RESUMEN
We have designed, synthesized, and evaluated 5-benzylidenerhodanine- and 5-benzylidenethiazolidine-2,4-dione-based compounds as inhibitors of bacterial enzyme MurD with E. coli IC(50) in the range 45-206 µM. The high-resolution crystal structure of MurD in complex with (R,Z)-2-(3-[{4-([2,4-dioxothiazolidin-5-ylidene]methyl)phenylamino}methyl)benzamido)pentanedioic acid [(R)-32] revealed details of the binding mode of the inhibitor within the active site and provides a good foundation for structure-based design of a novel generation of MurD inhibitors.
Asunto(s)
Antibacterianos/síntesis química , Proteínas de Escherichia coli/antagonistas & inhibidores , Ácido Glutámico/análogos & derivados , Péptido Sintasas/antagonistas & inhibidores , Rodanina/análogos & derivados , Rodanina/síntesis química , Tiazolidinedionas/síntesis química , Tiazolidinas/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Dominio Catalítico , Cristalografía por Rayos X , Ácido Glutámico/síntesis química , Ácido Glutámico/química , Ácido Glutámico/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Rodanina/química , Rodanina/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Tiazolidinedionas/química , Tiazolidinedionas/farmacología , Tiazolidinas/química , Tiazolidinas/farmacologíaRESUMEN
Mur ligases catalyze the biosynthesis of the UDP-MurNAc-pentapeptide precursor of peptidoglycan, an essential polymer of bacterial cell-wall. They constitute attractive targets for the development of novel antibacterial agents. Here we report on the synthesis of a series of 2,4-diaminoquinazolines, quinazoline-2,4(1H,3H)-diones, 5-benzylidenerhodanines and 5-benzylidenethiazolidine-2,4-diones and their inhibitory activities against MurD from Escherichia coli. Compounds (R)-27 and (S)-27 showed inhibitory activity against MurD with IC(50) values of 174 and 206 microM, respectively, which makes them promising starting points for optimization.
Asunto(s)
Antibacterianos/síntesis química , Péptido Sintasas/antagonistas & inhibidores , Antibacterianos/farmacología , Compuestos de Bencilideno/síntesis química , Compuestos de Bencilideno/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Escherichia coli/enzimología , Ácido Glutámico , Concentración 50 Inhibidora , Quinazolinas/síntesis química , Quinazolinas/farmacologíaRESUMEN
The Mur ligases have an essential role in the intracellular biosynthesis of bacterial peptidoglycan, and they represent attractive targets for the design of novel antibacterials. A series of compounds with an N-acylhydrazone scaffold were synthesized and screened for inhibition of the MurC and MurD enzymes from Escherichia coli. Compounds with micromolar inhibitory activities against both MurC and MurD were identified, and some of them also showed antibacterial activity.