Glyceraldehyde-3-phosphate dehydrogenase (PfGAPDH): Design, Isolation, Synthesis and preliminary anti-malarial activity against Plasmodium falciparum 3D7 strains.

Résumé

Abstract Glyceraldehyde-3-phosphate dehydrogenase (PfGAPDH) for Plasmodium falciparum is a key glycolytic enzyme that catalyzes the conversion of glyceraldehyde 3-phosphate (G3P) into 1,3-bisphosphate glycerate (1,3-BPG), with the concomitant reduction of nicotinamide adenine dinucleotide (NAD+) to NADH. Compounds from the Cameroon Natural Product Library (CANAPL), were screened by molecular docking studies against the enzyme target PfGAPDH. Amongst these docking hits were the lupeol cinnamate (1) and oleanane cinnamate (2) with binding energies (Eb) of -10.55 kcal/mol and − 10.51 kcal/mol respectively, compared to PfGAPDH inhibitors; heptelidic acid (-6.47 kcal/mol), iodoacetate (-3.98 kcal/mol) and pentalenolactone (-6.87 kcal/mol). To validate the docking results, triterpenoids with structural similarities to (1) and (2) were isolated from Baillonella toxisperma (Pierre); olean-12-en-3β-hexadecanoate (3), 3-β-trans cinnamoyloxylup-20(29)-ene (4), oleanoic acid benzoate (5), 3β-amyrin (6), taraxerol (7), betulonic acid (8), β-sitosterol (9), betulinic acid (10), 3β-(trans-p-Coumaroyl)oxylup-20(29)-en-28-oïc acid (11), and screened alongside Betuline (12) and oleanolic acid (13). The favorable compounds 8 and 11 with 100% growth inhibition on Plasmodium falciparum 3D7 strains together with compounds 4, 10 and 12 were structurally optimized to afford new lupane derivatives with the privilege α-β unsaturated carbonyl medicinal scaffolds; - betulonic acid acryl aldehyde (14), betulin acryl aldehyde (15), 3β-(trans-p-Coumaroyl)oxylup-20(29)-en-28-oïc acid acryl aldehyde (16), 30-hydroxy betulinic acid (17), betulinic acid acryl aldehyde (18) and 3-β-trans cinnamoyloxylup-20(29)-ene acryl aldehyde (19) exhibiting more potent anti-malarial activities. Their assays afforded IC50 values of 0.703 µM, 2.15 µM, 1.28 µM, and 3.79 µM for compounds 14, 15, 16 and 18 respectively. These results validate our docking scores and indicate that the modified compounds with the privilege α,β- unsaturated carbonyl medicinal scaffolds could be further optimized into potent antimalarial agents.

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