D-Glucose-Derived 1,2,4-Trioxepanes: Synthesis, Conformational Study, and Antimalarial Activity

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Parasitology

Background:

• 1,2,4-trioxepanes are a class of organic compounds with potential biological activities.
• D-glucose serves as a chiral starting material for synthesizing complex organic molecules.
• Drug resistance in malaria necessitates the development of novel antimalarial agents.

Purpose of the Study:

• To synthesize novel, enantiomerically pure 1,2,4-trioxepanes from D-glucose.
• To investigate the conformational properties of these synthesized compounds.
• To evaluate the in vitro antimalarial activity of the new derivatives.

Main Methods:

• Enantioselective synthesis of 1,2,4-trioxepanes.
• Low-temperature Nuclear Magnetic Resonance (NMR) spectroscopy for conformational analysis.
• Density Functional Theory (DFT) calculations to support conformational studies.
• In vitro antimalarial activity assays against Plasmodium falciparum.

Main Results:

• Successful synthesis of enantiomerically pure 1,2,4-trioxepanes (10a,b/11a,b) from D-glucose.
• Conformational analysis revealed distinct behaviors, corroborated by DFT calculations.
• The adamantyl derivative 11b exhibited low micromolar IC50 values.
• Compound 11b showed particular potency against the W2 chloroquine-resistant Plasmodium falciparum strain (IC50 = 0.15 ± 0.12 μM).

Conclusions:

• Novel 1,2,4-trioxepanes derived from D-glucose possess promising antimalarial properties.
• The adamantyl derivative 11b represents a potential lead compound for further antimalarial drug development.
• Understanding the structure-activity relationship is crucial for optimizing antimalarial efficacy.