RESUMO
A series of 1,3-benzoxazole-4-carbonitriles was synthesized and evaluated for its antifungal activity, solubility, and metabolic stability. Among those compounds, 4-cyano-N,N,5-trimethyl-7-[(3S)-3-methyl-3-(methylamino)pyrrolidin-1-yl]-6-phenyl-1,3-benzoxazole-2-carboxamide (16b) exhibited potent in vitro activity against Candida species, higher water solubility, and improved metabolic stability compared to lead compound 1. Compound 16b showed potent in vivo efficacy against mice Candida infection models and good bioavailability in rats.
Assuntos
Antifúngicos/química , Benzoxazóis/química , Nitrilas/química , Animais , Antifúngicos/síntese química , Antifúngicos/uso terapêutico , Benzoxazóis/síntese química , Benzoxazóis/uso terapêutico , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Camundongos , Testes de Sensibilidade Microbiana , Nitrilas/síntese química , Nitrilas/uso terapêutico , Ratos , Solubilidade , Relação Estrutura-AtividadeRESUMO
Preparations and in vitro antifungal activities of triazolopyridines, imidazopyridines, and a pyrazolopyridine were reported. Among those scaffolds, triazolopyridine was found to be the specific inhibitor of the synthesis of beta-1,6-glucan, an essential component of the fungal cell wall, and to show potent antifungal activities against several Candida species.
Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Imidazóis/química , Imidazóis/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Triazóis/química , Triazóis/farmacologia , beta-Glucanas/antagonistas & inibidores , beta-Glucanas/metabolismo , Antifúngicos/química , Antifúngicos/metabolismo , Candidíase/tratamento farmacológico , Estabilidade de Medicamentos , Humanos , Imidazóis/síntese química , Imidazóis/metabolismo , Microssomos Hepáticos/metabolismo , Pirazóis/síntese química , Pirazóis/metabolismo , Piridinas/síntese química , Piridinas/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Triazóis/síntese química , Triazóis/metabolismoRESUMO
Synthesis and in vitro antifungal evaluations of 1,3-benzoxazole-7-carbonitrile 3, 1,3-benzoxazole-4-carbonitrile 4, benzofuran 5, benzoxazine 7, and benzimidazole 8 were reported. Among them, 1,3-benzoxazole-4-carbonitrile was found to be a superior scaffold structure with moderate growth inhibition against Candida species. 1,3-Benzoxazole-4-carbonitrile 6 showed potent activity against Candida species compared to 5-desmethyl compound 4 and triazolopyridine 2. Compound 6 was efficiently prepared from versatile intermediate 24, which possessed six different substituents on the benzene ring. Conversion of benzene 24 into various 1,3-benzoxazole derivatives such as 2-aliphatic 34, 2-amino 35, and lactone 38 was demonstrated.
Assuntos
Antifúngicos/química , Benzimidazóis/química , Nitrilas/química , beta-Glucanas/metabolismo , Antifúngicos/síntese química , Antifúngicos/farmacologia , Compostos Bicíclicos com Pontes/química , Candida/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Nitrilas/síntese química , Nitrilas/farmacologia , beta-Glucanas/antagonistas & inibidoresRESUMO
Tributyltin hydride and tris(trimethylsilyl)silane promote sequential/cascade free radical cyclization reactions of dienoate tethered vinyliodides or alkynes. These processes produce [4 + 1] and [4 + 2] annulated products. In contrast, the electrochemical reductions of the vinyliodides afford monocyclic compounds. Both the regiochemical and stereochemical courses of the sequential radical cyclizations strongly depend on substrate structure. Especially important is the balance between steric and stereoelectronic (Baldwin's rules) factors that serve to control cyclization regiochemistry.