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The control of malaria is challenged by drug resistance, and new antimalarial drugs are needed. New drug discovery efforts include consideration of hybrid compounds as potential multitarget antimalarials. Previous work from our group has demonstrated that hybrid structures resulting from cinnamic acid conjugation with heterocyclic moieties from well-known antimalarials present improved antimalarial activity. Now, we report the synthesis and SAR analysis of an expanded series of cinnamic acid derivatives displaying remarkably high activities against both blood- and liver-stage malaria parasites. Two compounds judged most promising, based on their in vitro activity and druglikeness according to the Lipinski rules and Veber filter, were active in vivo against blood-stage rodent malaria parasites. Therefore, the compounds reported represent a new entry as promising dual-stage antimalarial leads.

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Novel primaquine derivatives, obtained by conjugation of the drug's aliphatic amine with different cinnamic acids, resulted in increased in vitro activity, compared to primaquine, against liver-stage malarial parasites. The compounds were non-cytotoxic to human hepatoma cells, suggesting that they are a promising new class of agents for the treatment and prevention of malaria.Effective and safe antimalarial drugs active against both liver and erythrocytic parasite stages will be valuable components of malaria eradication strategies.1 Mammalian infection by malarial parasites is initiated by an infected mosquito bite, followed by a clinically silent liver-stage infection, during which thousands of merozoites are formed to be released into the bloodstream and trigger the clinically relevant erythrocytic stage of the life cycle. 2Drugs able to act on the liver stage are highly relevant, as they can be used in chemoprophylaxis to prevent all clinical manifestations of malaria.3 Moreover, such drugs are particularly relevant in P. vivax and P. ovale infections, as in these species latent forms that are called hypnozoites are not eliminated by most available therapies, persist in the liver for long periods, and subsequently cause malaria relapses. At present, drugs acting against parasite liver forms are scarce, and primaquine (PQ, 1 in Scheme 1) remains the only drug in clinical use that acts against liver stages of all Plasmodium species, 4 including P. vivax and P. ovale hypnozoites.5 Unfortunately, PQ's low oral bioavailability and high hemotoxicity hold back its clinical use, especially in vulnerable populations including pregnant women, infants and the elderly. In addition, PQ causes hemolysis in patients with congenital deficiency of glucose-6-phosphate dehydrogenase, 5 complicating its use to treat P. vivax and P. ovale malaria and limiting its use in chemoprophylaxis.For the past decade, we have been working on chemical approaches to mask the PQ aliphatic amine in order to obtain analogues resistant to oxidative deamination, the major metabolic pathway underlying the drug's low oral bioavailability (Scheme 1) by conversion into an inactive metabolite, carboxyprimaquine (2 in Scheme 1).5 To this end, we have successfully developed imidazoquines (3 in Scheme 1) 6,7 and primacenes (4 in Scheme 1), 8,9 peptidomimetic and organometallic derivatives of PQ with promising antimalarial properties, respectively. Now, we disclose a new family of PQ derivatives, the PRIMACINS (5 in Scheme 1), obtained by coupling PQ to cinnamic acids, as the latter was formerly reported to possess interesting antimalarial properties.10 PRIMACINS were found to have higher in vitro activity than PQ against the liver-stage of the rodent malarial parasite P. berghei (Fig. 1).PRIMACINS were tested against liver stages of the rodent parasite P. berghei and against erythrocytic stages of the human parasite P. falciparum (Table 1). Compounds 5 were two-or more-fold more potent than PQ against liver stage P. berghei and were non-toxic to Huh7 hum...