Abstract
The discovery of novel antiparasitic drugs for neglected tropical diseases (NTDs) constitutes a global urgency and requires a range of innovative strategies to ensure a sustainable pipeline of lead compounds. Thus far, primaquine (PQ) is the only transmission-blocking antimalarial that is clinically available, displaying marked activity against gametocytes of all causative species of human malaria (Plasmodium spp.). Chagas disease, caused by Trypanosoma cruzi, is another PQ-sensitive illness besides malaria. One of the major drawbacks of PQ is its metabolism into carboxyprimaquine (CPQ), which is less active than the parent drug. In this study, we developed different synthetic pathways to confer N-protection to PQ through introduction of thioxo-imidazolidin-4-one. The introduction of this group prevents the formation of CPQ, counteracting one major drawback of the parent drug. After that, we evaluated the potential biological activity of the novel 2-thioxo-imidazolidin-4-one derivative of PQ, which showed relevant in vitro activity against Trypanosoma cruzi (IC50 1.4 μM) compared to PQ (IC50 1.7 μM) and the reference drug benznidazole (IC50 1.6 μM). Noting its acceptable pharmacokinetic profile, this PQ conjugate may be a potential scaffold for novel drug exploration against Chagas disease.
Highlights
Protozoan parasites that infect humans represent a significant threat to health, causing more than a billion deaths annually, in developing countries
Results and Discussion of oxidant hemolysis with G6Pd can culminate in acute hemolytic anemia
The main metabolite of PQ in human plasma is CPQ, which has of a chemotherapeutic treatments for neglected tropical diseases (NTDs) mostly rely on singleofdrugs cause associated several adslower clearance and lower distribution
Summary
Protozoan parasites that infect humans represent a significant threat to health, causing more than a billion deaths annually, in developing countries. Through different synthetic pathways (Figure 2), we developed a 2-thioxo-imidazolin-4-one PQ derivative (8) that may prevent the formation of one major metabolite of 1 through N-protection with a 2-thioxo-imidazolidin-4-one group. Our research group recently developed a new synthetic pathway to protect metabolization of PQ into CPQ through the introduction of the imidazolidin-4-one group (Imd, 3, Figure 1). These derivatives inhibited the sporogonic cycle of P. berghei, affecting the appearance of oocysts in the midgut of mosquitoes [21]. One of the hypotheses for the anti-trypanosomal activity of 1 and related 8-aminoquinolines (8-AQ) relies on the metabolic formation of free radicals that increase the oxidative stress on T. cruzi [24].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
