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. 2017 Oct 15;27(20):4597-4600.
doi: 10.1016/j.bmcl.2017.09.030. Epub 2017 Sep 14.

Synthesis, characterization, and cellular localization of a fluorescent probe of the antimalarial 8-aminoquinoline primaquine

Adonis McQueen  1 , Lynn D Blake  1 , Ala Azhari  2 , M Trent Kemp  1 , Tommy W McGaha Jr  2 , Niranjan Namelikonda  3 , Randy W Larsen  3 , Roman Manetsch  4 , Dennis E Kyle  5
Affiliations

Synthesis, characterization, and cellular localization of a fluorescent probe of the antimalarial 8-aminoquinoline primaquine

Adonis McQueen et al. Bioorg Med Chem Lett. .

Abstract

Primaquine (PQ) is the only commercially available drug that clears dormant liver stages of malaria and blocks transmission to mosquito vectors. Although an old drug, much remains to be known about the mechanism(s) of action. Herein we develop a fluorescent tagged PQ to discover cellular localization in the human malaria parasite, Plasmodium falciparum. Successful synthesis and characterization of a primaquine-coumarin fluorescent probe (PQCP) demonstrated potency equivalent to the parent drug and the probe was not cytotoxic to HepG2 carcinoma cells. Cellular localization was found primarily in the cytosol of the asexual erythrocytic and gametocyte stages of parasite development.

Keywords: 8-Aminoquinoline; Fluorescent probe; Malaria; Plasmodium falciparum; Primaquine.

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Figures

Fig. 1.
Fig. 1.
Structures of antimalarial 8-aminoquinoline primaquine and primaquine-coumarin fluorescent probe.
Fig. 2.
Fig. 2.
Synthesis of the fluorescent PQCP probe.
Fig. 3.
Fig. 3.
A) Normalized optical absorption spectra of PQ, PQCP and coumarin; B) Normalized steady state emission spectra of PQ, PQCP and coumarin (excitation: 320 nm).
Fig. 4.
Fig. 4.
A) Concentration response curves for PQ and PQCP against A) asexual blood stages of P. falciparum (D6 clone) and B) P. berghei liver stages in vitro.
Fig. 5.
Fig. 5.
A) Images of P. falciparum asexual blood stages showing localization of PQCP (blue) in the cytoplasm, mitochondria (red, stained with Mitotracker red), and apicoplast (green, GFP-tagged ACP leader). B) Images showing reduced concentration of PQCP in trophozoite stages pre-exposed to PQ (150 μM).
Fig. 6.
Fig. 6.
Images of P. falciparum gametocytes (A, stage IV; B, stage V) showing localization of PQCP in the cytoplasm (blue) in the cytoplasm and the mitochondria (red, stained with Mitotracker red (MTR)).
See this image and copyright information in PMC

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