N-Substituted Phenylhydrazones Kill the Ring Stage of Plasmodium falciparum
Date
2024
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
BioMed Research International
Abstract
Antimalarial resistance has hampered the effective treatment of malaria, a parasitic disease caused by Plasmodium species. As part
of our campaign on phenotypic screening of phenylhydrazones, a library of six phenylhydrazones was reconstructed and
evaluated for their in vitro antimalarial and in silico receptor binding and pharmacokinetic properties. The structures of the
phenylhydrazone hybrids were largely confirmed using nuclear magnetic resonance techniques. We identified two compounds
which exhibited significant antimalarial potential against the ring stage (trophozoite) of 3D7 chloroquine-sensitive (CS) strain
and DD2 chloroquine-resistant (CR) strains of Plasmodium falciparum with monosubstituted analogs bearing meta or para
electron-donating groups showing significant activity in the single-digit micromolar range. Structure activity relationship is
presented showing that electron-donating groups on the substituent hydrophobic pharmacophore are required for antimalarial
activity. Compounds PHN6 and PHN3 were found to be the most potent with pIC50s (calculated form in vitro IC50s) of 5.37
and 5.18 against 3D7 CS and DD2 CR strains, respectively. Our selected ligands (PHN3 and PHN6) performed better when
compared to chloroquine regarding binding affinity and molecular stability with the regulatory proteins of Plasmodium
falciparum, hence predicted to be largely responsible for their in vitro activity. Pharmacokinetic prediction demonstrated that
the phenylhydrazones may not cross the blood-brain barrier and are not P-glycoprotein (P-gp) substrates, a good absorption
of 62% to 69%, and classified as a category IV compound based on toxicity grading.
Description
Research Article
Keywords
Phenylhydrazones, Ring Stage, falciparum