RESUMEN
New linear and cyclic guanidines were synthesized and tested in vitro for their antifungal activity toward clinically relevant strains of Candida species, in comparison to fluconazole. Macrocyclic compounds showed a minimum inhibitory concentration in the micromolar range and a biological activity profile in some cases better than that of fluconazole. One macrocyclic derivative was also tested against Aspergillus species and showed high antifungal activity comparable to that of amphotericin B and itraconazole.
Asunto(s)
Aspergillus/efectos de los fármacos , Candida/efectos de los fármacos , Guanidina/análogos & derivados , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacología , Urea/análogos & derivados , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Diseño de Fármacos , Guanidina/síntesis química , Guanidina/química , Guanidina/farmacología , Humanos , Compuestos Macrocíclicos/química , Pruebas de Sensibilidad Microbiana , Urea/síntesis química , Urea/química , Urea/farmacologíaRESUMEN
Previous studies on agmatine and its derivatives suggested that the presence of hydrophobic groups on the guanidine moiety was a crucial key for inhibitory activity of maize polyamine oxidase. Accordingly, new lipophilic agmatine and iminoctadine derivatives were synthesized and tested for their ability to inhibit this enzyme. Several compounds showed an affinity in the nanomolar range, while a cyclopropylmethyl derivative of iminoctadine was found to be the most potent inhibitor of maize polyamine oxidase reported so far (Ki = 0.08 nM).
Asunto(s)
Agmatina/análogos & derivados , Inhibidores Enzimáticos/síntesis química , Guanidinas/síntesis química , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/antagonistas & inhibidores , Zea mays/enzimología , Agmatina/farmacología , Sitios de Unión , Unión Competitiva , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Guanidinas/farmacocinética , Guanidinas/farmacología , Relación Estructura-Actividad , Poliamino OxidasaRESUMEN
Nitric oxide (NO) is a gaseous mediator that exerts key regulatory functions in mammalian cells. Low levels of NO exert homeostatic functions and counteract inflammation, whereas high amounts of NO cause tissue destruction and cellular death. Herein we describe a new class of nitric oxide synthase (NOS) inhibitor NO-donating drugs (NI-NODs). Human endothelial cells and human monocyte-based activity screening showed that NI-NODs inhibit IL-1beta production, modulate PGE(2) production, and protect against apoptosis. In a rodent model of colitis, NI-NOD1 and NI-NOD2 potently decreased inflammation. These data show that NI-NODs are effective in both in vitro and in vivo models of inflammation, mimicking the positive effects of low levels of NO and suppressing NOS-induced NO production.
