Joëlle Mayrargue

Synthesis and in vitro Trichomonacidal activities of some new dialkylperoxides and 1,2,4-trioxanes

Two series of three trioxanes and 18 disubstituted peroxides were synthesised and evaluated for their in vitro trichomonacidal activity against Trichomonas vaginalis. The most active compound, 2-methylprop-2-yl 2-methoxyeth-1-yl peroxide exhibited an IC(50) value of 1.0+/-0.2 microM whereas other dialkyl peroxides had various IC(50) values which could not be correlated to their molecule structure. The best compound was about five times more active than metronidazole. The amount of generated oxygen or free radicals cannot explain completely the activity suggesting another way of action for these compounds on T. vaginalis.

Synthesis and antimalarial activity of 2-methoxyprop-2-yl peroxides derivatives

2-Methoxyprop-2-yl peroxides were synthesized and evaluated in vitro against Plasmodium falciparum. These acyclic artemisinin-related peroxides revealed moderate to good activity but were devoid of alkylating property towards the synthetic model of heme Mn(II)-TPP.

Synthesis of cardamom peroxide analogues by radical cyclization of hydroperoxyalkenes

Three pinenic hydroperoxides were synthesized according to the Dussault method. Two of them could cyclize under radical conditions to give the exo-trig isomer as a single regioisomer. Only five- and six-member ring peroxides were obtained, whereas none of the possible seven-member ones was observed. This strategy could be employed in the total synthesis of cardamom peroxide.

Alkylation of manganese(II) tetraphenylporphyrin by a synthetic antimalarial trioxane

The synthesis and the antimalarial activity of a new kind of polycyclic 1,2,4-trioxanes are reported. The alkylation of the heme model MnIITPP by the biologically active (IC 50 = 320 nmol L-1) hemiperketal 2 is presented.

Alkylating properties of synthetic trioxanes related to artemisinin

The synthesis and reactivity toward a haem model of trioxane derivatives bearing a 1,2-dioxacyclohexane cycle instead of a 1,2-dioxacycloheptane as in artemisinin, and lacking the lactone ring, are reported. The fact that a trioxane able to generate a C-centred radical (without alkylating ability toward a haem model) was devoid of toxicity against Plasmodium also suggests that the efficiency of antimalarial trioxanes is not due to an oxidant stress.

Synthesis of 4-trifluoromethyl-1,2,4-trioxanes, simplified analogues of artemisinin

Abstract A short synthesis of C4 trifluoro-substituted 1,2,4-trioxanes with antimalarial potential is reported. This is the first example using a trifluorosilylated enol ether function as a protective group for a trifluoromethyl carbonyl.

TRIFLUOROMETHYLKETONES CHEMISTRY : EFFICIENT ACCESS TO SILYL ENOL ETHERS OR SILYL CARBINOLS USING LITHIUM DIISOPROPYLAMIDE

Abstract Lithium diisopropylamide, reacts with trifluoromethylketones either as a base in polar solvents or as a hydride donor in hexane. In the presence of tert -Butyldimethylsilyl chloride, Lithium diisopropylamide allows the transformation of trifluoromethylketones into silyl enol ethers or silyl carbinols using an appropriate solvent.

Synthesis and trichomonacidal activity of perketals and hydroperoxides

Some perketals were synthesized by the Dussault procedure using simple bromides and 2-methoxyprop-2-yl hydroperoxide. Treatment with acetic acid gave the corresponding hydroperoxides. Both perketals and hydroperoxides were tested in vitro as trichomonacidal agents. Most of them exhibited very good activities. The most powerful compound was 2-methoxyprop-2-yl hexadec-l-yl peroxide which exhibited an IC50 value of 0.51 microM being 10 times more effective than the reference compound Metronidazole.

Diastereoselective Synthesis of a Simplified Analogue of Artemisinin with a Substituted Ring Junction

A tricyclic 1,2,4-trioxane was synthesised in a diastereoselective way via a photooxygenation of an enol ether readily derived from a chiral ß-ketoester in four steps. Introduction Artemisinin I is the active principle isolated from the Qinghao (Artemisia annua 1.(1)), which was used to treat malaria in traditional Chinese herbal medicine. Important biological activities displayed by artemisinin and its analogues have stimulated the development of synthetic strategies for the preparation of this class of sesquiterpene endoperoxides (2). Numerous modifications of artemisinin have been made, principally on the lactone ring, in order to increase biological activity against drug resistant forms of malaria, notably Plasmodium falciparum. Examination of the structure-activity relationship suggests that the 1,2,4-trioxane system is essential, whereas the lactone ring is not crucial (la,3). Curiously, no angular substitution at the A-C ring junction has ever been undertaken.

Erratum to “Synthesis and in vitro Trichomonacidal activities of some new dialkylperoxides and 1,2,4-trioxanes”: [Eur. J. Med. Chem. 36 (10) (2001) 837–842

Erratum to ‘‘Synthesis and in vitro Trichomonacidal activities of some new dialkylperoxides and 1,2,4-trioxanes’’ [Eur. J. Med. Chem. 36 (10) (2001) 837–842 Boris Camuzat-Dedenis , Olivier Provot *, Laure Cointeaux , Viviane Perroux , Jean-Francois Berrien , Christian Bories , Philippe M. Loiseau , Joelle Mayrargue a a Laboratoire de Chimie Organique, ESA 8076 BioCIS, Faculte de Pharmacie, F-92296 Châtenay-Malabry cedex, France b Laboratoire de Parasitologie EA 398, Faculte de Pharmacie, F-92296 Châtenay-Malabry cedex, France www.elsevier.com/locate/ejmech