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  3. Design, synthesis and in vitro assessment of di-/tri-methoxy-aryl-substituted mono-spiro-1,2,4,5-tetraoxanes for antiplasmodial and anticancer use

Design, synthesis and in vitro assessment of di-/tri-methoxy-aryl-substituted mono-spiro-1,2,4,5-tetraoxanes for antiplasmodial and anticancer use

  • Eur J Med Chem. 2025 Dec 15:300:118159. doi: 10.1016/j.ejmech.2025.118159.
Mohit K Tiwari 1,  Malgorzata Kucinska 2,  Agnieszka Zgoła-Grześkowiak 3,  Marziyeh Raeispour 2,  Marek Murias 2,  Philippe Grellier 4,  Łukasz Marczak 5,  Tomasz Goslinski 6
Affiliations

Affiliations

  • 1 Poznan University of Medical Sciences, Department of Chemical Technology of Drugs, Rokietnicka 3, Poznań, 60-806, Poland. Electronic address: [email protected].
  • 2 Poznan University of Medical Sciences, Department of Toxicology, Rokietnicka 3, Poznań, 60-806, Poland.
  • 3 Institute of Chemistry and Technical Electrochemistry, Poznan University of Technology, Berdychowo 4, Poznań, 60-965, Poland.
  • 4 UMR7245 MCAM, CNRS, National Museum of Natural History, CP 52, 57 rue Cuvier, Paris, 75005, France.
  • 5 Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, Poznań, 61-704, Poland.
  • 6 Poznan University of Medical Sciences, Department of Chemical Technology of Drugs, Rokietnicka 3, Poznań, 60-806, Poland.
PMID: 40975009 DOI: 10.1016/j.ejmech.2025.118159
Abstract

In the present article, a library of novel non-symmetrical di-/tri-methoxy-aryl-substituted mono-spiro-1,2,4,5-tetraoxanes (5a-m) has been prepared from methyltrioxorhenium(VII) complex-catalysed two-step one-pot direct oxidation approach. The in vitro antiplasmodial and cytotoxic potentials of all non-symmetrical di-/tri-methoxy-aryl-substituted mono-spiro-1,2,4,5-tetraoxanes (5a-m) have been assessed against the chloroquine-resistant FcB1 strain of Plasmodium falciparum, HeLa, A549 and A2780 Cancer cells. The in vitro biological assessment has afforded eight di-/tri-methoxy-aryl-substituted mono-spiro-1,2,4,5-tetraoxane derivatives (5b-e, 5g, 5i, 5k-l) with nanomolar antiplasmodial activity (IC50 = 34-91 nM and Selectivity Index = 109-2900). Along with this, two tri-OMe-aryl substituted mon-spiro-1,2,4,5-tetraoxane analogues (5i and 5l) have also shown dual potency with strong antiplasmodial (5i, IC50 = 46 nM; 5l, IC50 = 48 nM), and in vitro micromolar cytotoxicity against the A2780 ovarian Cancer (5i, IC50 = 3.82 μM; 5l, IC50 = 1.98 μM) and HeLa cells (5i, LD50 = 10.85 μM; 5l, LD50 = 5.8 μM). In addition, potential drug-target interactions prediction for representative compounds (5d, 5i, and 5l) has been examined using different computational-based techniques. Through this study, the selective incorporation of functionalized di-/tri-methoxy-aryl moieties on the mon-spiro-1,2,4,5-tetraoxane skeleton has proved efficient in improving the overall biological activities of the resulting molecules.

Keywords

Antiplasmodial; Cytotoxicity; Structure-activity relationship; Tetraoxanes.

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