2.2.4. Antimalarial and Anti-Farnesyltransferase Activities

Compounds **1**–**6** were evaluated for activity against *Plasmodium falciparum* (NF54 chloroquine sensitive and FcM29-Cameroon chloroquine-resistant strains) and protozoal and human protein farnesyltransferases. The results are presented in Table 1. We have previously determined that the structurally-related marine meroterpene scabellone B exhibited moderate antimalarial activity (IC50 4.8 μM, *Pf* K1 strain) [3]. Evaluation of **1**–**6** against *P. falciparum* identified precursor quinones **5** and **6** to be the most active, followed by regioisomers **3** and **4**, while natural products **1** and **2** were deemed inactive. We have previously determined that the structurally-related marine meroterpene scabellone B exhibited moderate antimalarial activity (IC50 4.8 μM, *Pf* K1 strain). [3] Taken together, these results show that compounds containing only the tricyclic pyranoquinone core structure (*i.e.*, rings B-C-D) such as in compounds **5**, **6** and scabellone B are more active antimalarial agents than those compounds that also contain an additional dioxothiazine ring. The results also suggest that amongst the dioxothiazine-containing compounds **1**–**4**, anti-*Pf* activity is sensitive to the particular regiochemistry of the dioxothiazine ring. With regard to the protein farnesyltransferase (FTase) bioassays, a high degree of correlation was observed between results for FTases of both protozoal and human origin for most of the compounds. In the cases of compounds **2** and **6**, a slightly higher degree of selectivity for human FTase was observed. Of note was the sub-micromolar inhibition of both FTases by the natural product thiaplidiaquinone A (**1**) and regioisomeric analogues **3** and **4**, with the latter exhibiting particularly potent activities (IC50 0.098 and 0.054 μM).



IC50 values (μM) are reported as the average of three assays with an associated deviation, except for *Pf* data for **5** and **6** which is reported as the average of two independent assays; <sup>a</sup> *Plasmodium falciparum*; **<sup>b</sup>** *Trypanosoma brucei* farnesyltransferase; **<sup>c</sup>** Human farnesyltransferase; <sup>d</sup> *Plasmodium falciparum*, FcM29-Cameroon strain (chloroquine-resistant); <sup>e</sup> *Plasmodium falciparum*, NF54 strain (chloroquine sensitive), IEF stage; <sup>f</sup> Chloroquine and FTI 276 were used as positive controls.
