Artemisinin An Anti-Malaria Essay, Research Paper

INTRODUCTION

The number people affected by malaria is increasing enormously. This increasing is due to the novel drug resistant variants of the parasite that causes malaria the Plasmodium.

This resistance is a consequence of the massive use of the quinoline-related drugs over the last decades. In this scenario, it became important to search for new drugs, active against novel biochemical parasite targets.

The drug known as artemisin or Qinghaosu (1), is a result of Chinese government campaign, to search for new active drugs against malaria, in Chinese medicinal plants.

In the general mechanism accepted for the action of artemisin, the free haem group, obtained during the haemoglobin digestion is proposed to catalyse the formation of oxyl radicals, by oxidation of the Fe(II) to Fe(III) and the reduction of the endoperoxide bond. These oxyl radicals rearrange in to C-centred radicals that are cytotoxic to the parasite by alkylation of vital parasite proteins.

In the experiments directed in Liverpool, the first step was to try to synthesise novel artemisin derivatives and then to do a biomimetic study, with these compounds and the iron salt FeCl.

In the first experiment carried, it was tried to synthesise an ether (2) of the dihydroartemisin (3) and tetrazol chloride (4), using a method developed by University of Algarve Organic Chemistry group (see scheme 1)

Scheme 1

In the following experiments, and using a different methodology, it was tried to synthesise, with artemisin benzoate (5) and p-trifluoromethoxi phenol (6) as starting material, the trifluoromethoxi phenol substituted compound (7) (see scheme 2)

Scheme 2

At last, it was done a biomimetic study, reacting the obtained compound with the iron salt FeCl (scheme 3), originating two different products: the one resulting from the formation of a primary carbon centred radical (8); and from the formation of a secondary C-centered radical (9).

Scheme 3

EXPERIMENTAL SECTION AND RESULTS

Experiment I: Synthesis of Compound 2

The tetrazole chloride (0,12 g, 0,67 mmol) was added to a solution of dihydroartemisin and NaH (0,053 mmol) in dried tetrahydrofuran. The solution was stirred for 1 hour.

The T.L.C. show that after this time, there wasn t any product on the reaction pot and the reaction should stay longer stirring

Experiment II: Synthesis of Compound 7

A solution of benzoate (0.409, 1mmol) in anhydrous dychlorometane (5 ml) was added to a mixture of p-trifluoromethyl phenol (0.811, 5 mmol) and ZnCl2 (0.1759, 1.25 mmol) in anhydrous dychloromethane (4 ml), at 0| C..

The reaction was stirred for 1 hour and 15 minutes and followed by T.L.C. using as eluent a solution of 75% hexane, 25% ethyl acetate.

The reaction was then, diluted with ethyl acetate and washed 3 times with a solution of 5% of citric acid, saturated aqueous solution of Sodium hydrogencarbonate and dried with magnesium sulphate. The solvent was evaporated to dryness and the desired product was isolated using a silica gel flash chromatography column (with the same eluent used on the T.L.C.), recristalized, and was done an N.M.R. spectroscopy.

The yield of this reaction was 19,7%.

Experiment III: Synthesis of Compound 7

The former procedure was repeated as previously described but in this experiment, the reaction was stirred at 0|C. for 2 hours, and left stirring during the night at room temperature. The eluent used in the T.L.C. and in the silica flash chromatography column was also changed. It was used a solution of 85% of toluene, 15% of dychloromethane.

In this case there wasn t a great improve in the yield (33.3%), so the next step will be to use a greater amount of the Lewis acid.

Experiment IV: Synthesis of Compound 7

The former procedure was repeated as previously described but in this experiment, it was used 5mmol of the Lewis acid (ZnCl2) and the reaction was stopped after two hours.

The eluent used in the T.L.C. and in the silica flash chromatography column was also changed. It was used a solution of 75% of dychloromethane and 25% of hexane.

In the present experiment, the yield was 67,7%.

Experiment V: Isomerization of the compound 7

The FeCl (68 mg, 0,33 mmol) was added to a solution of the compound III (150 mg, 0,34 mmol) in acetonitrile and was stirred for 45 minutes. The reaction was followed by T.L.C. using 60% toluene, 40% dychloromethane as eluent.

The solution was filtered with celite, washed with dychloromethane and ethyl acetate and evaporated until dryness.

The oil collected was purified using a silica gel flash chromatography column with the same eluent.

Only a small amount of product was isolated since it seemed like the products interact with the silica gel.

Experiment VI:

The former experiment was repeated, but to isolate the product, since it was suspected that the resulting products somehow interact with the silica gel a neutral alumina column was used with a solution of 80% petroleum ether, 20% ethyl acetate as eluent.

At list one of the products was isolated but the yield was not determined.

ACKNOWLEDGMENTS

I wish to thank to:

Professora Lurdes and Professor Amadeu, not only for the contribution that made this great opportunity happen, but also for all patience, assistance and knowledge given me during the last year.

Dr. Storr and Dr. Paul O Neill whose kindness, sympathy, comprehension and support, made this dream possible.

Rui, Ricardo, Steve, Vick, Tatiana and Ollie for all the help and friendship.

I also would like to thank to the University of Liverpool for allowing me to use all the facilities.