Antiparasitic compounds from a library of N-benzenesulfonyl derivatives of heterocycles.

MIANA, GE., VERA, DMA., MAZZIERI, MR.

Punta Ballena

Simposio; International Symposium "Thiol Metabolism and Redox Regulation of Cellular Functions".; 2011

Instituto Pasteur de Montevideo. Universidad de la República Uruguay

ANTIPARASITIC COMPOUNDS FROM A LIBRARY OF N-BENZENESULFONYL DERIVATIVES OF HETEROCYCLES Miana G E1, Vera DMA2, Mazzieri M R1 1 Dto Farmacia, Fac. Cs Químicas, Universidad Nacional Córdoba, Haya de la Torre esq.Medina Allende. Ciudad Universitaria. 5000. Córdoba. Argentina. 2 Dto Química, Fac. Cs Exactas y Naturales, Universidad Nacional Mar del Plata, Funes 3350.7600. Mar del Plata. Buenos Aires. Argentina. Discovery of compounds with anti-trypanosome activity is the aim of this project. The fragment based drug design strategy was used to generate a chemical library of N-benzenesulfonyl derivatives of heterocycles; all the compounds qualify as drug like. Currently, 109 derivatives were synthesized and the library is enlarging continuously. The compounds already prepared were assayed for in vitro anti-trypanosome activity; six of them showed IC50 (10M) with good cytotoxicity, and were selected as prototypes1. To go further in the optimizing step, we are trying to carry out structure-activity relationship (SAR) and Molecular Modeling studies. The project also includes virtual screening, by docking/scoring strategy, integrated with in vitro biological determinations and reducing properties of the compounds. For molecular docking, we have selected Trypanothione Reductase and Cysteine protease,both consider promising target for the design of new drugs with activity against Trypanosome cruzi. Furthermore, Trypanothione Reductase is the central enzyme in redox balance that is mantained by the dithiol trypanothione. Trypanothione counteracts environmental oxidative stress through a variety of protective oxidative reactions2. We expect that results from the described integrated studies will help to find the best analogues and shed light on the action mode of new active compounds. References: 1- Pagliero RJ. El grupo bencenosulfonilo en el diseño racional de drogas [tesis doctoral]. Córdoba, Argentina. Fac. de Cs Químicas, UNC. 2010. 2- Richardson JL et al. Improved tryciclic inhibitors of Trypanothione Reductase by screening and chemical synthesis. ChemMedChem 2009, 4, 1333.