ABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/pharmacology , Piperazines/pharmacology , Quinolines/pharmacology , Topoisomerase II Inhibitors/pharmacology , Anti-Bacterial Agents/chemical synthesis , Humans , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Molecular Structure , Piperazines/chemical synthesis , Proof of Concept Study , Quinolines/chemical synthesis , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/pharmacology , Solid-Phase Synthesis Techniques , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemical synthesis , Transcriptional Regulator ERG/metabolismABSTRACT
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.
Subject(s)
Boronic Acids/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Aldehydes/chemical synthesis , Aldehydes/chemistry , Boronic Acids/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Combinatorial Chemistry Techniques , CyclizationABSTRACT
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.
Subject(s)
Aldehydes/chemistry , Azides/chemistry , Boronic Acids/chemistry , CyclizationABSTRACT
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.
