RESUMO
The C-4 side chain modification of lead compound 1 has resulted in the identification of a potent and selective Candida albicans N-myristoyltransferase (CaNmt) inhibitor RO-09-4609, which exhibits antifungal activity against C. albicans in vitro. Further modification of its C-2 substituent has led to the discovery of RO-09-4879, which exhibits antifungal activity in vivo. The drug design is based on X-ray crystal analysis of a CaNmt complex with benzofuran derivative 4a. The optimization incorporates various biological investigations including a quasi in vivo assay and pharmacokinetic study. The computer aided drug design, synthesis, structure-activity relationships, and biological properties of RO-09-4879 are described in detail.
Assuntos
Aciltransferases/antagonistas & inibidores , Antifúngicos/síntese química , Benzofuranos/síntese química , Animais , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Benzofuranos/farmacocinética , Benzofuranos/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/enzimologia , Candidíase/tratamento farmacológico , Desenho de Fármacos , Farmacorresistência Fúngica/genética , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Proteínas Fúngicas/antagonistas & inibidores , Concentração Inibidora 50 , Masculino , Ligação Proteica , Ratos , Ratos Endogâmicos F344 , Relação Estrutura-AtividadeRESUMO
A new series of acid-stable antifungal agents having strong inhibitory activity against Candida albicans N-myristoyltransferase (CaNmt) has been developed starting from acid-unstable benzofuranylmethyl aryl ether 2. The inhibitor design is based on X-ray crystallographic analysis of a CaNmt complex with aryl ether 3. Among the new inhibitors, pyridine derivative 8b and benzimidazole derivative 8k showed clear antifungal activity in a murine systemic candidiasis model.
Assuntos
Aciltransferases/antagonistas & inibidores , Antifúngicos/síntese química , Benzofuranos/síntese química , Proteínas Fúngicas/antagonistas & inibidores , Animais , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Benzofuranos/farmacocinética , Benzofuranos/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/enzimologia , Modelos Animais de Doenças , Desenho de Fármacos , Estabilidade de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Camundongos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
Modification of the C-2 position of a benzofuran derivative 6 (RO-09-4609), an N-myristoyltransferase (Nmt) inhibitor, has led us to discover antifungal agents that are active in a murine systemic candidiasis model. The drug design is based on the analysis of a crystal structure of a Candida Nmt complex with 2. The optimization has been guided by various biological evaluations including a quasi in vivo assay and pharmacokinetic analysis.
