RESUMO
There is an emerging global need for new and more effective antibiotics against multi-resistant bacteria. This situation has led to massive industrial investigations on novel bacterial topoisomerase inhibitors (NBTIs) that target the vital bacterial enzymes DNA gyrase and topoisomerase IV. However, several of the NBTI compound classes have been associated with inhibition of the hERG potassium channel, an undesired cause of cardiac arrhythmia, which challenges medicinal chemistry efforts through lengthy synthetic routes. We herein present a solid-phase strategy that rapidly facilitates the chemical synthesis of a promising new class of NBTIs. A proof-of-concept library was synthesized with the ability to modulate both hERG affinity and antibacterial activity through scaffold substitutions.
Assuntos
Antibacterianos/farmacologia , Piperazinas/farmacologia , Quinolinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antibacterianos/síntese química , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperazinas/síntese química , Estudo de Prova de Conceito , Quinolinas/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Técnicas de Síntese em Fase Sólida , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Regulador Transcricional ERG/metabolismoRESUMO
A four-component reaction for the synthesis of heterocyclic boronates is reported. Readily available hydrazides, α-hydroxy aldehydes, and two orthogonally reactive boronic acids are combined in a single step to give structurally distinct bicyclic boronates, termed dioxadiazaborocines (DODA borocines). In this remarkable process, one boronic acid reacts as a carbon nucleophile and the other as a boron electrophile to provide enantio- and diastereomerically pure heterocyclic boronates with multiple stereocenters in high yields.
Assuntos
Ácidos Borônicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Aldeídos/síntese química , Aldeídos/química , Ácidos Borônicos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Técnicas de Química Combinatória , CiclizaçãoRESUMO
A build/couple/pair strategy for the synthesis of complex and densely functionalized small molecules is presented. The strategy relies on synthetically tractable building blocks (build), that is, diversely substituted hydrazides, α-hydroxy aldehydes, and boronic acids, which undergo Petasis 3-component reactions (couple) to afford densely functionalized anti-hydrazido alcohols. The resulting scaffolds can subsequently be converted via chemoselective cyclization reactions (pair), including intramolecular Diels-Alder or Ru-alkylidene catalyzed ring-closing metathesis, into sets of structurally diverse heterocycles in good yields in only 3-4 steps.
Assuntos
Aldeídos/química , Azidas/química , Ácidos Borônicos/química , CiclizaçãoRESUMO
An application of readily available hydrazides in the Petasis 3-component coupling reaction is presented. An investigation of the substrate scope was performed to establish a general, synthetically useful protocol for the formation of hydrazido alcohols, which were selectively converted to oxazolidinone and oxadiazolone ring systems through triphosgene-mediated cyclization reactions.