A novel bi-triazole (4RJ) with potent dual-stage antiplasmodial and transmission-blocking activity against Plasmodium falciparum and Plasmodium vivax.

Malaria is an infection caused by protozoa of the genus Plasmodium, responsible for more than 282 million cases annually. Despite the availability of antimalarial drugs, controlling the disease remains a challenge due to resistance and the lack of compounds effective at various stages of the parasite's life cycle. Bi-triazole derivatives are emerging as a growing class in the development of new antimalarials. The compound 4RJ, for example, has demonstrated activity against the asexual stages of resistant Plasmodium falciparum strains in previous studies. However, its effects on field isolates against the sexual forms (transmission blockade) of both species, as well as its interaction with the reference drug, have not yet been reported, and such data are fundamental to consolidating the antimalarial profile of this class. In this study, we evaluated the activity of 4RJ against the asexual and sexual stages of P. falciparum and P. vivax using compound combination studies, ex vivo evaluation of field isolates collected from malaria patients in Porto Velho, Rondônia, Brazil, exflagellation analysis, and ookinete formation assays. 4RJ significantly inhibited asexual parasite growth in field isolates of P. falciparum and P. vivax (IC₅₀ 6.95 and 8.85 μM, respectively), suppressed microgametocyte exflagellation (≥80%), and inhibited ookinete formation (46-89%), also revealing an additive interaction profile (FIC₅₀ = 1) with the reference drug. These results broaden the antimalarial profile of 4RJ and reinforce its potential as a candidate for the development of antimalarials.