results suggest that a detailed understanding of the structure–activity relationship of abietane diterpenoids might provide strategies to exploit this class of compounds for malaria treatment.

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