Introduction 3
Definition and background 3
Structure and properties of Artemisinin 4
Structure 4
Properties of Artemisinin 5
Synthesis of artemisinin 5
Activation of artemisinin 7
Mechanism of Artemisinin action in the body 8
Side effect 10
Conclusion 10
References 13
- Table of Figures
Figure 1: Structure of Artemisinin2 4
Figure 2: A synthetic strategy of chemical synthesis from cyclohexenone. 7,9,10 6
Figure 3: Reductive scission model: Homolytic mechanisms of bioactivation of the endoperoxide bridge of artemisinin and derivatives 8
Figure 4: Proposed mechanism for artemisinin mediated lipid peroxidation of membranes 3 9
Figure 5: Acting mechanism between heme& Artemisinin.3, 10 10
- Introduction
Artemisinin is one of the most considerable drugs discovered for anti-malarial properties. This new substance has with unique properties that make it interesting for fundamental studies, as well as future applications in pharmaceuticals. Its accurate anti-malarial machinery is still unknown. Besides artemisinins, some other derivatives are also synthesized with different backbones, some of which demonstrated similar or even higher anti-malarial effects2. This essay aims to study the Artemisinin in detail, from its structural and physical properties to the synthesis and mode of action in Malaria. The essay is divided into several sections. The first part of the essay describes the background, definition, molecular formula and structure of Artemisinin with its additional properties. In the next part, the synthesis of Artemisinin is detailed. The mode of activation of Artemisinin inside parasitic body and the targets of artemisinin derivatives are discussed.
- Definition and background
Artemisinin is a drug that is extracted from the plant Artemisia Annua, an active ingredient of traditional Chinese herbal medicine used in malaria for more than thousand years. The unique pharmacological perspective and the tremendous paucity of the natural ingredient with its complex structure provoked to analyze the whole synthesis of Artemisinin 1, 3, 4. The successful isolation of artemisinin from the plant, and its structural recognition were presented to the world in 1979. Excellent anti-malarial efficiency, extraordinary chemical structure and low natural production led to the exploration of substitutive chemical synthesis method. These efforts resulted in the thriving semi-synthesis of this complex from artemisinic acid and a complete synthesis method in 1983. 1, 2, 5
- Structure and properties of Artemisinin
Structure
Figure 1: Structure of Artemisinin2
Artemisinin 1 is a sesquiterpene endoperoxide lactone molecule with an endoperoxide, 1,2,4-trioxane ring. It is a natural drug for treating malaria, particularly against cerebral and drug-resistant malaria.6 The architectural complexity is due to the presence of seven chiral centers, with tetracyclic framework attached with endoperoxide unit.1,6 The basic chemistry of Artemisinins involve C-O, C = O, CH, CH2, CH3, C – O – C and C – O – O.
The NMR studies suggest that the functional group of Artemisinin plays the main role in its pharmacokinetics. They demonstrated that peroxide and ether as the main functional groups that are involved in reactions. The iron (II)–heme activates the peroxide functioning of the artemisinin and during the process alkylation occurs at meso positions through a C4-centered radical. The NMR studies have illustrated that adducts of α-, β-, and δ-meso positions are major products while alkylation of γ-meso position is minor 6.
The endoperoxide, which is unsymmetrical, might be responsible for activation against malaria. The IUPAC name of arimisinin is (4S,5R,8S,9R,12S,13R)-1,5,9-Trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13] hexadecan-10-one and the empirical formula (C15H22O5).
Properties of Artemisinin
Artemisinin is a crystalline compound that shows poor solubility in water and oil while it shows instability in the presence of acid and alkali. Due to low solubility in water or oil, its carbonyl group is reduced to achieve its derivatives. Their derivative such as artesunate shows high water solubility and artemether and arteether exhibit oil solubility. That’s why derivatives demonstrate greater antimalarial activity 2.
Artemisinin is effectual against asexual and sexual both type of parasitic stages. It has great potential of killing malaria parasites with reduction ratio of around 10,000 per erythrocytic cycle.
Artemisinin is the fastest drugs against all life cycle stages of malaria parasites, but it has a very small elimination half-life (∼1 h). 1,9
- Synthesis of artemisinin
As mentioned previously, artemisinin is extracted naturally from the Artemisia plant and then, simply purified the product by crystallization process 2. Further, it can be synthesized in the laboratory using various chemical methods. Figure 2 below describes the overview of chemical synthesis of artemisinin via cyclohexenone7,10.
