Post-Artemisinin anti-malarial discovery from nature: unaltered natural products, lead optimisation, and advanced techniques in the discovery.

Malaria remains a severe health burden and demands a continuous quest for new anti-plasmodial agents. Several notable anti-malarial discoveries from nature since artemisinin, with no comprehensive review available. A systematic data curation, collection, and collation were performed in accordance with the PRISMA protocol. A total of 88 potent anti-plasmodium compounds were reported including notable artemisinin comparable anti-plasmodium, habropetaline A 20 (IC50 3.05 nM (P.f.K1) and 2.8 nM (P.f.NF54), thiaplakortones A 33 (IC50 5.1 nM(P.f.3D7) and 6.6 nM (P.f.Dd2) simalikalactone D 58 (IC50 3.34 nM(P.f.W2) and 3.14 nM (P.f.D6), verrucarin L acetate 61 (IC50 1.11 nM (P.f.D6) and 1.29 nM (P.f.W2). Anti-plasmodial efficacy was improved through analogue studies. New techniques have also been used to facilitate efficient anti-malarial isolation. Overall, natural products play a significant role as a source of anti-malarial molecular scaffolds, and multiple approaches are necessary to discover potent and safe anti-plasmodial agents.