RESUMEN
A new series of coumarin inhibitors of DNA gyrase B bearing a N-propargyloxycarbamate at C-3' of various 5',5'-dialkylnoviose, including RU79115, were synthesised and their antibacterial activities have been delineated. Introduction of dialkyl substituents at 5'5'-position of noviose leads to coumarin analogues with improved in vitro and in vivo antibacterial activity.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Antiinfecciosos/química , Antiinfecciosos/farmacología , Cumarinas/química , Cumarinas/farmacología , Hexosas/farmacología , Hexosas/química , Pruebas de Sensibilidad MicrobianaRESUMEN
The synthesis and biological profile in vitro of a series of coumarin inhibitors of gyrase B bearing a N-propargyloxycarbamate at C-3' of noviose is presented. Replacement of the 5-methylpyrrole-2-carboxylate of coumarin drugs with an N-propargyloxycarbamate bioisostere leads to analogues with improved antibacterial activity. Analysis of crystal structures of coumarin antibiotics with the 24 kDa N-terminal domain of the gyrase B protein provides a rational for the excellent inhibitory potency of C-3' N-alkoxycarbamates.
Asunto(s)
Carbamatos/síntesis química , Cumarinas/síntesis química , Inhibidores Enzimáticos/síntesis química , Pirroles/química , Inhibidores de Topoisomerasa II , Antibacterianos/síntesis química , Antibacterianos/farmacología , Carbamatos/farmacología , Cumarinas/farmacología , Girasa de ADN , ADN Superhelicoidal/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Escherichia coli/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos , EstereoisomerismoRESUMEN
Two series of aminosubstituted coumarins were synthesised and evaluated in vitro as inhibitors of DNA gyrase and as potential antibacterials. Novel novobiocin-like coumarins, 4-(dialkylamino)methylcoumarins and 4-((2-alkylamino)ethoxy)coumarins, were discovered as gyrase B inhibitors with promising antibacterial activity in vitro.
Asunto(s)
Cumarinas/síntesis química , Inhibidores de Topoisomerasa II , Antibacterianos/síntesis química , Antibacterianos/farmacología , Cumarinas/farmacología , Girasa de ADN , ADN Superhelicoidal/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Escherichia coli/enzimología , Bacterias Grampositivas/efectos de los fármacos , Estructura Molecular , Novobiocina/análogos & derivados , Novobiocina/farmacología , Péptidos Cíclicos/farmacología , Relación Estructura-ActividadRESUMEN
A series of novobiocin-like coumarincarboxylic acids has been prepared bearing the L-rhamnosyl moiety as the sugar portion of the molecule. The similar DNA gyrase inhibitory activity of the novel class of coumarins to that of novobiocin demonstrates that L-rhamnose can effectively replace L-noviose. Introduction of alkyl side-chains at C-5 of coumarin leads to improved in vitro antibacterial properties in the novel series.
Asunto(s)
Cumarinas/síntesis química , Inhibidores de Topoisomerasa II , Antibacterianos/síntesis química , Antibacterianos/farmacología , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacología , Cumarinas/farmacología , Girasa de ADN , ADN Superhelicoidal/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Escherichia coli/enzimología , Estructura Molecular , Novobiocina/análogos & derivados , Novobiocina/farmacología , Ramnosa/análogos & derivadosRESUMEN
The design, synthesis, and in vitro biological activity of a series of novel coumarin inhibitors of gyrase B is presented. Replacement of the 3-acylamino residue (3-NHCOR) of coumarin drugs with reversed isosteres C(=O)R, C(=N-OR)R', COOR, CONHR and CONHOR leads to highly potent analogues which displayed excellent inhibition of the negative supercoiling of the relaxed DNA and antibacterial activity.
