Schistosomiasis chemotherapy.

After malaria, schistosomiasis (or bilharzia) is the second most prevalent disease in Africa, and is occurring in over 70 countries in tropical and subtropical regions. It is estimated that 600 million people are at risk of infection, 200 million people are infected, and at least 200,000 deaths per year are associated with the disease. All schistosome species are transmitted through contact with fresh water that is infested with free-swimming forms of the parasite, which is known as cercariae and produced by snails. When located in the blood vessels of the host, larval and adult schistosomes digest red cells to acquire amino acids for growth and development. Vaccine candidates have been unsuccessful up to now. Against such devastating parasitic disease, the antischistosomal arsenal is currently limited to a single drug, praziquantel, which has been used for more than 35 years. Because the question of the reduction of the activity of praziquantel was raised recently, it is thus urgent to create new and safe antischistosomal drugs that should be combined with praziquantel to develop efficient bitherapies.

Design and synthesis of new antioxidants predicted by the model developed on a set of pulvinic acid derivatives.

Antioxidative activity expressed as protection of thymidine has been investigated for a set of 30 pulvinic acid derivatives. A combination of in vitro testing and in silico modeling was used for synthesis of new potential antioxidants. Experimental data obtained from a primary screening test based on oxidation under Fenton conditions and by an UV exposure followed by back-titration of the amount of thymidine remaining intact have been used to develop a computer model for prediction of antioxidant activity. Structural descriptors of 30 compounds tested for their thymidine protection activity were calculated in order to define the structure-property relationship and to construct predictive models. Due to the potential nonlinearity, the counter-propagation artificial neural networks were assessed for modeling of the antioxidant activity of these compounds. The optimized model was challenged with 80 new molecules not present in the initial training set. The compounds with the highest predicted antioxidant activity were considered for synthesis. Among the predicted structures, some coumarine derivatives appeared to be especially interesting. One of them was synthesized and tested on in vitro assays and showed some antioxidant and radioprotective activities, which turned out as a promising lead toward more potent antioxidants.

Synthesis and antioxidant properties of pulvinic acids analogues.

The synthesis of three types of pulvinic acid analogues, using a diversity-oriented strategy starting from a single compound, dimethyl l-tartrate, is described. Lacey-Dieckmann condensation, alcohol dehydration and Suzuki-Miyaura cross-couplings were employed in the course of the analogues syntheses. The evaluation of the antioxidant properties of the 28 synthesized analogues was carried out using antioxidant capacity assays (protection of thymidine and ß-carotene) and free radical scavenging assays (DPPH radical and ABTS radical cation). This allowed to assess the relative influence of the groups bonded to the tetronic ring and to the exocyclic double bond on the activity, as well as the importance of this exocyclic double bond. It was shown that the presence of an electron-donating group on the 3-position of the tetronic ring had a beneficial effect. It was shown in several assays that the presence of the exocyclic bond was not crucial to the activity.