Fluorene-Chloroquine Hybrids: Synthesis, in vitro Antiplasmodial Activity, and Inhibition of Heme Detoxification Machinery of Plasmodium falciparum.

Abstract

Fluorene-chloroquine hybrids have been identified as a new promising class of antiplasmodial agents. The most active compound 9 d exhibited good in vitro antiplasmodial activity against a chloroquine-sensitive NF54 strain of the human malaria parasite Plasmodium falciparum with an IC50 value of 139 nM. UV-visible absorption, FTIR spectral and 1 H NMR titration data corroborated the binding of 9 d to monomeric and μ-oxodimeric heme as well as inhibition of β-hematin formation, which collectively supported the inhibition of heme detoxification machinery in P. falciparum. In silico docking studies revealed the binding interactions of the hybrids in the active site of the wild type as well as quadruple mutant of Pf-DHFR-TS dihydrofolate enzyme. Further, the ADMET parameters were predicted and were in good agreement with the expected values, suggesting the drug likeness of the synthesized hybrid molecules.