RESUMEN
We recently reported the discovery of nontoxic cyclam-derived compounds that are active against drug-resistant Mycobacterium tuberculosis. In this paper we report exploration of the structure-activity relationship for this class of compounds, identifying several simpler compounds with comparable activity. The most promising compound identified, possessing significantly improved water solubility, displayed high levels of bacterial clearance in an in vivo zebrafish embryo model, suggesting this compound series has promise for in vivo treatment of tuberculosis.
Asunto(s)
Antituberculosos/farmacología , Compuestos Aza/farmacología , Compuestos Heterocíclicos con 1 Anillo/farmacología , Compuestos Macrocíclicos/farmacología , Animales , Antituberculosos/síntesis química , Antituberculosos/química , Compuestos Aza/síntesis química , Compuestos Aza/química , Carga Bacteriana/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Farmacorresistencia Bacteriana , Compuestos Heterocíclicos con 1 Anillo/síntesis química , Compuestos Heterocíclicos con 1 Anillo/química , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Metales Pesados/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mycobacterium marinum/efectos de los fármacos , Solubilidad , Relación Estructura-Actividad , Tuberculosis/tratamiento farmacológico , Pez CebraRESUMEN
Fluorescent molecular probes for metal ions have a raft of potential applications in chemistry and biomedicine. We report the synthesis and photophysical characterisation of 1,8-disubstituted-cyclam/naphthalimide conjugates and their zinc complexes. An efficient synthesis of 1,8-bis-(2-azidoethyl)cyclam has been developed and used to prepare 1,8-disubstituted triazolyl-cyclam systems, in which the pendant group is connected to triazole C4. UV/Vis and fluorescence emission spectra, zinc binding experiments, fluorescence quantum yield and lifetime measurements and pH titrations of the resultant bis-naphthalimide ligand elucidate a complex pattern of photophysical behaviour. Important differences arise from the inclusion of two fluorophores in the one probe and from the variation of triazole substitution pattern (dye at C4 vs. N1). Introducing a second fluorophore greatly extends fluorescence lifetimes, whereas the altered substitution pattern at the cyclam amines exerts a major influence on fluorescence output and metal binding. Crystal structures of two key zinc complexes evidence variations in triazole coordination that mirror the solution-phase behaviour of these systems.
