RESUMO
Two chiral cyclohexanones were linked to polystyrene resin. The polymer-bound auxiliaries were subjected to a sequence of four reactions, the last of which cleaves the desired alpha-chiral carbonyl compound off the resin, concurrently regenerating the resin-bound auxiliary in its original form. The resin can then be reused.
Assuntos
Álcoois/síntese química , Aldeídos/síntese química , Ácidos Carboxílicos/síntese química , Técnicas de Química Combinatória/métodos , Cicloexanonas/química , Poliestirenos/química , Álcoois/química , Aldeídos/química , Ácidos Carboxílicos/química , Mentol/química , Estrutura Molecular , EstereoisomerismoRESUMO
Semisynthetic modifications at Hydroxy tyrosine (Htyr) unit of mulundocandin (1) were carried out to improve its aqueous solubility. A single step introduction of substituted aminomethyl groups at the ortho position(s) of phenolic hydroxyl of HTyr unit of mulundocandin has been achieved in 7-85% yield. The in vitro screening of Mannich products against Candida albicans and Aspergillus fumigatus, retained the in vivo activity of parent by oral and intraperitoneal route. Compound 20, showed significant improvement in activity over mulundocandin (1) and activity compares well with that of fluconazole.
Assuntos
Antifúngicos/química , Bases de Mannich/síntese química , Peptídeos Cíclicos/química , Água/química , Animais , Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Equinocandinas , Bases de Mannich/administração & dosagem , Bases de Mannich/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Modelos Animais , Estrutura Molecular , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/farmacologia , SolubilidadeRESUMO
Semisynthetic modifications at position-12 (ornithine-5-position, hemiaminal function) of mulundocandin were carried out to improve its chemical stability. New carbon-carbon (C-C) and carbon-hydrogen (C-H) linkage at hemiaminal function -12 has been achieved. Lewis acid catalyzed introduction of electron rich aryl group at position-12 of mulundocandin is developed. Synthesized mulundocandin analogues were evaluated for their chemical stability and antifungal activity against C. albicans and A. fumigatus.
Assuntos
Antifúngicos/farmacologia , Ornitina/farmacologia , Peptídeos Cíclicos/farmacologia , Aminas/química , Animais , Antifúngicos/administração & dosagem , Antifúngicos/química , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Candidíase/tratamento farmacológico , Estabilidade de Medicamentos , Equinocandinas , Injeções Intraperitoneais , Camundongos , Ornitina/química , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/químicaRESUMO
Mulundocandin (1), is an echinocandin class of lipopeptide. It has wide spectrum of antifungal activity against Candida and Aspergillus species. Semisynthetic modification at Ornithine-5-hydroxyl (hemiaminal function) of 1 was carried out to improve solution stability and hence in vivo activity. Synthesis of ether (C-OR), thioether (C-SR) and C-N linkage at hemiaminal function have been described. All synthetic analogues were evaluated for their stability in aqueous solution and found to be more stable than mulundocandin. Antifungal activity of Orn-5 analogues was evaluated both in vitro against Candida albicans and Aspergillus fumigatus by agar well method and in vivo (oral and intraperitoneal) in C. albicans infected Swiss mice. Results of in vivo assays of analogues 2-9 by the oral route suggests that the introduction of either oxygen nucleophiles (-OR) or sulphur nucleophiles (-SR), at either Orn-5 or at both Orn-5 and HTyr-4 positions, results in retaining the activity of the parent compound with improved aqueous stability in most cases. Compound 9 has shown improved antifungal activity in comparison to mulundocandin by oral application in Swiss mice.