Santos Barbosa P., Souza GE., Maluf SEC., Bonatto V., Moura CS., Mendes GR., Valdes TA., Annunciato Y., Rossetto BDS., Ventura PDDS., Ortin GGD., da Silva W., Icimoto MY., Ferreira ADS., Cruz FC., Teles CBG., Pereira DB., Cassiano GC., Santana S., Prudêncio M., Barbosa CS., Moura IMR., Giampauli RM., De Sousa IL., Rocco SA., Gazarini ML., Correia CRD., Aguiar ACC., Guido RVC.

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.

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

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