@article{WelkerKerstenMuelleretal.2021, author = {Welker, Armin and Kersten, Christian and M{\"u}ller, Christin and Madhugiri, Ramakanth and Zimmer, Collin and M{\"u}ller, Patrick and Zimmermann, Robert and Hammerschmidt, Stefan and Maus, Hannah and Ziebuhr, John and Sotriffer, Christoph and Schirmeister, Tanja}, title = {Structure-Activity Relationships of Benzamides and Isoindolines Designed as SARS-CoV Protease Inhibitors Effective against SARS-CoV-2}, series = {ChemMedChem}, volume = {16}, journal = {ChemMedChem}, number = {2}, doi = {10.1002/cmdc.202000548}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225700}, pages = {340 -- 354}, year = {2021}, abstract = {Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PL\(^{pro}\)) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the noncovalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS-CoV PL\(^{pro}\). Moreover, we report the discovery of isoindolines as a new class of potent PL\(^{pro}\) inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PL\(^{pro}\) are valuable starting points for the development of new pan-coronaviral inhibitors.}, language = {en} } @article{TackeLinohAttarBashietal.1982, author = {Tacke, Reinhold and Linoh, Haryanto and Attar-Bashi, Moayad T. and Sheldrick, William S. and Ernst, Ludger and Niedner, Roland and Frohnecke, Joachim}, title = {Sila-Pharmaka, 26. Mitt. [1] Darstellung und Eigenschaften potentiell curarewirksamer Silicium-Verbindungen, III}, series = {Zeitschrift f{\"u}r Naturforschung B}, volume = {37}, journal = {Zeitschrift f{\"u}r Naturforschung B}, number = {11}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128402}, pages = {1461-1471}, year = {1982}, abstract = {The potentially curare-like silicon compounds 8a- 8f were synthesized and investigated with respect to their structure-activity relationships. The conformations of the compounds in the solid state and in solution were studied by X-ray diffraction analysis (8a- 8e) and IR NMR spectroscopy (8a- 8f), respectively. The muscle relaxing properties of 8a- 8f were investigated on the mouse. The observed structure-activity relationships are not in accordance with the classical "14 {\AA} model" for neuromuscular blocking agents.}, language = {de} } @article{TackeBentlageSheldricketal.1982, author = {Tacke, R. and Bentlage, A. and Sheldrick, W. S. and Ernst, L. and Towart, R. and Stoepel, K.}, title = {Sila-Pharmaka, 24. Mitt. [1]. Sila-Analoga von Nifedipin-{\"a}hnlichen 4-Aryl-2.6-dimethyl-1.4-dihydropyridin- 3.5-dicarbons{\"a}ure-dialkylestern, II.}, series = {Zeitschrift f{\"u}r Naturforschung B}, volume = {37}, journal = {Zeitschrift f{\"u}r Naturforschung B}, number = {4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128381}, pages = {443-450}, year = {1982}, abstract = {In the course of systematic studies on sila-substituted drugs the nifedipine-like 1.4-dihydropyridine derivatives 4a, 4b and 4c were prepared and investigated with respect to sila-substitution effects. By X-ray diffraction analyses 4a, 4b and 4c were found to be isostructural. The C/Si-analogues exhibit similar spasmolytic activities (in vitro, guinea pig ileum), comparable with that of nifedipine. However, the compounds differ substantially in their in vivo activity, as measured by the antihypertensive effect on the renal-hypertensive rat. The experimental results are discussed with respect to the carbon/silicon exchange.}, language = {de} } @article{DirimanovHoegger2019, author = {Dirimanov, Stoyan and H{\"o}gger, Petra}, title = {Screening of inhibitory effects of polyphenols on Akt-phosphorylation in endothelial cells and determination of structure-activity features}, series = {Biomolecules}, volume = {9}, journal = {Biomolecules}, number = {6}, issn = {2218-273X}, doi = {10.3390/biom9060219}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197333}, pages = {219}, year = {2019}, abstract = {Polyphenols exert beneficial effects in type 2 diabetes mellitus (T2DM). However, their mechanism of action remains largely unknown. Endothelial Akt-kinase plays a key role in the pathogenesis of cardiovascular complications in T2DM and therefore the modulation of its activity is of interest. This work aimed to characterize effects of structurally different polyphenols on Akt-phosphorylation (pAkt) in endothelial cells (Ea.hy926) and to describe structure-activity features. A comprehensive screening via ELISA quantified the effects of 44 polyphenols (10 µM) on pAkt Ser473. The most pronounced inhibitors were luteolin (44 ± 18\%), quercetin (36 ± 8\%), urolithin A (35 ± 12\%), apigenin, fisetin, and resveratrol; (p < 0.01). The results were confirmed by Western blotting and complemented with corresponding experiments in HUVEC cells. A strong positive and statistically significant correlation between the mean inhibitory effects of the tested polyphenols on both Akt-residues Ser473 and Thr308 (r = 0.9478, p = 0.0003) was determined by immunoblotting. Interestingly, the structural characteristics favoring pAkt inhibition partially differed from structural features enhancing the compounds' antioxidant activity. The present study is the first to quantitatively compare the influence of polyphenols from nine different structural subclasses on pAkt in endothelial cells. These effects might be advantageous in certain T2DM-complications involving over-activation of the Akt-pathway. The suggested molecular mode of action of polyphenols involving Akt-inhibition contributes to understanding their effects on the cellular level.}, language = {en} }