Fluorescent Marinoquinoline Derivative as Inhibitors of Plasmodium falciparum : SAR Analysis, Mode of Action and In Vivo Studies

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Abstract We present insights into the mechanism of action of marinoquinolines (MQ), a novel class of lead candidates. Using a divergent synthetic approach, we developed a series of 20 new analogues with fluorescence properties. Structure–activity relationships analysis identified 19 as an attractive compound showing a combination of favorable in vitro (IC503D7 = 0.28 μM; CC50HepG2 = 53 μM), ex vivo (EC50Pf = 1.2 μM; EC50Pv = 0.53 μM), in vivo (3 × 50 mg/kg oral dose resulted in a 96% reduction in parasitemia in Plasmodium berghei-infected mice), physicochemical (Sol7.4 = 171 μM; LogD7.4 = 3.9), and pharmacokinetic (P_app = 9.4 × 10–6 cm/s, human Clinthep,mic = 0.61–0.68 μL min–1 mg–1) properties. Compound 19 selectively accumulates in infected erythrocytes, enters the digest vacuole and inhibits Plasmodium falciparum proteolytic activity, suggesting that MQs act as protease inhibitors. These findings strengthen the evidence that MQs are promising lead candidates for antimalarial drug discovery.

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