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)
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)
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).
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 0º 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...