Het(aryl)isatin to het(aryl)aminoindoline scaffold hopping: A route to selective inhibitors of matrix metalloproteinases

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endoproteases known to exert multiple regulatory roles in tumor progression. A variety of chemical classes have been explored for targeting individual MMP isoforms. In the present study, we further developed our isatin based scaffold BB0223107 capable of binding to and inactivating MMP-2 in a zinc-independent manner (Agamennone et al., 2016). Forty four new compounds were synthesized based on the modified BB0223107. All compounds were tested in enzyme inhibition assays against MMP-2, ?8 and ?13. SAR studies demonstrated that 5-het(aryl)-3-aminoindolin-2-ones (37–39) were active toward MMP-2 and MMP-13. The most potent compounds 33 and 37 displayed an IC₅₀ of 3 µM against MMP-13 and showed a negligible activity toward MMP-8; almost all new compounds were inactive toward MMP-8. Replacement of the isatin ring with a biaryl system (compound 33) did not decrease the potency against MMP-13 but reduced the selectivity. Structure-based computational studies were carried out to rationalize the inhibitory activity data. The analysis of binding geometries confirmed that all fragments occupied the S1′ site in the three enzymes while no ligand was able to bind the catalytic zinc ion. To the best of our knowledge, this is the first example of 3-aminoindolin-2-one-based MMP inhibitors that, based on the computer modeling study, do not coordinate the zinc ion. Thus, the het(aryl)-3-aminoindolin-2-one derivatives emerge as a drug-like and promising chemotype that, along with the hetaryl variations, represents an alternative and thrifty tool for chemical space exploration aimed at MMP inhibitor design.     

New stereoselective synthesis of the peptidic aminopeptidase inhibitors bestatin, phebestin and probestin

Peptidic aminopeptidase inhibitors, bestatin, phebestin and probestin have been prepared by stereo- and regiocontrolled reactions from a common α,β-epoxy ester precursor.     

A new approach towards peptidosulfonamides: synthesis of potential inhibitors of bacterial peptidoglycan biosynthesis enzymes MurD and MurE

Peptidosulfonamides are an emerging group of peptidomimetics with a variety of applications in medicinal chemistry. We present a novel approach to the synthesis of peptidosulfonamides, and apply it to a series of new potential inhibitors of the bacterial peptidoglycan biosynthesis enzymes MurD and MurE. The synthesis was conducted via N-phthalimido β-aminoethanesulfonyl chlorides, which are new building blocks for the synthesis of peptidosulfonamides. In the most crucial step, sulfonic acids or their sodium salts were converted into the corresponding sulfonyl chlorides using an excess of either SOCl₂ or SOCl₂/DMF, and then coupled to the C-protected amino acid. None of the compounds significantly inhibited MurD, however, some inhibited MurE; one had an IC₅₀ below 200 μM, which constitutes a promising starting point for further development. Molecular modelling simulations were performed on two analogues to investigate the absence of inhibitory activity of the sulfonamide compounds on MurD.     

Current methods for site-directed structure generation

Summary There has been a rapid growth of interest in techniques for site-directed drug design, fuelled by the increasing availability of structural models of proteins of therapeutic importance, and by studies reported in the literature showing that potent chemical leads can be obtained by these techniques. Structure generation programs offer the prospect of discovering highly original lead structures from novel chemical families. Due to the fact that this technique is more-or-less still in its infancy, there are no case studies available that demonstrate the use of structure generation programs for site-directed drug design. Such programs were first proposed in 1986, and became commercially available in early 1992. They have shown their ability to reproduce, or suggest reasonable alternatives for, ligands in well-defined binding sites. This brief review will discuss the recent advances that have been made in the field of site-directed structure generation.     

Inhibitors of biotin biosynthesis as potential herbicides

Isosteric derivatives and analogues of the 7-keto-8-aminopelargonic acid (KAPA), 7,8-diaminopelargonic acid (DAPA) and desthiobiotin (DTB) vitamer intermediates involved in the biosynthetic pathway of biotin were prepared and evaluated as potential herbicides. The most active compound was desmethyl-KAPA which displayed a GR₅₀ (concentration of the active compound that causes a 50% growth inhibition) value of 8 ppm, where values <50 ppm are considered herbicidal. Other KAPA analogs where the terminal Me group was replaced by bulkier substituents such as Et, i-Pr and HOCH₂ showed moderate activity.     

Application of enzyme-field effect transistor sensor arrays as detectors in a flow-injection analysis system for simultaneous monitoring of medium components. Part II. Monitoring of cultivation processes

Glucose, maltose, sucrose, lactose, ethanol and urea concentrations were monitored simultaneously during the cultivation of Escherichia coli and Saccharomyces cerevisiae by means of enzyme field effect transistors (EnFETs) applying glucose dehydrogenase (GDH), maltase (MAL)/GDH, invertase (INV)/GDH, β-galactosidase (β-GAL)/galactosedehydrogenase (GALDH), alcoholdehydrogenase (ADH)/aldehydedehydrogenase (ALDH), and urease. These enzymes were (co)immobilized on the pH sensitive gates of an eight-FET array. The FET array was integrated in a commercial FIA system.     

The structure-activity relationship of inhibitors of serotonin uptake and receptor binding

Summary An analysis of five different datasets of inhibitors of serotonin uptake has yielded quantitative structure/ activity relationships (QSARs) which delineate the role of steric and hydrophobic properties essential for inhibition by phenylethylamine-type analogues.     

Synthesis and biological evaluation of 6-oxa-nor-tropane glycomimetics as glycosidase inhibitors

The preparation of polyhydroxylated 6-oxa-nor-tropane glycomimetics structurally related to the glycosidase inhibitor family of the calystegines is reported. The synthetic strategy involves the furanose→piperidine rearrangement of 5-deoxy-5-ureido-l-idose precursors, followed by intramolecular glycosylation involving the primary hydroxyl group. Inversion of the configuration at C-3 in the resulting 6-oxa-(+)-calystegine B₂ analogue allows accessing the elusive 3-epi-6-oxa-(+)-calystegine B₂ skeleton. Acid-catalyzed opening of the nor-tropane bicycle was observed, however, which could be avoided by careful neutralization of the reaction mixture. The inhibition results suggest that (+)-calystegine B₂ derivatives and the corresponding C-3 epimers can be seen as glucomimetics and galactomimetics, respectively, pointing to a 1-azasugar mode of action for this family of alkaloids.     

Bioisosterism between Sulfonyl Group and Phosphoryl Group-The Synthesis of New ALS Inhibitors N-(Arylamino Hydroxyl Phosphoryl)-N'-(4,6-Dimethoxypyrimidine-2-yl)ureas

Sulfonylureaherbicidesisanewclassofherbicidesdiscoveredinthemid-l97O's',whosemodeofactionhasbeenestablishedastheinhibitionofacetolactatesynthase(ALS,alsoreferredasacetohydroxyacidsynthase)'-Muchattentionhasbeenfocussedonthiskindofcompound,sincetheyhaveunprecedenteduserates,ahighdegreeofselectivity,andexcellentenvironmentalsafety'.NumerousmodificationsofthestrUctureofthisclassofherbicideshavebeenreported'.Wehavetakenattentiontothesimi1alltybetweenthesulfonylgroup(-SO2-)andphosphoryIgroup[-P…