Abstract
Leishmaniasis remains one of the ten Neglected Tropical Diseases with significant morbidity and mortality in humans. Current treatment of visceral leishmaniasis is difficult due to a lack of effective, non-toxic, and non-extensive medications. This study aimed to evaluate the selectivity of 12 synthetic endoperoxides (1,2,4-trioxolanes; 1,2,4,5-tetraoxanes) and uncover their biochemical effects on Leishmania parasites responsible for visceral leishmaniasis. The compounds were screened for in vitro activity against L. infantum and L. donovani and for cytotoxicity in two monocytic cell lines (J774A.1 and THP-1) using the methyl thiazol tetrazolium assay. Reactive oxygen species formation, apoptosis, and mitochondrial impairment were measured by flow cytometry. The compounds exhibited fair to moderate anti-proliferative activity against promastigotes of the 2 Leishmania species, with IC50 values ranging from 13.0 ± 1.7 µM to 793.0 ± 37.2 µM. Tetraoxanes LC132 and LC138 demonstrated good leishmanicidal activity on L. infantum amastigotes (IC50 13.2 ± 5.2 and 23.9 ± 2.7 µM) with low cytotoxicity in mammalian cells (SIs 22.1 and 118.6), indicating selectivity towards the parasite. Furthermore, LC138 was able to induce late apoptosis and dose-dependent oxidative stress without affecting mithocondria. Compounds LC132 and LC138 can be further explored as potential antileishmanial chemotypes.
Funder
Fundação para a Ciência e Tecnologia
Subject
Drug Discovery,Pharmaceutical Science,Molecular Medicine
Cited by
5 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
1. Bridged 1,2,4-Trioxolanes: SnCl4—Catalyzed Synthesis and an In Vitro Study against S. mansoni;Molecules;2023-06-22
2. An overview on the antimalarial activity of 1,2,4‐trioxanes, 1,2,4‐trioxolanes and 1,2,4,5‐tetraoxanes;Medicinal Research Reviews;2023-05-24
3. Integrated computational and experimental approach for novel anti-leishmanial molecules by targeting Dephospho-coenzyme A kinase;International Journal of Biological Macromolecules;2023-03
4. Synthesis, Structure and Antileishmanial Evaluation of Endoperoxide–Pyrazole Hybrids;Molecules;2022-08-24
5. Unravelling the Structure of Peroxides with Antiparasitic Activity: The Relative Impact of a Trioxolane or a Tetraoxane Pharmacophore on the Overall Molecular Structure;ChemPlusChem;2022-08