Structure–activity relationships of 4-N-substituted ferroquine analogues: Time to re-evaluate the mechanism of action of ferroquine

Antimalarial activities of ferroquine conjugates with either glutathione reductase inhibitors or glutathione depletors via a hydrolyzable amide linker

“…They have a maximum and show a decreased inhibition or non-inhibition at high concentration as previously discussed for FQ (bell-shaped curve). 48 It was also shown that the new dual molecules inhibit the GR enzyme to a lower extent than M 5 itself. As our dual molecules can be considered as prodrugs, this result was expected because the carboxylic function of the naphthoquinone moiety is required for the affinity to the target GR enzyme (establishment of a salt bridge with an Arg residue).…”

“…This earlier observation was first interpreted as a possible phenomenon of self-aggregation of the ferrocenyl drug to explain the apparent lower drug concentration in the assay. 48 In the view of the present data with all dual molecules built through a tertiary amide bond from a short FQ analogue and a GR inhibitor, all displaying a sharp bell-shaped curve of inhibition of b-hematin formation as illustrated with compound 18 (Fig. 2), it seems that the apparent decrease of inhibition of b-hematin formation at increasing concentration of drug:hematin ratio, could be interpreted as the result of a lower concentration of hematin in the assay or to a lower concentration of the drug following degradation by Fenton reaction.…”

“…48 From these experiments, it could be concluded that the extended structure of diprotonated FQ in water changes in neutral FQ to a more compact conformation via an additional intramolecular hydrogen bond in apolar media. This flip/flop hydrogen bond between the open conformation (charged FQ) and the folded conformation (uncharged FQ) was supposed to help transport from water to the hydrophobic membranes.…”

“…The original version of Egan's assay 47 was slightly modified as recently reported. 32,48 The IC 50 values were defined as the number of drug equivalents, related to 1 equiv of hematin, necessary for reaching 50% of maximal inhibition. They were determined at increasing concentrations of the drug from 0 to 5 mM.…”

Platinum(II) and palladium(II) complexes with (N,N′) and (C,N,N′)− ligands derived from pyrazole as anticancer and antimalarial agents: Synthesis, characterization and in vitro activities

“…The Pd-cyclometallated derivative 5c was more efficient than Pt-protoporphyrin against P. falciparum (38 μM) [77]. However, these compounds were less potent against the two P. falciparum clones 3D7 and W2 than Fe-derivatives, such as ferroquine and analogs [78,79], ferrocenic derivatives from ciprofloxacin [80], or Ru, such as ruthenoquine and analogs [42].…”