SAR and Structural Analysis of Siderophore-Conjugated Monocarbam Inhibitors of Pseudomonas aeruginosa PBP3.

A main challenge in the development of new agents for the treatment of Pseudomonas aeruginosa infections is the identification of chemotypes that efficiently penetrate the cell envelope and are not susceptible to established resistance mechanisms. Siderophore-conjugated monocarbams are attractive because of their ability to hijack the bacteria's iron uptake machinery for transport into the periplasm and their inherent stability to metallo-ß-lactamases. Through development of the SAR we identified a number of modifications to the scaffold that afforded active anti-P. aeruginosa agents with good physicochemical properties. Through crystallographic efforts we gained a better understanding into how these compounds bind to the target penicillin binding protein PBP3 and factors to consider for future design.

Discovery of efficacious Pseudomonas aeruginosa-targeted siderophore-conjugated monocarbams by application of a semi-mechanistic pharmacokinetic/pharmacodynamic model.

To identify new agents for the treatment of multi-drug-resistant Pseudomonas aeruginosa, we focused on siderophore-conjugated monocarbams. This class of monocyclic ß-lactams are stable to metallo-ß-lactamases and have excellent P. aeruginosa activities due to their ability to exploit the iron uptake machinery of Gram-negative bacteria. Our medicinal chemistry plan focused on identifying a molecule with optimal potency and physical properties and activity for in vivo efficacy. Modifications to the monocarbam linker, siderophore, and oxime portion of the molecules were examined. Through these efforts, a series of pyrrolidinone-based monocarbams with good P. aeruginosa cellular activity (P. aeruginosa MIC90 = 2 µg/mL), free fraction levels (>20% free), and hydrolytic stability (t1/2 ≥ 100 h) were identified. To differentiate the lead compounds and enable prioritization for in vivo studies, we applied a semi-mechanistic pharmacokinetic/pharmacodynamic model to enable prediction of in vivo efficacy from in vitro data.

Stereocontrolled alkylative construction of quaternary carbon centers.

Protocols for the stereodefined formation of alpha,alpha-disubstituted enolates of pseudoephedrine amides are presented followed by the implementation of these in diastereoselective alkylation reactions. Direct alkylation of alpha,alpha-disubstituted pseudoephedrine amide substrates is demonstrated to be both efficient and diastereoselective across a range of substrates, as exemplified by alkylation of the diastereomeric pseudoephedrine alpha-methylbutyramides, where both substrates are found to undergo stereospecific replacement of the alpha-C-H bond with alpha-C-alkyl, with retention of stereochemistry. This is shown to arise by sequential stereospecific enolization and alkylation reactions, with the alkyl halide attacking a common pi-face of the E- and Z-enolates, proposed to be opposite the pseudoephedrine alkoxide side chain. Pseudoephedrine alpha-phenylbutyramides are found to undergo highly stereoselective but not stereospecific alpha-alkylation reactions, which evidence suggests is due to facile enolate isomerization. Also, we show that alpha,alpha-disubstituted pseudoephedrine amide enolates can be generated in a highly stereocontrolled fashion by conjugate addition of an alkyllithium reagent to the s-cis-conformer of an alpha-alkyl-alpha,beta-unsaturated pseudoephedrine amide, providing alpha,alpha-disubstituted enolate substrates that undergo alkylation in the same sense as those formed by direct deprotonation. Methods are presented to transform the alpha-quaternary pseudoephedrine amide products into optically active carboxylic acids, ketones, primary alcohols, and aldehydes.

O Garmic e a luta por moradia para idosos na cidade de São Paulo / Garmic and the struggle for housing for elderly people in the city of São Paulo

Relato de experiência sobre o movimento de moradia dos idosos de São Paulo - Garmic, organização de idosos voltada especificamente para a luta por moradia. Desenvolve trabalhos com idosos filiados à entidade, quanto a organização dos mesmos, com o objetivo de buscar - junto ao poder público e instituições da sociedade civil - a criação de políticas públicas de habitação para a população idosa de baixa renda, na cidade de São Paulo (AU)

Report of an experience about Garmic, the movement towards housing organized by the elderly people of São Paulo. It develops works with elderly people affliated to the entity regarding their organization, and its objective is that the public power and civil society institutions create public policies of housing for the low-income elderly population in the city of São Paulo (AU)

O Garmic e a luta por moradia para idosos na cidade de São Paulo / Garmic and the struggle for housing for elderly people in the city of São Paulo

Relato de experiência sobre o movimento de moradia dos idosos de São Paulo - Garmic, organização de idosos voltada especificamente para a luta por moradia. Desenvolve trabalhos com idosos filiados à entidade, quanto a organização dos mesmos, com o objetivo de buscar - junto ao poder público e instituições da sociedade civil - a criação de políticas públicas de habitação para a população idosa de baixa renda, na cidade de São Paulo

Report of an experience about Garmic, the movement towards housing organized by the elderly people of São Paulo. It develops works with elderly people affliated to the entity regarding their organization, and its objective is that the public power and civil society institutions create public policies of housing for the low-income elderly population in the city of São Paulo