Eur. J. Med. Chem. (2026) 311: 118826. https://doi.org/10.1016/j.ejmech.2026.118826

Identification of Fluoro-methoxy-phenyl-substituted N-sulfonylpiperidine-mono-spiro-1,2,4,5-tetraoxanes as Multispecies-targeting Molecules

Tiwari M. K., Bakun P., Forest E., Bola J.-M., Murias M., Kucinska M., Zgoła-Grześkowiak A., Cicha E., Marczak Ł., Cavalier J.-F., Grellier P., Goslinski T.

Herein, we report a novel series of heterocyclic fluoro-methoxy-phenyl-substituted N-sulfonylpiperidine monospiro-1,2,4,5-tetraoxanes (5a-l; 50-93%) that have been successfully synthesised under metal-free and environmentally benign conditions. The inhibitory effects of all derivatives (5a-l) were determined in vitro on Plasmodium falciparum, Trypanosoma brucei, Mycobacterium, HeLa, and A2780 ovarian cancer cell cultures. The heterocyclic 1,2,4,5-tetraoxanes (5a-l; IC50 = 4.1-16.2 μM) displayed interesting micromolar antiplasmodial potential against chloroquine-resistant FcB1 strains of P. falciparum. Moreover, four representative analogues (5e, 5h, 5k, 5b) were evaluated in Danio rerio larvae, showing no lethality within the tested range, with sublethal morphological alterations observed at higher concentrations. As a result of a complex biological activity assessment, compounds with micromolar antiparasitic and antimycobacterial activities were identified, within an acceptable cytotoxicity range. Notably, the presented study constitutes the first evidence of a non-steroidal monomeric p-OCF3-Ph-based 2-fluoro-p-OMe-phenyl ring-substituted N-sulfonylpiperidine mono-spiro-1,2,4,5-tetraoxane (5j; Pf FcB1 IC50 = 5.5 μM, Tbb IC50 = 25.6 μM, M. tuberculosis H37Ra MIC50 = 40 μM) exhibiting efficient multispecies-targeting susceptibilities.