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The iron storage protein bacterioferritin (BfrB) is central to bacterial iron homeostasis. The mobilization of iron from BfrB, which requires binding by a cognate ferredoxin (Bfd), is essential to the regulation of cytosolic iron levels in P. aeruginosa. This paper describes the structure-guided development of small molecule inhibitors of the BfrB–Bfd protein–protein interaction. The process was initiated by screening a fragment library and followed by obtaining the structure of a fragment hit bound to BfrB. The structural insights were used to develop a series of 4-(benzylamino)- and 4-((3-phenylpropyl)amino)-isoindoline-1,3-dione analogs that selectively bind BfrB at the Bfd binding site. Challenging P. aeruginosacells with the 4-substituted isoindoline analogs revealed a dose-dependent growth phenotype. Further investigation determined that the analogs elicit a pyoverdin hyperproduction phenotype that is consistent with blockade of the BfrB–Bfd interaction and ensuing irreversible accumulation of iron in BfrB, with concomitant depletion of iron in the cytosol. The irreversible accumulation of iron in BfrB prompted by the 4-substituted isoindoline analogs was confirmed by visualization of BfrB-iron in P. aeruginosacell lysates separated on native PAGE gels and stained for iron with Ferene S. Challenging P. aeruginosacultures with a combination of commercial fluoroquinolone and our isoindoline analogs results in significantly lower cell survival relative to treatment with either antibiotic or analog alone. Collectively, these findings furnish proof of concept for the usefulness of small molecule probes designed to dysregulate bacterial iron homeostasis by targeting a protein–protein interaction pivotal for iron storage in the bacterial cell.

In this study, methyl ±12nitrobenzyl4oxo2cyclohexene1carboxylate and methyl ±2nitrobenzyl4oxo2cyclopentene1carboxylate were prepared and subjected to reductive cyclization under dissolving metal conditions. The two reactants showed divergent behavior with the sixring substrate reacting at the ester carbonyl and the fivering substrate closing on the enone double bond. The difference in reactivity is attributed to the conformational flexibility, relative reactivity, and steric environment of C4substituted six and fivemembered cyclic enones. J. Heterocyclic Chem., 2009.

Efficient syntheses of the title ring systems have been developed from 1Hindole2butanoic acid, which was easily prepared from 2fluoro1nitrobenzene in four steps. Heating 1Hindole2butanoic acid in toluene containing ptoluenesulfonic acid at 110°C furnished 1,2,3,9tetrahydro4Hcarbazol4one in 88 yield. Heating this same acid in toluene with no added acid gave 8,9dihydropyrido1,2aindol67Hone in 90 yield. The tetrahydro4Hcarbazol4one was also prepared directly in 92 yield from methyl 62nitrophenyl5oxohexanoate by a tandem reduction—cycloaromatization—acylation reaction with iron in concentrated hydrochloric acid at 110°C. Application of this approach to the closure of five and sevenmembered rings was also successful. J. Heterocyclic Chem., 2009.

An efficient, simple, and mild one‐pot synthesis of the title compounds (III) from the compounds (I) or (IV) by using inexpensive reagents is presented.

2,3‐Dihydro‐4(1H)‐quinolinone derivatives of type (V) and (IX) are prepared via reductive cyclization of o‐nitrophenylpropenone (IV) or related 2‐nitrochalcone derivatives (VIII) using Fe‐powder in conc.

Simple and efficient syntheses of quinolinones (IV), (VI) and (VIII) are developed using an adaption of the Leimgrueber‐Batcho indole synthesis.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.