MMV693183 

MMV693183 is an orally active inhibitor of Plasmodium falciparum acetyl-CoA synthetase (AcAS), with an IC₅₀ of 300 nM against Plasmodium falciparum. MMV693183 exhibits potent inhibitory activity against clinical isolates of malaria parasites, including Artemisinin (HY-B0094)-resistant strains. MMV693183 is metabolized in vivo into the active antimetabolite CoA-MMV693183, which exerts effects of killing asexual blood-stage parasites and blocking transmission to Anopheles mosquitoes by binding to and inhibiting the function of acetyl-CoA synthetase, thereby reducing the levels of acetyl-CoA and 4'-phosphopantetheine. In humanized mouse models, MMV693183 shows favorable in vivo efficacy, drug-like properties, and no significant cytotoxicity or off-target activity against human cells. MMV693183 is widely used in malaria-related research as a parasiticide and metabolic disruptor^[1].

MMV693183 potently inhibits the in vitro asexual blood-stage growth of Plasmodium falciparum strains with an IC₅₀ of 2.1-2.8 nM; it also inhibits the in vitro growth/schizont maturation of clinical isolates of Plasmodium falciparum and P. vivax with low nanomolar activity^[1].
MMV693183 inhibits the viability of Plasmodium falciparum NF54-HGL gametocytes, with an IC₅₀ of 17.8-38.8 nM at 72 h. MMV693183 also potently inhibits female gametocyte activation (IC₅₀=12 nM), but shows weak activity against male gametogenesis (IC₅₀=1 μM)^[1].
MMV693183 (1.5 nM, 500 nM; 72 h) renders AcAS conditional knockdown Plasmodium falciparum parasites 5-fold hypersensitive under AcAS knockdown conditions^[1].
MMV693183 (10 μM) exhibits no in vitro cytotoxicity in human hepatocytes or HepG2 cells, and shows no significant off-target activity against human receptors, enzymes or channels at the concentration of 10 μM^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

MMV693183 (50 mg/kg; p.o.; single dose) reduces P. falciparum parasitemia below detectable levels in humanized NSG mice within three days^[1].
MMV693183 clears P. falciparum parasitemia to undetectable levels in humanized NSG mice within 4-6 days, with a modeled MIC of 3.2 ng/mL and MPC₉₀ of 38.4 ng/mL^[1].
MMV693183 (10-50 mg/kg; daily; 4 days) does not cause hemolytic toxicity in G6PD-A-deficient human erythrocyte-engrafted NSG mice^[1].
MMV693183 (10-1000 mg/kg; p.o.; daily; 3-8 days) is well tolerated in Wistar Han rats at doses up to 1000 mg/kg for 3 days, with a >30-fold exposure safety margin at 30 mg/kg/day relative to predicted human efficacious exposure^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

362.34

C₁₆H₂₁F₃N₂O₄

2446681-27-0

OCC(C)(C)[C@@H](O)C(NC[C@H](C)NC(C1=C(C=C(C(F)=C1)F)F)=O)=O

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• [1]. de Vries LE, et al. Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183. Nat Commun. 2022;13(1):2158. Published 2022 Apr 20.  [Content Brief]