Safety evaluation of the migration in oily cosmetic products in contact with plastic packagings

International audienc

Selection of a trioxaquine as an antimalarial drug candidate

Trioxaquines are antimalarial agents based on hybrid structures with a dual mode of action. One of these molecules, PA1103/SAR116242, is highly active in vitro on several sensitive and resistant strains of Plasmodium falciparum at nanomolar concentrations (e.g., IC50 value = 10 nM with FcM29, a chloroquine-resistant strain) and also on multidrug-resistant strains obtained from fresh patient isolates in Gabon. This molecule is very efficient by oral route with a complete cure of mice infected with chloroquine-sensitive or chloroquine-resistant strains of Plasmodia at 26–32 mg/kg. This compound is also highly effective in humanized mice infected with P. falciparum. Combined with a good drug profile (preliminary absorption, metabolism, and safety parameters), these data were favorable for the selection of this particular trioxaquine for development as drug candidate among 120 other active hybrid molecules

Novel Endoperoxide-Based Transmission-Blocking Antimalarials with Liver- and Blood-Schizontocidal Activities

[Image: see text] In a search for effective compounds against both the blood- and liver-stages of infection by malaria parasites with the ability to block the transmission of the disease to mosquito vectors, a series of hybrid compounds combining either a 1,2,4-trioxane or 1,2,4,5-tetraoxane and 8-aminoquinoline moieties were synthesized and screened for their antimalarial activity. These hybrid compounds showed high potency against both exoerythrocytic and erythrocytic forms of malaria parasites, comparable to representative trioxane-based counterparts. Furthermore, they efficiently blocked the development of the sporogonic cycle in the mosquito vector. The tetraoxane-based hybrid 5, containing an amide linker between the two moieties, effectively cleared a patent blood-stage P. berghei infection in mice after i.p. administration. Overall, these results indicate that peroxide-8-aminoquinoline hybrids are excellent starting points to develop an agent that conveys all the desired antimalarial multistage activities in a single chemical entity and, as such, with the potential to be used in malaria elimination campaigns

Computer-Aided Drug Discovery from Marine Compounds: Identification of the Three-Dimensional Structural Features Responsible for Antimalarial Activity

An integrated computational approach, based on molecular dynamics/mechanics, semi-empirical, and DFT calculations as well as dynamic docking studies, has been employed to gain insight into the mechanism of action of new antimalarial agents characterized by the scaffold of the marine compounds plakortin and aplidinone. The results of this approach show that these molecules, after interaction with Fe(II), likely coming from the heme molecule, give rise to the formation of radical species, that should represent the toxic intermediates responsible for subsequent reactions leading to plasmodium death. The three-dimensional structural requirements necessary for the activity of these new classes of antimalarial agents have been identified and discussed throughout the chapter