RESUMEN
The synthesis and antibacterial activity of heterocyclic methylsulfone hydroxamates is presented. Compounds in this series are potent inhibitors of the LpxC enzyme, a key enzyme involved in the production of lipopolysaccharide (LPS) found in the outer membrane of Gram-negative bacteria. SAR evaluation of compounds in this series revealed analogs with potent antibacterial activity against challenging Gram-negative species such as Pseudomonas aeruginosa and Klebsiella pneumoniae.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/química , Inhibidores Enzimáticos/química , Bacterias Gramnegativas/efectos de los fármacos , Ácidos Hidroxámicos/química , Amidohidrolasas/metabolismo , Antibacterianos/síntesis química , Antibacterianos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/química , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Klebsiella pneumoniae/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Relación Estructura-Actividad , Sulfonas/químicaRESUMEN
The development of a novel intermolecular oxidative amination reaction, a synthetic transformation that involves the simultaneous functionalization of both a N-H and C-H bond, is described. The process, which is mediated by an I(III) oxidant and contains no metal catalysts, provides a rapid and green method for synthesizing protected anilines from simple arenes and phthalimide. Mechanistic investigations indicate that the reaction proceeds via nucleophilic attack of the phthalimide on an aromatic radical cation, as opposed to the electrophilic aromatic amination that has been reported for other I(III) amination reactions. The application of this new reaction to the synthesis of a variety of substituted aniline derivatives is demonstrated.
Asunto(s)
Compuestos de Anilina/síntesis química , Tecnología Química Verde/métodos , Aminación , Compuestos de Anilina/química , Catálisis , Tecnología Química Verde/economía , Oxidación-Reducción , Ftalimidas/síntesis química , Ftalimidas/químicaRESUMEN
In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid.