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Review
. 2016 Nov 1:10:3575-3590.
doi: 10.2147/DDDT.S118116. eCollection 2016.

Endoperoxide antimalarials: development, structural diversity and pharmacodynamic aspects with reference to 1,2,4-trioxane-based structural scaffold

Mithun Rudrapal  1 , Dipak Chetia  1
Affiliations
Review

Endoperoxide antimalarials: development, structural diversity and pharmacodynamic aspects with reference to 1,2,4-trioxane-based structural scaffold

Mithun Rudrapal et al. Drug Des Devel Ther. .

Abstract

Malaria disease continues to be a major health problem worldwide due to the emergence of multidrug-resistant strains of Plasmodium falciparum. In recent days, artemisinin (ART)-based drugs and combination therapies remain the drugs of choice for resistant P. falciparum malaria. However, resistance to ART-based drugs has begun to appear in some parts of the world. Endoperoxide compounds (natural/semisynthetic/synthetic) representing a huge number of antimalarial agents possess a wide structural diversity with a desired antimalarial effectiveness against resistant P. falciparum malaria. The 1,2,4-trioxane ring system lacking the lactone ring that constitutes the most important endoperoxide structural scaffold is believed to be the key pharmacophoric moiety and is primarily responsible for the pharmacodynamic potential of endoperoxide-based antimalarials. Due to this reason, research into endoperoxide, particularly 1,2,4-trioxane-, 1,2,4-trioxolane- and 1,2,4,5-teraoxane-based scaffolds, has gained significant interest in recent years for developing antimalarial drugs against resistant malaria. In this paper, a comprehensive effort has been made to review the development of endoperoxide antimalarials from traditional antimalarial leads (natural/semisynthetic) and structural diversity of endoperoxide molecules derived from 1,2,4-trioxane-, 1,2,4-trioxolane- and 1,2,4,5-teraoxane-based structural scaffolds, including their chimeric (hybrid) molecules, which are newer and potent antimalarial agents.

Keywords: 1,2,4-trioxane; antimalarial; endoperoxide; pharmacodynamic; pharmacophore; structural diversity.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Artemisinin and its first-generation derivatives.
Figure 2
Figure 2
Some important drugs used in combination with artesunate.
Figure 3
Figure 3
Some second-generation derivatives of artemisinin.
Figure 4
Figure 4
Some newer synthetic endoperoxides.
Figure 5
Figure 5
Newer aza and fluorinated endoperoxides.
Figure 6
Figure 6
1,2,4-Trioxane scaffold in artemisinin. Abbreviation: ART, artemisinin.
Figure 7
Figure 7
Some 1,2,4-trioxane-based antimalarials.
Figure 8
Figure 8
Some 1,2,4-trioxolane-based antimalarials.
Figure 9
Figure 9
Some 1,2,3,4-tetraoxane-based antimalarial agents.
Figure 10
Figure 10
Artemisinin hybrids.
Figure 11
Figure 11
Trioxaquines and trioxane–coumarin hybrids.
Figure 12
Figure 12
Some steroidal 1,2,4-trioxane hybrids.
Figure 13
Figure 13
Trioxalaquines and trioxolane–vinylsulfone hybrids.
Figure 14
Figure 14
Tetraoxaquines and related hybrid analogs.
Figure 15
Figure 15
Some 1,2,3,4-tetraoxane steroids.
Figure 16
Figure 16
Blood stages of malaria parasites. Abbreviation: RBC, red blood cell.
Figure 17
Figure 17
Hemoglobin degradation mechanism and enzymatic/nonenzymatic targets of antimalarial drug action. Abbreviations: FV, food vacuole; FP, ferriprotoporphyrin; PE, protease enzymes; FPdeg, FP degraded; Pfhrps, Plasmodium falciparum histidine-rich proteins; HP, heme polymerase; SOD, superoxide dismutase; CAT, catalase; GSH, reduced glutathione; GSSG, oxidized glutathione; GPx, glutathione peroxidase.
Figure 18
Figure 18
Mechanism of action of endoperoxide antimalarials. Abbreviation: ART, artemisinin.
Figure 19
Figure 19
Heme activation reactions – generation of free radicals.
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