High-Content Phenotypic Screen of a Focused TCAMS Drug Library Identifies Novel Disruptors of the Malaria Parasite Calcium Dynamics.

The search for new antimalarial drugs with unexplored mechanisms of action is currently one of the main objectives to combat the resistance already in the clinic. New drugs should target specific mechanisms that once initiated lead inevitably to the parasite's death and clearance and cause minimal toxicity to the host. One such new mode of action recently characterized is to target the parasite's calcium dynamics.

Antimalarial , -Dialkyldioxonaphthoimidazoliums: Synthesis, Biological Activity, and Structure-activity Relationships.

Here we report the nanomolar potencies of , -dialkyldioxonaphthoimidazoliums against asexual forms of sensitive and resistant . Activity was dependent on the presence of the fused quinone-imidazolium entity and lipophilicity imparted by the N/N alkyl residues on the scaffold. Gametocytocidal activity was also detected, with most members active at IC < 1 μM.

Viability Screen of LOPAC Reveals Tyrosine Kinase Inhibitor Tyrphostin A9 as a Novel Partner Drug for Artesunate Combinations To Target the Ring Stage.

The emergence of artemisinin-resistant poses a major threat to current frontline artemisinin combination therapies. Artemisinin resistance is widely associated with mutations in the Kelch13 (PfKelch13) propeller region, leading to delayed parasite clearance and increased survival of early-ring-stage parasites. There is therefore a need to discover novel drugs that are effective against artemisinin-resistant In view of this, our study aimed to identify compounds from the Library of Pharmacologically Active Compounds (LOPAC) that could increase the efficacy of artesunate and be used as a potential partner drug for treatment against artemisinin-resistant falciparum malaria.

Targeted Phenotypic Screening in and Reveals Novel Modes of Action of Medicines for Malaria Venture Malaria Box Molecules.

The Malaria Box collection includes 400 chemically diverse small molecules with documented potency against malaria parasite growth, but the underlying modes of action are largely unknown. Using complementary phenotypic screens against and , we report phenotype-specific hits based on inhibition of overall parasite growth, apicoplast segregation, and egress or host invasion, providing hitherto unavailable insights into the possible mechanisms affected. First, the Malaria Box library was screened against tachyzoite stage and the half-maximal effective concentrations (ECs) of molecules showing ≥80% growth inhibition at 10 µM were determined.

High-Content Screening of the Medicines for Malaria Venture Pathogen Box for Plasmodium falciparum Digestive Vacuole-Disrupting Molecules Reveals Valuable Starting Points for Drug Discovery.

infections leading to malaria have severe clinical manifestations and high mortality rates. Chloroquine (CQ), a former mainstay of malaria chemotherapy, has been rendered ineffective due to the emergence of widespread resistance. Recent studies, however, have unveiled a novel mode of action in which low-micromolar levels of CQ permeabilized the parasite's digestive vacuole (DV) membrane, leading to calcium efflux, mitochondrial depolarization, and DNA degradation.

Distribution of Alox15 in the Rat Brain and Its Role in Prefrontal Cortical Resolvin D1 Formation and Spatial Working Memory.

Docosahexaenoic acid (DHA) is enriched in membrane phospholipids of the central nervous system (CNS) and has a role in aging and neuropsychiatric disorders. DHA is metabolized by the enzyme Alox15 to 17S-hydroxy-DHA, which is then converted to 7S-hydroperoxy,17S-hydroxy-DHA by a 5-lipoxygenase, and thence via epoxy intermediates to the anti-inflammatory molecule, resolvin D1 (RvD1 or 7S,8R,17S-trihydroxy-docosa-Z,9E,11E,13Z,15E,19Z-hexaenoic acid). In this study, we investigated the distribution and function of Alox15 in the CNS.