Second generation, orally active, antimalarial, artemisinin-derived trioxane dimers with high stability, efficacy,...

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Artemisinin, a natural product, is a key antimalarial drug.
• Development of more potent and stable artemisinin derivatives is crucial for combating malaria and other diseases.
• Exploring novel chemical modifications of artemisinin can lead to compounds with improved therapeutic profiles.

Purpose of the Study:

• To synthesize novel C-10-carba trioxane conjugated diene dimers from artemisinin.
• To evaluate the antimalarial and anticancer properties of the synthesized dimers.
• To assess the stability and efficacy of these new compounds in comparison to existing drugs.

Main Methods:

• Two-step synthesis of artemisinin dimer 4 with 63% overall yield.
• Transformation of dimer 4 into phthalate dimer 5 via a 4 + 2-cycloaddition reaction.
• Further modification to yield bis-benzyl alcohol dimer 7 and its phosphorylated analogues 8 and 9.

Main Results:

• Bis-benzyl alcohol dimer 7 demonstrated 10-fold higher in vitro antimalarial potency than artemisinin.
• Dimer 7 showed superior oral (1.5x) and subcutaneous (37x) efficacy in rodents compared to sodium artesunate.
• Phthalate dimer 5 and bis-benzyl alcohol dimer 7 exhibited significant in vitro growth inhibition and selective killing of human cancer cells, including cervical cancer cells, without affecting normal cells. Both dimers are thermally stable.

Conclusions:

• Novel artemisinin dimers, particularly bis-benzyl alcohol dimer 7, possess significantly enhanced antimalarial activity and efficacy.
• These dimers display potent and selective anticancer properties against various human cancer cell lines.
• The synthesized dimers represent promising candidates for further development as antimalarial and anticancer therapeutics due to their improved potency, efficacy, and stability.