RESUMO
Therapeutic agents brequinar sodium and leflunomide (Arava) work by binding in a hydrophobic tunnel formed by a highly variable N-terminus of family 2 dihydroorotate dehydrogenase (DHODH). The X-ray crystallographic structure of an analog of brequinar bound to human DHODH was determined. In silico screening of a library of compounds suggested another subset of brequinar analogs that do not inhibit human DHODH as potentially effective inhibitors of Plasmodium falciparum DHODH.
Assuntos
Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Animais , Cristalografia por Raios X , Di-Hidro-Orotato Desidrogenase , Mononucleotídeo de Flavina/metabolismo , Humanos , Ligação de Hidrogênio , Ácido Orótico/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/química , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Especificidade da EspécieRESUMO
Tandem reactions that proceed with a single metal catalyst precursor offer novel opportunities for developing efficient new reaction sequences. In this regard, reaction conditions have been identified that allows for a tandem ring-closing metathesis-olefin isomerization sequence catalyzed by a common ruthenium precursor. Specifically, the tandem process generates cyclic enol ethers from a variety of readily available acyclic dienes in a single reaction vessel using Grubbs' ruthenium alkylidene.
