2 research outputs found
Nanomolar Antimalarial Agents against Chloroquine-Resistant <i>Plasmodium falciparum</i> from Medicinal Plants and Their Structure–Activity Relationships
Inspired by the discovery of the
antimalarial drug artemisinin
from a traditional Chinese medicine (TCM), a natural product library
of 44 lindenane-type sesquiterpenoids was assessed for activities
against the Dd2 chloroquine-resistant strain of the malaria parasite <i>Plasmodium falciparum</i>. These compounds were mainly isolated
from plants of the <i>Chloranthus</i> genus, many species
of which are named “Sikuaiwa” in TCM and have long been
used to treat malaria. The compounds consisted of 41 sesquiterpenoid
dimers and three monomers, including the 12 new dimers <b>1</b>–<b>12</b> isolated from <i>Chloranthus fortunei</i>. The results showed that 16 dimers exhibited potent antiplasmodial
activities (<100 nM); in particular, compounds <b>1</b>, <b>14</b>, and <b>19</b> exhibited low nanomolar activities
with IC<sub>50</sub> values ranging from 1 to 7 nM, which is comparable
to the potency of artemisinin, and selectivity index values toward
mammalian cells greater than 500. A comprehensive structure–activity
relationship study indicated that three functional groups are essential
and two motifs can be modified
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