Lupane derivatives: Design, isolation, synthesis and evaluation of antiplasmodial activity against Plasmodium falciparum 3D7 strain

To search for leads against malaria, compounds from the Cameroon Natural Product Library (CANAPL), were screened by molecular docking studies against the enzyme target glyceraldehyde-3-phosphate dehydrogenase (PfGAPDH) of Plasmodium falciparum. Amongst the docking hits were lupeol cinnamate (1) and oleanane cinnamate (2). Triterpenoids with structural similarities to (1) and (2) were isolated from Baillonella toxisperma (Pierre); olean-12-en-3β-decanoate (3), 3-β-trans cinnamoyloxylup-20(29)-ene (4), 3β-amyrin acetate (5), taraxerol (6), betulonic acid (7), β-sitosterol (8), betulinic acid (9), 3β-(trans-p-Coumaroyl)oxylup-20(29)-en-28-oïc acid (10) and screened alongside Betuline (11) and oleanolic acid (12). The favorable compounds 7 and 10 with 100 % growth inhibition on P. falciparum 3D7 strain together with compounds 4, 9 and 11 were structurally optimized to afford new lupane derivatives with the privileged α,β-unsaturated carbonyl medicinal scaffolds; betulonic acid acryl aldehyde (13), betulin acryl aldehyde (14), 3β-(trans-p-Coumaroyl)oxylup-20(29)-en-28-oïc acid acryl aldehyde (15), betulinic acid acryl aldehyde (16) and 3-β-trans cinnamoyloxylup-20(29)-ene acryl aldehyde (17) exhibiting more potent antiplasmodial activities with IC₅₀ values of 0.703 μM, 2.15 μM, 1.28 μM, and 3.79 μM for compounds 13, 14, 15 and 16 respectively. The presence of the α,β-unsaturated carbonyl moiety increased binding interactions during docking analyses. The modified compounds with the privileged α,β-unsaturated carbonyl medicinal scaffolds could be further optimized into potent antimalarial agents.