1,2,4-Trioxolane and 1,2,4,5-Tetraoxane Endoperoxides against Old-World Leishmania Parasites: In Vitro Activity and Mode of Action

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.

An overview on the antimalarial activity of 1,2,4‐trioxanes, 1,2,4‐trioxolanes and 1,2,4,5‐tetraoxanes

“…Their primary reason for development is to solve the discrepencies in current ART‐based front‐line treatment 214 . Furthermore, 1,2,4‐trioxolanes are much additional efficient than artesunate 3b and artemether 2a , both in vivo and in vitro 215,216 …”

“…214 Furthermore, 1,2,4-trioxolanes are much additional efficient than artesunate 3b and artemether 2a, both in vivo and in vitro. 215,216 F I G U R E 30 Geraniol-derived derivatives of The spiro adamantane moiety is required for AM action. The asymmetrical ozonides 158a-d also outperformed the more regularly utilized ozonides 158.…”

Bridged 1,2,4-Trioxolanes: SnCl4—Catalyzed Synthesis and an In Vitro Study against S. mansoni

“…Organic peroxides related to the natural peroxide Artemisinin and its semisynthetic derivatives are a promising class of compounds for medicinal chemistry due to their antimalarial [ 1 , 2 , 3 , 4 ], antileishmanial [ 5 , 6 ], antischistosomal [ 7 , 8 ], anticancer [ 9 , 10 , 11 ], antifungal [ 12 , 13 , 14 ], antitubercular [ 15 , 16 ], and antiviral [ 17 , 18 , 19 ] activities ( Figure 1 ). Among the synthetic peroxides, ozonides are the most attractive class.…”

Unravelling the Structure of Peroxides with Antiparasitic Activity: The Relative Impact of a Trioxolane or a Tetraoxane Pharmacophore on the Overall Molecular Structure

“…This approach has yielded the ozonide OZ439 (artefenomel, Figure 1), [9] which is currently on Phase IIb of clinical trials, [10,11] and the 1,2,4,5tetraoxane E209 (Figure 1), [7] a superior next-generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome PfK13-C580Y-dependent artemisinin resistance, the main liability of artemisinin derivatives nowadays. [12] Besides their impressive antimalarial activity, [7,8,13] 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes revealed other biological activities, namely anticancer, [14][15][16][17][18][19][20] antimycobacterial, [21,22] antiprotozoan, [17,[23][24][25] and antiparasitic. [26][27][28][29][30][31][32] Despite their potential medical and veterinary applications, fundamental studies on the structures of trioxolanes and tetraoxanes are scarce.…”