RESUMEN
A novel antifungal strategy targeting the inhibition of calcineurin is described. To develop a calcineurin based inhibitor of pathogenic fungi, analogs of FK506 were synthesized that were able to permeate mammalian but not fungal cells. Antagonists in combination with FK506 were not immunosuppressive and retained antifungal activity in A. fumigatus. To reduce the dosage burden of the antagonist, murine oral PK was improved an order of magnitude relative to previous FK506 antagonists.
Asunto(s)
Antifúngicos/farmacología , Inhibidores de la Calcineurina/farmacología , Tacrolimus/análogos & derivados , Tacrolimus/farmacología , Animales , Antifúngicos/síntesis química , Antifúngicos/farmacocinética , Antifúngicos/toxicidad , Aspergillus fumigatus/efectos de los fármacos , Inhibidores de la Calcineurina/síntesis química , Inhibidores de la Calcineurina/farmacocinética , Inhibidores de la Calcineurina/toxicidad , Chlorocebus aethiops , Células Hep G2 , Humanos , Interleucina-2/metabolismo , Células Jurkat , Tacrolimus/síntesis química , Tacrolimus/farmacocinética , Tacrolimus/toxicidad , Proteína 1A de Unión a Tacrolimus/química , Células VeroRESUMEN
C1 Nitrogen iminocyclitols are potent inhibitors of N-acetyl-beta-hexosaminidases. Given hexosaminidases' important roles in osteoarthritis, we developed two straightforward and efficient syntheses of C1 nitrogen iminocyclitols from two readily available starting materials, D-mannosamine hydrochloride and the microbial oxidation product of fructose. A diversity-oriented synthetic strategy was then performed by coupling these core structures with various aldehydes, carboxylic acids, and alkynes to generate three separate libraries. High-throughput screening of the generated libraries with human N-acetyl-beta-hexosaminidases produced only moderate inhibitory activities. However, the synthetic approach and screening strategy for these compounds will be applied to develop new potent inhibitors of human N-acetyl-beta-hexosaminidases, particularly when combined with the structural information of these enzymes.