RESUMEN
A combination of a literature survey, structure-based virtual screening and synthesis of a small library was performed to identify hits to the potential antimycobacterial drug target, glutamine synthetase. The best inhibitor identified from the literature survey was (2S,5R)-2,6-diamino-5-hydroxyhexanoic acid (4, IC(50) of 610+/-15microM). In the virtual screening 46,400 compounds were docked and subjected to a pharmacophore search. Of these compounds, 29 were purchased and tested in a biological assay, allowing three novel inhibitors containing an aromatic scaffold to be identified. Based on one of the hits from the virtual screening a small library of 15 analogues was synthesized producing four compounds that inhibited glutamine synthetase.
Asunto(s)
Aminoácidos/farmacología , Caproatos/farmacología , Diseño de Fármacos , Glutamato-Amoníaco Ligasa/antagonistas & inhibidores , Mycobacterium tuberculosis/enzimología , Aminoácidos/química , Sitios de Unión/efectos de los fármacos , Caproatos/química , Simulación por Computador , Relación Dosis-Respuesta a Droga , Hidroxilisina/análogos & derivados , Modelos Moleculares , Conformación Molecular , Compuestos Organofosforados , Bibliotecas de Moléculas Pequeñas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A microwave-enhanced copper-catalyzed protocol for N-arylation using water as the solvent is reported. This fast transformation allows the reaction between various amino acids or amino acid esters and a diverse set of substituted aryl bromides in less than 40 min, affording good yields of non-protected N-arylated amino acids with only minor racemization (6% or less). In addition, online ESI-MS and MS/MS analysis were used to "fish-out" an anionic Cu-containing amino acid complex directly from an ongoing N-arylation reaction.