Hemisynthesis of lupeol and betulin derivatives and their <i>in vitro</i> antimalarial activity against <i>Plasmodium falciparum</i> FCR3

In view of the emergence of drug-resistant strains of <i>Plasmodium falciparum,</i> there is an urgent need for the development of new effective antimalarial agents to mitigate the issue of drug resistance. In this study, a series of lupeol (<b>2</b>) and betulin (<b>3</b>) derivatives were synthesised, characterised and evaluated for their antimalarial activity against the <i>P. falciparum</i> FCR3 strain. Eight compounds, including lupenone (<b>1</b>), displayed good anti-plasmodial potency with IC₅₀ values ranging from 0.03-9.9 µM. Moreover, <i>in vitro</i> results showed that compound <b>1</b> and derivatives <b>4a</b> and <b>4b</b> were the most active compounds with potent inhibitory activity of (0.3 ± 0.3, 0.03 ± 0.05 and 0.7 ± 0.8 μM), respectively, compared to the reference drugs artemisinin and chloroquine (0.7 ± 0.3 and 10.3 ± 2.9 μM), respectively. Furthermore, molecular docking analysis of these compounds revealed good affinity to the binding site of the <i>P. falciparum</i> protein of the <i>Pf</i>ATP6 with a binding affinity between -9.8 and -8.4 kcal mol^-1<i>via</i> multiple hydrophobic interactions with the amino acid of the <i>Pf</i>ATP6 protein. The results showed hydrogen bonds and various hydrophobic interactions between the studied compounds and the amino acid of the <i>Pf</i>ATP6 protein, such as ASN1039, VAL984, ILE981 and ILE1041. Therefore, these compounds could be promising lead structures for further validation as potential candidates in developing new antimalarial drugs.