13ª Semana Integrada do Instituto de Física de São Carlos

Antiplasmodial activity assessment of the natural compound batzelladine L and synthetic derivatives as lead candidates for malaria

21 de ago. de 2023 14:00

1h 30m

Salão de Eventos USP

Básica 14h00 - 15h30

Descrição

Malaria is a parasitic disease caused by the pathogenic protozoa Plasmodium spp., which has a significant global impact on human health. (1) The increasing resistance of P. falciparum strains to approved drugs highlights the urgent need for the discovery of new antimalarial candidates. Guanidine alkaloids emerged as promising natural products with antiparasitic activity. Batzelladines are tricyclic guanidine derivatives that exhibit potent biological activities, including antiparasitic. (2-3) In this investigation, we aimed at to investigate the parasitological profile of the natural alkaloid batzelladine L against P. falciparum, as well as of 43 synthetic guanidine derivatives as potential anti-plasmodial agents. The inhibitory activity of batzelladine L was first evaluated against chloroquine-sensitive P. falciparum 3D7 strain. The natural alkaloid exhibited P. falciparum inhibitory activity in the submicromolar range (IC503D7 = 0.4 ± 0.1 μM), consistent with the previous report on the antiplasmodial activity of batzelladine L against a FcB1 chloroquine-resistant P. falciparum strain (IC50 = 0.3 μM). (3) Furthermore, batzelladine L presented moderate cytotoxicity against HepG2 cells (IC50HepG2 = 14 μM) with a selectivity index (SI) of 35. We subsequently investigated the parasitological profile of batzelladine L. Assessment of time of action revealed that the compound is a fast-acting inhibitor, exhibiting pronounced activity against P. falciparum ring and trophozoite stages. Combination of batzelladine L with artesunate exhibited an antagonistic profile. Additionally, the inhibitory activity of batzelladine L was evaluated against a panel of P. falciparum resistant strains. Results indicated no cross-resistance with the Dd2 (RI = 1.5), K1 (RI = 2.0), and Dd2R_DSM265 (RI = 2.0) strains. Finally, we assessed the in vivo antimalarial activity of batzelladine L using P. berghei NK65 strain in an animal model. The treated group showed a 33% reduction in parasitemia at day 5 post-infection. Such promising results led us to develop the synthesis of batzelladine L simplified analogues. Therefore, 43 guanidine derivatives were synthesized and tested against the P. falciparum 3D7 strain. Among these derivatives, 24 exhibited significant antiplasmodial activity (IC503D7 ≤ 10 µM). One derivative RCPA37P displayed inhibitory activity in the similar range of batzelladine L (IC503D7 = 0.21 ± 0.08 μM) with improved selectivity against HepG2 cells (SI = 58). These findings suggest that both natural and synthetic guanidine derivatives hold promise as attractive compounds for the development of future lead candidates against malaria.

Referências

1 PHILLIPS, M. A. et al. Malaria. Nature Reviews Disease Primers, v. 3, p. 17050-1-17050-24, 2017. DOI: https://doi.org/10.1038/nrdp.2017.50.

2 RANI, N. Z. A.et al. Fused tricyclic guanidine alkaloids: insights into their structure, synthesis and bioactivity. Marine Drugs, v. 20, n. 9, p. 579-579-45, 2022. DOI: https://doi.org/10.3390/md20090579.

3 LAVILLE, R. et al. Bioactive guanidine alkaloids from two caribbean marine sponges. Journal of Natural Products, v. 72, n. 9, p. 1589-1594, 2009. DOI: https://doi.org/10.1021/np900244g.