Figure 2: A synthetic strategy of chemical synthesis from cyclohexenone. 7,10,12
- Activation of artemisinin
As mentioned earlier, in order to make artemisinin an effective treatment for malaria, the Endoperoxide Bridge of artemisinin should be activated. The key of the activation is the reduction of the Endoperoxide Bridge by reducing agent in order to produce oxygen centered free radicals that are subsequently converted to the analog deoxoartemisinin3. The reductive agent can be haem F+2 or other sources of ferrous ions within the malaria parasite 3.
Artemisinin has unsymmetrical endoperoxide that allows the oxygen atoms of peroxide linkage to associate with ferrous ions through two routes (figure 3). First, the correlation of Fe+2 ions with oxygen-1 gives the oxy radical which generates an intermediate primary carbon-centered radical (12a). Then, this intermediate compound might produce the ring-contracted tetrahydrofuran (12b).3 Second, while correlation with oxygen-2 gives oxygen radical species which could produce an intermediate secondary carbon-centered radical (12c) through a 1,5-H shift. Again, this intermediate produces a final stable product called hydroxydeoxoartemisinin (12d). 3 The research suggests that each carbon radical species act as a mediator in antimalarial activity. It is also predicted that the alkylation of bio-macromolecules for example haem, particular proteins and several other targets by these reactive carbon-radical intermediates might result in the decease of malaria parasites .3
Figure 3: Reductive scission model: Homolytic mechanisms of bioactivation of the endoperoxide bridge of artemisinin and derivatives
Mechanism of Artemisinin action in the body
As any anti-malaria, there are many proposed hypotheses which describe the action of artemisinin mechanism inside the body. As mentioned previously, the activation of artemisinin gives carbon-radical intermediates that effectively reacts bio-macromolecules in the different mechanism 12.
In this essay, the bio-macromolecules interactions with artemisinin are dealt with three targets that are:
1- Protein as target
2- Heme
3- Mitochondria
Protein targets: The studies have shown that the artemisinin associates with parasitic proteins through alkylation process. For example, the discovery of cysteine protease adducts of artemisinin derived radicals has suggested that the alkylation of cysteine, which is a kind of protein, might hinder the parasitic proteins function. Also, it could inhibit the function of derivative enzymes of cysteine that damage the hemoglobin inside human's body. 3, 13
Figure 4: Proposed mechanism for artemisinin mediated lipid peroxidation of membranes 3
Target of the heme polymerization: In this mechanism, heme is produced by degradation of hemoglobin. Then, it reacts with Artemisinin-derived free radicals to form heme-artemisinin adducts. The product undergoes demetallation to remove iron metal. The final product is toxic for parasite. 3, 13
Figure 5: Acting mechanism between heme& Artemisinin.3, 11
Mitochondria: The research has noticed the effective role of mitochondria to active the artemisinin. The activation process is performed by transformation of the electron chain to artemisinin. Then, the artemisinin generates reactive oxygen species (ROS) which disrupt the parasite mitochondria.13
- Side effect
Artemisinin drugs have extremely short activity (half-life) so it needs a longer period to be effective. Thus, a prolonged usage of a drug multiple times a day may exhibit some effects7, 10, 15. 7, 10, 15
Like any drug, artemisinins has side effects that are similar to symptoms of malaria such as vomiting, anorexia, dizziness and nausea. Another side effect of artemisinin is liver inflammation that occurs because a prolonged use of high doses of artemisinins14, 16.
- Conclusion
This essay has highlighted the structure and properties of Artemisinin with its background. It also has discussed many of the interesting properties of this unique drug and its mode of action inside body. Pharmaceutical studies indicate that Artemisinins are very significant drugs and have been used for a long time to fight malaria. Their ability to kill the parasite has put it in the superior drug category. Apart from the natural extraction from origin plant, many semi-synthetic methods are evolved to increase the production of such a valuable drugs. The use of ammonium molybdate catalyst in the semi synthesis delivers the comparatively high yield of Artemisinin. Though, more thorough studies are required to understand the parasitic clearance kinetics and the resistance activity of this drug.
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Please rearrange again follow the aliphatic.
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