Endoperoxides as Antimalarials: Development, Structural Diversity, and Pharmacodynamic Aspects of 1,2,4,5-Tetraoxane-Based Structural Scaffolds

Abstract

Malaria poses a serious threat to human life and is prevalent in tropical and subtropical areas across the globe. Drugs such as quinine, chloroquine (a synthetic version of quinine), artemisinin, and its derivative compounds have been used to treat malaria. Developing highly effective chemical scaffolds with minimal toxicity is necessary because malarial parasites have become resistant to existing drugs. In this context, 1,2,4,5-tetraoxanes have emerged as a crucial framework with notable antimalarial properties. To improve the effectiveness and combat resistance to various antimalarial drugs, 1,2,4,5-tetraoxanes have been combined with a variety of alicyclic, aryl, heteroaryl, and spiro groups including steroid-based, aminoquinoline-based, dispiro-based, triazine-based, diaryl-based, and piperidine-based 1,2,4,5-tetraoxanes. We provide an overview of the synthesis and most important in vitro and in vivo investigations carried out on hybrids based on 1,2,4,5-tetraoxane as antimalarial drugs. The future development of malaria treatment may be influenced by the structural changes in different hybrids of 1,2,4,5-tetraoxane. 1 Introduction 2 Synthetic Methods for Tetraoxanes 3 Antimalarial Activities of Tetraoxane Derivatives 3.1 Cycloalkanone-Based Tetraoxanes 3.2 Steroid-Based Tetraoxanes 3.3 Adamantane-Based Tetraoxanes 3.4 Dispiro-Based Tetraoxanes 3.5 Diaryl-Based Tetraoxanes 3.6 Di-adamantane-Based Tetraoxanes 3.7 Benzylamino- and Aryloxy-Based Tetraoxanes 3.8 Aminoquinoline-Based Tetraoxanes 3.9 2-Cyanopyrimidine-Based Tetraoxanes 4 Mannich Base Based Tetraoxanes 4.1 N -Sulfonylpiperidine-Based Tetraoxanes 4.2 N -Benzoylpiperidine-Based Tetraoxanes 5 Mechanism of Action of Dispiro-1,2,4,5-tetraoxanes 6 Conclusion. © 2025. The Author(s). SynOpen.