Synthesis and antimalarial activity of novel C30-aminated betulin derivatives

A series of new C30-aminated lupane analogues was prepared from betulin in three straightforward steps and evaluated for inhibitory activity against Plasmodium falciparum. Taking advantage of the Meinwald rearrangement of the terminal C20/29 racemic epoxide in acidic conditions, reductive amination of the resulting aldehyde allowed the generation of C30-aminated analogues in good yields with a significant increase of hydrophilicity. The approach avoids the use of protecting groups and is compatible with a broad range of primary and secondary amines. Screening of the seventeen synthesized C30-aminated betulin derivatives for antimalarial activity revealed that the C30-tryptamine analogue 5g exhibited good inhibitory activity against P. falciparum 3D7 and the chloroquine-mefloquine-pyrimethamine multiresistant strain P. falciparum Dd2 with IC₅₀ values of 0.62 μM and 0.24 μM, respectively. Moreover, the compound did not cause red blood cell lysis at concentrations up to 25 μM and displayed moderate cytotoxicity with an IC₅₀ value of 4.2 μM against human keratinocytes HaCaT cells. These results highlight the great potential of the prop-1-en-2-yl moiety on lupane triterpenoids to improve biological and physicochemical properties and support the extension of the chemical diversity at the C30 position towards new bioactive antiprotozoal betulin analogues.