1 research outputs found
Design, Synthesis and Evaluation of Bifunctional Acridinine−Naphthalenediimide Redox-Active Conjugates as Antimalarials
A novel class of bifunctional molecules
was synthesized integrating
acridine (Ac) and redox-active naphthalenediimide (NDI) scaffolds
directly and through a flexible linker (en). We evaluated in vitro
antiplasmodial activity, physicochemical properties, and a possible
mode of action. Theoretical studies suggested electronic segmentation
between the electron-rich Ac and electron-deficient NDI scaffolds.
Orthogonal Ac–NDI molecules showed activities in the micromolar
to submicromolar range against a chloroquine (CQ)-sensitive strain
of human malaria pathogen Plasmodium falciparum (maximum activity, IC<sub>50</sub>: 0.419 μM). The flexible
Ac–en–NDI molecules were most potent and showed activity
in the nanomolar range against both CQ-sensitive (with most effective
compounds, IC<sub>50</sub>: 3.65 and 4.33 nM) as well as CQ-resistant
(with most effective compounds, IC<sub>50</sub>: 52.20 and 28.53 nM)
strains of P. falciparum. Significantly,
with CQ-resistant strains, the activity of the most effective compounds
was 1 order of magnitude better than that of standard drug CQ. Ac–en–NDI-conjugated
molecules were significantly more potent than the individual NDI and
Ac-based molecules. The structure–activity relationship (SAR)
suggests that the flexible spacer (en) linking the Ac and NDI scaffolds
plays a vital role in exhibiting improved potency. None of the molecules
triggered hemolysis in culture, and the most potent compounds did
not show cytotoxicity in vitro against mammalian fibroblast NIH3T3
cells at their respective IC<sub>50</sub> values. The other significant
outcome of this work is that some of the investigated molecules have
the potential to affect multiple processes in the parasite including
the hemozoin formation in digestive vacuoles (DVs), mitochondrial
membrane potential, and the redox homeostasis of the parasite