Abstract
Natural products are a prolific source for the identification of new biologically active compounds. In the present work, we studied the in vitro and in vivo antimalarial efficacy and ADME-Tox profile of a molecular hybrid (AM1) between 4-aminoquinoline and a quinolizidine moiety derived from lupinine (Lupinus luteus). The aim was to find a compound endowed with the target product profile-1 (TCP-1: molecules that clear asexual blood-stage parasitaemia), proposed by the Medicine for Malaria Venture to accomplish the goal of malaria elimination/eradication. AM1 displayed a very attractive profile in terms of both in vitro and in vivo activity. By using standard in vitro antimalarial assays, AM1 showed low nanomolar inhibitory activity against chloroquine-sensitive and resistant P. falciparum strains (range IC50 16–53 nM), matched with a high potency against P. vivax field isolates (Mean IC50 29 nM). Low toxicity and additivity with artemisinin derivatives were also demonstrated in vitro. High in vivo oral efficacy was observed in both P. berghei and P. yoelii mouse models with IC50 values comparable or better than those of chloroquine. The metabolic stability in different species and the pharmacokinetic profile in the mouse model makes AM1 a compound worth further investigation as a potential novel schizonticidal agent.
Highlights
Malaria is an infectious disease caused by Plasmodium parasites; two species, P. falciparum andP. vivax, are responsible for more than 400,000 deaths/year worldwide
We extended the previous observations by completing in vivo efficacy studies studies of racemic AM1 and its purified enantiomers in two rodent malaria models (P. berghei and of racemic AM1 and its purified enantiomers in two rodent malaria models (P. berghei and P. yoelii) with
The emergence and spread of resistant P. falciparum strains significantly affected the use of chloroquine as monotherapy, research on a new generation of 4-aminoquinolines effective against multiresistant P. falciparum strains never stopped and novel compounds are presently in development
Summary
Malaria is an infectious disease caused by Plasmodium parasites; two species, P. falciparum and. In some of the countries where P. falciparum has been eliminated (Central Asia, Argentina, Belize, Mexico, and large parts of China) there is growing evidence for an increase in morbidity and mortality due to P. vivax infection [6,7,8] For these reasons, the discovery and development of new drugs active against different Plasmodium species remains a high priority. The 4-aminoquinoline class of drugs, represented by the classical antimalarial agent chloroquine (CQ), has been highly successful in the treatment of malaria for decades before resistance emerged and spread. Another member of the family, amodiaquine (AQ), is still used in ACT [9].
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