Jeremy I. Levin

Brominated furanones inhibit biofilm formation by Salmonella enterica serovar Typhimurium

ABSTRACT Salmonella enterica serovar Typhimurium is a main cause of bacterial food-borne diseases. As Salmonella can form biofilms in which it is better protected against antimicrobial agents on a wide diversity of surfaces, it is of interest to explore ways to inhibit biofilm formation. Brominated furanones, originally extracted from the marine alga Delisea pulchra, are known to interfere with biofilm formation in several pathogens. In this study, we have synthesized a small focused library of brominated furanones and tested their activity against S. enterica serovar Typhimurium biofilm formation. We show that several furanones inhibit Salmonella biofilm formation at non-growth-inhibiting concentrations. The most interesting compounds are (Z)-4-bromo-5-(bromomethylene)-3-alkyl-2(5H)-furanones with chain lengths of two to six carbon atoms. A microarray study was performed to analyze the gene expression profiles of Salmonella in the presence of (Z)-4-bromo-5-(bromomethylene)-3-ethyl-2(5H)-furanone. The induced genes include genes that are involved in metabolism, stress response, and drug sensitivity. Most of the repressed genes are involved in metabolism, the type III secretion system, and flagellar biosynthesis. Follow-up experiments confirmed that this furanone interferes with the synthesis of flagella by Salmonella. No evidence was found that furanones act on the currently known quorum-sensing systems in Salmonella. Interestingly, pretreatment with furanones rendered Salmonella biofilms more susceptible to antibiotic treatment. Conclusively, this work demonstrates that particular brominated furanones have potential in the prevention of biofilm formation by Salmonella serovar Typhimurium.

The synthesis of 2,3-dihydro-4(1H)-quinazolinone angiotensin II receptor antagonists

Abstract The synthesis and biological evaluation of a series of 2,3,-dihydro-4-(1H)-quinazolinone angiotensin II receptor antagonists is described.

The discovery of anthranilic acid-Based MMP inhibitors. Part 2: SAR of the 5-position and P11 groups

A novel series of anthranilic acid-based inhibitors of MMP-1, MMP-9, MMP-13, and TACE was prepared and evaluated. Selective inhibitors of MMP-9, MMP-13, and TACE were identified, including the potent, orally active MMP-13 inhibitor 4p.

Design and synthetic considerations of matrix metalloproteinase inhibitors.

ABSTRACT: Experimental evidence confirms that the matrix metalloproteinases (MMPs) play a fundamental role in a wide variety of pathologic conditions that involve connective tissue destruction including osteoarthritis and rheumatoid arthritis, tumor metastasis and angiogenesis, corneal ulceration, multiple sclerosis, periodontal disease, and atherosclerosis. Modulation of MMP regulation is possible at several biochemical sites, but direct inhibition of enzyme action provides a particularly attractive target for therapeutic intervention. Hypotheses concerning inhibition of specific MMP(s) with respect to disease target and/or side‐effect profile have emerged. Examples are presented of recent advances in medicinal chemistry approaches to the design of matrix metalloproteinase inhibitors (MMPIs), approaches that address structural requirements and that influence potency, selectivity, and bioavailability. Two important approaches to the design, synthesis, and biological evaluation of MMPIs are highlighted: (1) the invention of alternatives to hydroxamic acid zinc chelators and (2) the construction of nonpeptide scaffolds. One current example in each of these two approaches from our own work is described.

The discovery of anthranilic acid-based MMP inhibitors. Part 1: SAR of the 3-position

A novel series of anthranilic acid-based inhibitors of MMP-1, MMP-9, and MMP-13 was prepared and evaluated both in vitro and in vivo. The most potent compound, 6e, has in vivo activity in a rat sponge-wrapped cartilage model.

Chapter 16. TNF-α converting enzyme (TACE) as a therapeutic target

Abstract The most important unresolved issues impacting the design of future TACE inhibitors are the frequent discrepancies between activity measured in cell-free TACE assays and cellular assays of LPS-stimulated TNF-α, and the desired TACE/MMP selectivity profile to provide adequate efficacy and safety. Many factors, most natably cell permeability and protein binding have been considered in obtaining highly active compounds in cells. The possibility that differences in the membrane bound enzyme and cell-free enzyme alter the configuration of the S1′ and S3′ enzyme subsites has also been addressed (61). The assessment of preferred TACE/MMP selectivity profiles awaits further clinical testing of TACE inhibitors against various pathologies. The development of new enzyme assays, including a continuous fluorometric TACE assay and a high-throughput screen based on a phage-displayed TACE catalytic domain should also aid in the rapid identification of new inhibitors (62, 63). A recent study of the binding process for hydroxamate and carboxylate TACE ligands may also be valuable for inhibitor design (64).

Palladium-catalyzed coupling of an α-stannyl acrylate to aryl iodides and triflates. A one-step synthesis of aryl propenoic esters.

Abstract Aryl iodides undergo a Pd(0)-CuI catalysed coupling with methyl 3-(tributylstannyl)propenoate to provide the corresponding aryl propenoic esters. Triflates require Pd(0)-CuI-LiCl.

The discovery of anthranilic acid-based mmp inhibitors. Part 3: incorporation of basic amines

Anthranilic acid derivatives bearing basic amines were prepared and evaluated in vitro and in vivo as inhibitors of MMP-1, MMP-9, MMP-13, and TACE. Piperazine 4u has been identified as a potent, selective, orally active inhibitor of MMP-9 and MMP-13.

The synthesis and biological activity of a novel series of diazepine MMP inhibitors.

A novel series of diazepine-based hydroxamic acid inhibitors of MMP-1, MMP-9, and MMP-13 were prepared and evaluated both in vitro and in vivo.

Synthesis and evaluation of 4-Anilino-6,7-dialkoxy-3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade

4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-6,7-diethoxy-3-quinolinecarbonitrile (3) was identified as a MEK1 kinase inhibitor with exceptional activity against LoVo cells. The structure-activity relationships of the C-4 aniline substituents were explored, and water-solubilizing groups were added at the C-7 position to improve physical properties. Secondary cellular assays revealed that a compound possessing the appropriate aniline substituents inhibited MEK1 as well as MAPK phosphorylation, thereby acting as a dual inhibitor of the Ras-MAPK signaling cascade.