Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. Plasmodium 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- C-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 PfIspD recombinant enzyme. Here, we report PfIspD inhibition data for fosmidomycin (FOS) and 19 previously disclosed analogs and report parasite growth and PfIspD 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.
Four new lindenane sesquiterpenoid trimers, designated as trichloranoids A-D (1-4), along with a known analogue (5) were isolated from Chloranthus spicatus. Their structures were elucidated by a combination of diverse...
Antiplasmodial bioassay guided fractionation of a Madagascar collection of
Crinum firmifolium led to the isolation of seven compounds. Five of the
seven compounds were determined to be 2-alkylquinolin-4(1H)-ones with
varying side chains. Compounds 1 and 4 were determined to be
known compounds with reported antiplasmodial activities, while 5 was believed
to be a new branched 2-alkylquinolin-4(1H)-one, however, it was isolated
in limited quantities and in admixture and therefore was synthesized to confirm its
structure as a new antiplasmodial compound. Along with 5, two other new and
branched compounds 6 and 7 were synthesized as well.
Accompanying the five quinolones were two known compounds 2 and
3 which are inactive against Plasmodium falciparum. The
isolation, structure elucidation, total synthesis, and biological evaluation of these
compounds are discussed in this article.
Virtual ligand screening of a publicly
available database of antimalarial
hits using a pharmacophore derived from antimalarial MMV008138 identified
TCMDC-140230, a tetrahydro-β-carboline amide, as worthy of exploration.
All four stereoisomers of this structure were synthesized, but none
potently inhibited growth of the malaria parasite Plasmodium
falciparum. Interestingly, 7e, a minor byproduct
of these syntheses, proved to be potent in vitro against P. falciparum and was orally efficacious (40 mg/kg) in an in vivo mouse model of malaria.
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