Antimalarial efficacy of MMV390048, an inhibitor of phosphatidylinositol 4-kinase.

As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all life cycle stages, apart from late hypnozoites in the liver.

Lead optimization of imidazopyrazines: a new class of antimalarial with activity on Plasmodium liver stages.

Imidazopyridine 1 was identified from a phenotypic screen against P. falciparum (Pf) blood stages and subsequently optimized for activity on liver-stage schizonts of the rodent parasite P. yoelii (Py) as well as hypnozoites of the simian parasite P.

Targeting Plasmodium PI(4)K to eliminate malaria.

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P.

Selective and specific inhibition of the plasmodium falciparum lysyl-tRNA synthetase by the fungal secondary metabolite cladosporin.

With renewed calls for malaria eradication, next-generation antimalarials need be active against drug-resistant parasites and efficacious against both liver- and blood-stage infections. We screened a natural product library to identify inhibitors of Plasmodium falciparum blood- and liver-stage proliferation. Cladosporin, a fungal secondary metabolite whose target and mechanism of action are not known for any species, was identified as having potent, nanomolar, antiparasitic activity against both blood and liver stages.

Total synthesis and biological evaluation of the resveratrol-derived polyphenol natural products hopeanol and hopeahainol A.

The total synthesis and biological evaluation of the resveratrol-derived natural products hopeanol (2) and hopeahainol A (3) in their racemic and antipodal forms are described. The Friedel-Crafts-based synthetic strategy employed was developed from model studies that established the feasibility of constructing the C(7b) quaternary center through an intramolecular Friedel-Crafts reaction and a Grob-type fragmentation to introduce an obligatory olefinic bond in the growing molecule. The final stages of the synthesis involved an epoxide substrate and an intramolecular Friedel-Crafts reaction, followed by oxidation to afford, upon global deprotection, hopeahainol A (3).

Total synthesis and biological evaluation of cortistatins A and J and analogues thereof.

Total syntheses of the highly selective antiproliferative natural products cortistatins A (1) and J (5) in their naturally occurring enantiomeric forms are described. The modular and convergent strategy employed relies on an intramolecular oxa-Michael addition/aldol/dehydration cascade reaction to cast the ABCD ring framework of the molecule and both Sonogashira and Suzuki-Miyaura coupling reactions to assemble the necessary building blocks into the required heptacyclic skeleton. A divergent approach from a late-stage epoxy ketone leads to both target molecules in a stereoselective manner.

Chemical synthesis and biological evaluation of palmerolide A analogues.

Molecular design and chemical synthesis of several palmerolide A analogues allowed the first structure activity relationships (SARs) of this newly discovered marine antitumor agent. From several analogues synthesized and tested (ent- 1, 5- 14, 21- 26, 50, 51), compounds 25 (with a phenyl substituent on the side chain) and 51 (lacking the C-7 hydroxyl group) were the most interesting, exhibiting approximately a 10-fold increase in potency and equipotency, respectively, to the natural product. These findings point the way to more focused structure activity relationship studies.