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 <b>20</b> (IC₅₀ 3.05 nM (<i>P.f.</i>K1) and 2.8 nM (<i>P.f.</i>NF54), thiaplakortones A <b>33</b> (IC₅₀ 5.1 nM(<i>P.f.</i>3D7) and 6.6 nM (<i>P.f.</i>Dd2) simalikalactone D <b>58</b> (IC₅₀ 3.34 nM(<i>P.f.</i>W2) and 3.14 nM (<i>P.f.</i>D6), verrucarin L acetate <b>61</b> (IC₅₀ 1.11 nM (<i>P.f.</i>D6) and 1.29 nM (<i>P.f.</i>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.