Malaria Box-Inspired Discovery of <i>N</i>-Aminoalkyl-β-carboline-3-carboxamides, a Novel Orally Active Class of Antimalarials
Jopaul Mathew, Sha Ding, Kevin A. Kunz, Emily E. Stacy, Joshua H. Butler, Reagan S. Haney, Emilio F. Merino, Grant J. Butschek, Zaira Rizopoulos, Maxim Totrov, María B. Cassera, Paul R. Carlier
Abstract
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.
Topics & Concepts
PharmacophorePlasmodium falciparumMalariaVirtual screeningAmidePharmacologyIn vitroIn vivoAntimalarial AgentOrally activeChemistryCarboxamideLigand (biochemistry)StereochemistryCombinatorial chemistryMedicineBiologyBiochemistryImmunologyReceptorGeneticsMalaria Research and ControlComputational Drug Discovery MethodsSynthesis and bioactivity of alkaloids