ABSTRACT
A novel series of bacterial topoisomerase (3-aminoquinazolinediones) inhibitors are described. The side-chain SAR against Gram-positive and Gram-negative organisms as well as DNA gyrase activity is reported.
Subject(s)
Anti-Bacterial Agents , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/enzymology , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/enzymology , Quinazolinones , Topoisomerase II Inhibitors , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Combinatorial Chemistry Techniques , Fluoroquinolones/chemical synthesis , Fluoroquinolones/chemistry , Fluoroquinolones/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Quinazolinones/chemical synthesis , Quinazolinones/chemistry , Quinazolinones/pharmacology , Structure-Activity RelationshipABSTRACT
This article describes the design and optimization of a simple three-component aza[4+2]/allylboration reaction to access polysubstituted alpha-hydroxyalkyl piperidines in a highly diastereocontrolled fashion from maleimides, 4-boronohydrazonodienes, and aldehydes. The aldehyde component does not interfere with the first aza[4+2] step, and it was found that this tandem reaction provides better yields of piperidine products 5 when carried out in one-pot. The required 4-borono-hydrazonodienes 1 are synthesized efficiently from the condensation of 3-boronoacrolein pinacol ester (4) with hydrazines. Overall, the three-component process using N-substituted maleimides as dienophiles produces four stereogenic centers and is quite general. It tolerates the use of a wide variety of aldehydes and hydrazine precursors with different electronic and steric characteristics. By allowing such a wide substrate scope and up to four elements of diversity, this reaction process is particularly well adapted towards applications in diversity-oriented synthesis of polysubstituted piperidine derivatives. The suitability of the aza[4+2]/allylboration reaction for use in solid-phase chemistry was also demonstrated using a N-arylmaleidobenzoic acid functionalized resin. This novel multicomponent reaction thus offers a high level of stereocontrol and versatility in the preparation of densely functionalized nitrogen heterocycles.