Abstract
Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation.
Highlights
Malaria is one of the most prevalent parasitic diseases in the world
Synthesis and characterization of CQ analogs The structure of the two aminoquinoline derivatives, MAQ and BAQ, and their synthesis strategy are depicted in Scheme S1
Two CQ analogs MAQ and BAQ were obtained as low-cost antimalarial prototypes, which is important considering that disease transmission is concentrated in developing countries and is most frequent among the impoverished classes of several endemic countries [9]
Summary
Malaria is one of the most prevalent parasitic diseases in the world. It affects approximately 500 million individuals throughout the tropical and subtropical areas of developing countries and causes considerable morbidity and mortality with about 800,000 deaths worldwide each year [1]. The global importance of this disease, current limitations of vector control and the absence of an effective vaccine, makes the development of therapeutic antimalarial drugs the main strategy of malaria control [2]. The limited availability of ACT and the decreased susceptibility of P. falciparum to artemisinin derivatives [7,8] have required the development of novel antimalarial drugs [9,10,11]. Previous studies have described the discovery of novel antimalarial drugs through analysis of medicinal plants [12] and through novel drug synthesis protocols [13,14], no new active compound has been shown to be as effective as CQ
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