Antiplasmodial Chromanes and Chromenes from the Monotypic Plant Species <i>Koeberlinia spinosa</i>

Nine new compounds containing either a chromane or chromene ring moiety were isolated from the monotypic plant <i>Koeberlinia spinosa</i>. Compounds <b>1</b>–<b>4</b> are chromanes with all possible <i>E</i> and <i>Z</i> isomers of the isoprenoid side chain, with compound <b>5</b> a methylated derivative of <b>1</b>. Compounds <b>6</b> and <b>7</b> were assigned as diastereomeric cyclized derivatives of <b>2</b> and were probably artifacts formed during the extraction or the isolation processes. Compounds <b>8</b> and <b>9</b> were characterized as new chromenes. Structure elucidation of <b>1</b>–<b>9</b> was conducted via 1D and 2D NMR spectroscopic data interpretation, and absolute configurations were determined by ECD spectroscopic analysis. Compounds <b>2</b>, <b>5</b>, <b>6</b>, and <b>7</b> had weak antiplasmodial activity, while none of the compounds exhibited antiproliferative activity. The isolation, structure elucidation, and biological evaluation of these compounds are presented

Biological Studies and Target Engagement of the 2‑<i>C</i>‑Methyl‑d‑Erythritol 4‑Phosphate Cytidylyltransferase (IspD)-Targeting Antimalarial Agent (1<i>R</i>,3<i>S</i>)‑MMV008138 and Analogs

Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. <i>Plasmodium</i> parasites utilize the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are essential for parasite growth. Previously, we and others identified that the Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP. Further work has revealed that MMV008138 targets the enzyme 2-<i>C</i>-methyl-d-erythritol 4-phosphate cytidylyltransferase (IspD) in the MEP pathway, which converts MEP and cytidine triphosphate (CTP) to cytidinediphosphate methylerythritol (CDP-ME) and pyrophosphate. In this work, we sought to gain insight into the structure–activity relationships by probing the ability of MMV008138 analogs to inhibit <i>Pf</i>IspD recombinant enzyme. Here, we report <i>Pf</i>IspD inhibition data for fosmidomycin (FOS) and 19 previously disclosed analogs and report parasite growth and <i>Pf</i>IspD inhibition data for 27 new analogs of MMV008138. In addition, we show that MMV008138 does not target the recently characterized human IspD, reinforcing MMV008138 as a prototype of a new class of species-selective IspD-targeting antimalarial agents