RESUMO
Natural products have routinely been used both as sources of and inspiration for new crop protection active ingredients. The natural product UK-2A has potent anti-fungal activity but lacks key attributes for field translation. Post-fermentation conversion of UK-2A to fenpicoxamid resulted in an active ingredient with a new target site of action for cereal and banana pathogens. Here we demonstrate the creation of a synthetic variant of fenpicoxamid via identification of the structural elements of UK-2A that are needed for anti-fungal activity. Florylpicoxamid is a non-macrocyclic active ingredient bearing two fewer stereocenters than fenpicoxamid, controls a broad spectrum of fungal diseases at low use rates and has a concise, scalable route which is aligned with green chemistry principles. The development of florylpicoxamid represents the first example of using a stepwise deconstruction of a macrocyclic natural product to design a fully synthetic crop protection active ingredient.
Assuntos
Antifúngicos/farmacologia , Produtos Biológicos/farmacologia , Descoberta de Drogas , Compostos Macrocíclicos/farmacologia , Piridinas/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Ascomicetos/efeitos dos fármacos , Produtos Biológicos/síntese química , Produtos Biológicos/química , Relação Dose-Resposta a Droga , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Herein, we report the discovery of novel, proline-based factor Xa inhibitors containing a neutral P1 chlorophenyl pharmacophore. Through the additional incorporation of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one 22, as a P4 pharmacophore, we discovered compound 7 (PD 0348292). This compound is a selective, orally bioavailable, efficacious FXa inhibitor that is currently in phase II clinical trials for the treatment and prevention of thrombotic disorders.