Synthesis of New 4-Aminoquinolines and Evaluation of Their In Vitro Activity against Chloroquine-Sensitive and Chloroquine-Resistant Plasmodium falciparum

International audienceThe efficacy of chloroquine, once the drug of choice in the fight against Plasmodium falcipa-rum, is now severely limited due to widespread resistance. Amodiaquine is one of the most potent antimalarial 4-aminoquinolines known and remains effective against chloroquine-resistant parasites, but toxicity issues linked to a quinone-imine metabolite limit its clinical use. In search of new compounds able to retain the antimalarial activity of amodiaquine while circumventing quinone-imine metabolite toxicity, we have synthesized five 4-amino-quinolines that feature rings lacking hydroxyl groups in the side chain of the molecules and are thus incapable of generating toxic quinone-imines. The new compounds displayed high in vitro potency (low nanomolar IC 50), markedly superior to chloroquine and comparable to amodiaquine, against chloroquine-sensitive and chloroquine-resistant strains of P. falcipa-rum, accompanied by low toxicity to L6 rat fibroblasts and MRC5 human lung cells, and metabolic stability comparable or higher than that of amodiaquine. Computational studies indicate a unique mode of binding of compound 4 to heme through the HOMO located on a biphenyl moeity, which may partly explain the high antiplasmodial activity observed for this compound

Cytotoxicity of compounds 1–4 toward mammalian cells.

<p>^<i>a</i>CC₅₀: concentration of drug inducing 50% of cell growth arrest.</p><p>^<i>b</i>SI: Selectivity index expressed as (CC₅₀ to each mammalian cell line)/(IC₅₀ to <i>P</i>. <i>falciparum</i>). SI max corresponds to the most sensitive strain of <i>P</i>. <i>falciparum</i> and SI min toward the less sensitive parasite strain.</p><p>Cytotoxicity of compounds 1–4 toward mammalian cells.</p

Synthetic strategy for compound 1 and other new aminoquinolines.

<p>Synthetic strategy for compound 1 and other new aminoquinolines.</p

New aminoquinolines (1–5) and precursor amines (6–10) synthesized.

<p>New aminoquinolines (1–5) and precursor amines (6–10) synthesized.</p

Docked poses of 1 and 4 on heme.

<p>Both aminoquinoline molecules were employed in the diprotonated form. Atom color code: white: H, brown: C, blue: N, red: O, and gold: Fe. Only polar hydrogens are shown for clarity.</p

<i>In</i> vitro activities of compounds 1–5, CQ, and AQ against CQ-sensitive and CQ-resistant strains of <i>P</i>. <i>falciparum</i>.

<p>IC₅₀ ± SD values (nM) determined from independent experiments performed in triplicate in two laboratories (<b>A</b>, Marseille; <b>B</b>, Paris) under different assay conditions (see main text and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140878#sec008" target="_blank">Materials and Methods</a> Section for details). CQ: chloroquine, AQ: amodiaquine, -: not determined.</p><p>^bNote that Dd2 is CQ-resistant under the culture conditions of laboratory A and CQ-sensitive under the culture conditions of laboratory B.</p><p><i>In</i> vitro activities of compounds 1–5, CQ, and AQ against CQ-sensitive and CQ-resistant strains of <i>P</i>. <i>falciparum</i>.</p

HOMO’s of compounds 1 and 4.

<p>HOMO’s of compounds 1 and 4.</p

Aminoquinoline antimalarial drugs and drug candidates.

<p>Aminoquinoline antimalarial drugs and drug candidates.</p