ABSTRACT
The use of antibiotics directly correlates with the increase in antimicrobial resistance (AMR). Targeting novel antibiotics to patients with multidrug-resistant (MDR) pathogens should enhance their durability and slow development of resistance. The discovery, development, and clinical adoption of pathogen-targeted antibiotics have been hampered by technical and regulatory challenges. Growing insights into bacterial physiology and mechanisms of resistance, innovative clinical trial designs, streamlined regulatory approval pathways, and availability of rapid bacterial diagnostics are recent developments that can help address those challenges. Pathogen-targeted antibiotics provide an opportunity to treat patients with the right drug at the right time, leading to improved patient outcomes and better antimicrobial stewardship. Patient-centered pricing and reimbursement reform is needed to incentivize innovation.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Bacterial Infections/drug therapy , Drug Development , Drug Discovery , Animals , Antimicrobial Stewardship , Bacteria/drug effects , Biomedical Research , Humans , Technology TransferABSTRACT
[structure: see text]. An efficient three-step synthesis of chiral 3H-quinazoline-4-one derivatives from commercial materials is disclosed. The Mumm reaction of imidoyl chloride with alpha-amino acids followed by reductive cyclization affords enantiomerically pure (ee >93%) quinazoline-4-ones in good overall yield. A comparison with existing approaches indicates that this method is superior for hindered substrates.
Subject(s)
Quinazolinones/chemical synthesis , Chromatography, High Pressure Liquid , Cyclization , Molecular Structure , Quinazolinones/chemistry , StereoisomerismABSTRACT
An efficient one-pot preparation of alpha,beta-unsaturated-gamma-keto esters and amides has been developed. A zinc carbenoid-mediated chain extension of a beta-dicarbonyl substrate provides access to an intermediate zinc enolate, which is treated sequentially with a halogen and amine base. This method has been applied to a variety of ester and amide starting materials, as well as to amino acid-derived substrates and to a formal synthesis of (R,R)-(-)-pyrenophorin.
Subject(s)
Amides/chemical synthesis , Chemistry, Organic/methods , Lactones/chemical synthesis , Organometallic Compounds/chemistry , Zinc/chemistry , Esters/chemical synthesis , Magnetic Resonance Spectroscopy , Molecular Structure , StereoisomerismABSTRACT
A one-pot ring expansion/oxidation/elimination method has been developed in which beta-keto lactones are converted efficiently to alpha,beta-unsaturated-gamma-keto lactones. The reaction can be successfully applied to a variety of ring sizes. Alkene stereochemistry is dependent upon ring size and reaction conditions. The method was applied to the synthesis of (+)-patulolide A.
