Fluorene‐Chloroquine Hybrids: Synthesis, in vitro Antiplasmodial Activity, and Inhibition of Heme Detoxification Machinery of Plasmodium falciparum. (15th September 2022)

• Record Type: Journal Article
• Authors: Parth, ; Kaur, Navpreet; Korkor, Constance; Mobin, Shaikh M.; Chibale, Kelly; Singh, Kamaljit
• Is Part Of: ChemMedChem. Volume 17:Number 19(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-09-15
• Subjects: Fluorene -- Molecular hybrids -- Antiplasmodial agents -- Heme binding -- Lumefantrine -- Drug likeness; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202200414
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : Malaria detox : Fluorene‐chloroquine hybrids represent a new class of highly active antiplasmodial agents. The most active compound shows high in vitro antiplasmodial activity (IC50 =139 nM) against a chloroquine‐sensitive NF54 strain of the human malaria parasite Plasmodium falciparum . The hybrid binds to hemin and inhibits β‐hematin formation and impacts the detoxification machinery in P. falciparum .