TY - JOUR A1 - Matera, Carlo A1 - Kauk, Michael A1 - Cirillo, Davide A1 - Maspero, Marco A1 - Papotto, Claudio A1 - Volpato, Daniela A1 - Holzgrabe, Ulrike A1 - De Amici, Marco A1 - Hoffmann, Carsten A1 - Dallanoce, Clelia T1 - Novel Xanomeline-containing bitopic ligands of muscarinic acetylcholine receptors: design, synthesis and FRET investigation JF - Molecules N2 - In the last few years, fluorescence resonance energy transfer (FRET) receptor sensors have contributed to the understanding of GPCR ligand binding and functional activation. FRET sensors based on muscarinic acetylcholine receptors (mAChRs) have been employed to study dual-steric ligands, allowing for the detection of different kinetics and distinguishing between partial, full, and super agonism. Herein, we report the synthesis of the two series of bitopic ligands, 12-Cn and 13-Cn, and their pharmacological investigation at the M\(_1\), M\(_2\), M\(_4\), and M\(_5\) FRET-based receptor sensors. The hybrids were prepared by merging the pharmacophoric moieties of the M\(_1\)/M\(_4\)-preferring orthosteric agonist Xanomeline 10 and the M\(_1\)-selective positive allosteric modulator 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) 11. The two pharmacophores were connected through alkylene chains of different lengths (C3, C5, C7, and C9). Analyzing the FRET responses, the tertiary amine compounds 12-C5, 12-C7, and 12-C9 evidenced a selective activation of M\(_1\) mAChRs, while the methyl tetrahydropyridinium salts 13-C5, 13-C7, and 13-C9 showed a degree of selectivity for M\(_1\) and M\(_4\) mAChRs. Moreover, whereas hybrids 12-Cn showed an almost linear response at the M\(_1\) subtype, hybrids 13-Cn evidenced a bell-shaped activation response. This different activation pattern suggests that the positive charge anchoring the compound 13-Cn to the orthosteric site ensues a degree of receptor activation depending on the linker length, which induces a graded conformational interference with the binding pocket closure. These bitopic derivatives represent novel pharmacological tools for a better understanding of ligand-receptor interactions at a molecular level. KW - muscarinic acetylcholine receptors KW - Xanomeline KW - 77-LH-28-1 KW - bitopic hybrid ligands KW - synthesis KW - fluorescence resonance energy transfer Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311249 SN - 1420-3049 VL - 28 IS - 5 ER - TY - JOUR A1 - Seethaler, Marius A1 - Hertlein, Tobias A1 - Hopke, Elisa A1 - Köhling, Paul A1 - Ohlsen, Knut A1 - Lalk, Michael A1 - Hilgeroth, Andreas T1 - Novel effective fluorinated benzothiophene-indole hybrid antibacterials against S. aureus and MRSA strains JF - Pharmaceuticals N2 - Increasing antibacterial drug resistance threatens global health, unfortunately, however, efforts to find novel antibacterial agents have been scaled back by the pharmaceutical industry due to concerns about a poor return on investment. Nevertheless, there is an urgent need to find novel antibacterial compounds to combat antibacterial drug resistance. The synthesis of novel drugs from natural sources is mostly cost-intensive due to those drugs’ complicated structures. Therefore, it is necessary to find novel antibacterials by simple synthesis to become more attractive for industrial production. We succeeded in the discovery of four antibacterial compound (sub)classes accessible in a simple one-pot reaction based on fluorinated benzothiophene-indole hybrids. They have been evaluated against various S. aureus and MRSA strains. Structure- and substituent-dependent activities have been found within the (sub)classes and promising lead compounds have been identified. In addition, bacterial pyruvate kinase was found to be the molecular target of the active compounds. In conclusion, simple one-pot synthesis of benzothiophene-indoles represents a promising strategy for the search of novel antimicrobial compounds. KW - antibacterial drug resistance KW - structure activity KW - synthesis KW - inhibition KW - substituent Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288253 SN - 1424-8247 VL - 15 IS - 9 ER - TY - JOUR A1 - Gehrmann, Robin A1 - Hertlein, Tobias A1 - Hopke, Elisa A1 - Ohlsen, Knut A1 - Lalk, Michael A1 - Hilgeroth, Andreas T1 - Novel small-molecule hybrid-antibacterial agents against S. aureus and MRSA strains JF - Molecules N2 - Ongoing resistance developments against antibiotics that also affect last-resort antibiotics require novel antibacterial compounds. Strategies to discover such novel structures have been dimerization or hybridization of known antibacterial agents. We found novel antibacterial agents by dimerization of indols and hybridization with carbazoles. They were obtained in a simple one-pot reaction as bisindole tetrahydrocarbazoles. Further oxidation led to bisindole carbazoles with varied substitutions of both the indole and the carbazole scaffold. Both the tetrahydrocarbazoles and the carbazoles have been evaluated in various S. aureus strains, including MRSA strains. Those 5-cyano substituted derivatives showed best activities as determined by MIC values. The tetrahydrocarbazoles partly exceed the activity of the carbazole compounds and thus the activity of the used standard antibiotics. Thus, promising lead compounds could be identified for further studies. KW - antibacterial activity KW - synthesis KW - substituent KW - structure–activity KW - inhibition Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252371 SN - 1420-3049 VL - 27 IS - 1 ER - TY - JOUR A1 - Seethaler, Marius A1 - Hertlein, Tobias A1 - Wecklein, Björn A1 - Ymeraj, Alba A1 - Ohlsen, Knut A1 - Lalk, Michael A1 - Hilgeroth, Andreas T1 - Novel small-molecule antibacterials against Gram-positive pathogens of Staphylococcus and Enterococcus species JF - Antibiotics N2 - Defeat of the antibiotic resistance of pathogenic bacteria is one great challenge today and for the future. In the last century many classes of effective antibacterials have been developed, so that upcoming resistances could be met with novel drugs of various compound classes. Meanwhile, there is a certain lack of research of the pharmaceutical companies, and thus there are missing developments of novel antibiotics. Gram-positive bacteria are the most important cause of clinical infections. The number of novel antibacterials in clinical trials is strongly restricted. There is an urgent need to find novel antibacterials. We used synthetic chemistry to build completely novel hybrid molecules of substituted indoles and benzothiophene. In a simple one-pot reaction, two novel types of thienocarbazoles were yielded. Both indole substituted compound classes have been evaluated as completely novel antibacterials against the Staphylococcus and Enterococcus species. The evaluated partly promising activities depend on the indole substituent type. First lead compounds have been evaluated within in vivo studies. They confirmed the in vitro results for the new classes of small-molecule antibacterials. KW - antibacterial activity KW - synthesis KW - substituent KW - structure-activity KW - inhibition Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193130 SN - 2079-6382 VL - 8 IS - 4 ER - TY - JOUR A1 - Ashraf, Kerolos A1 - Yasrebi, Kaveh A1 - Hertlein, Tobias A1 - Ohlsen, Knut A1 - Lalk, Michael A1 - Hilgeroth, Andreas T1 - Novel effective small-molecule antibacterials against \(Enterococcus\) strains JF - Molecules N2 - \(Enterococcus\) species cause increasing numbers of infections in hospitals. They contribute to the increasing mortality rates, mostly in patients with comorbidities, who suffer from severe diseases. \(Enterococcus\) resistances against most antibiotics have been described, including novel antibiotics. Therefore, there is an ongoing demand for novel types of antibiotics that may overcome bacterial resistances. We discovered a novel class of antibiotics resulting from a simple one-pot reaction of indole and \(o\)-phthaldialdehyde. Differently substituted indolyl benzocarbazoles were yielded. Both the indole substitution and the positioning at the molecular scaffold influence the antibacterial activity towards the various strains of \(Enterococcus\) species with the highest relevance to nosocomial infections. Structure-activity relationships are discussed, and the first lead compounds were identified as also being effective in the case of a vancomycin resistance. KW - medicine KW - antibacterial activity KW - synthesis KW - derivatives KW - structure-activity KW - lead structure Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172628 VL - 22 IS - 12 ER - TY - JOUR A1 - Attia, Mohamed I. A1 - Herdeis, Claus A1 - Bräuner-Osborne, Hans T1 - GABA(B)-Agonistic Activity of Certain Baclofen Homologues JF - Molecules N2 - Baclofen (1) is a potent and selective agonist for bicuculline-insensitive GABAB receptors and is used clinically as an antispastic and muscle relaxant agent. In the search for new bioactive chemical entities that bind specifically to GABAB receptors, we report here the synthesis of certain baclofen homologues, namely (R,S)-5-amino-3-arylpentanoic acid hydrochlorides (R,S)-1a–h as well as (R,S)-5-amino-3-methylpentanoic acid [(RS)-1i] to be evaluated as GABABR agonists. Compound 1a is an agonist to GABAB receptors with an EC50 value of 46 μM on tsA201 cells transfected with GABAB1b/GABAB2/Gqz5, being the most active congener among all the synthesized compounds. KW - pharmacological evaluation KW - synthesis KW - GABA KW - baclofen homologues KW - GABAB receptor agonists Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129690 VL - 18 IS - 9 ER - TY - JOUR A1 - Darwish, Hany W. A1 - Attia, Mohamed I. T1 - New spectrofluorimetric methods for determination of melatonin in the presence of N-{2-[1-({3-[2-(acetylamino)ethyl]-5-methoxy-1H-indol-2-yl}methyl)-5-methoxy-1H-indol-3-yl]ethyl} acetamide: a contaminant in commercial melatonin preparations JF - Chemistry Central Journal N2 - Background: Melatonin (MLT) has many health implications, therefore it is of valuable importance to develop specific analytical methods for determination of MLT in the presence of its main contaminant, N-{2-[1-({3-[2(acetylamino)ethyl]-5-methoxy-1H-indol-2-yl}methyl)-5-methoxy-1H-indol-3-yl]ethyl}acetamide (10). For development of these analytical methods, compound 10 had to be prepared in an adequate amount. Results: Compound 10 was synthesized in six steps starting from 5-methoxyindole-2-carboxylic acid (1). Analytical performance of the proposed spectrofluorimetric methods was statistically validated with respect to linearity, accuracy, precision and specificity. The proposed methods were successfully applied for the assay of MLT in laboratory prepared mixtures containing up to 60 % of compound 10 and in commercial MLT tablets with recoveries not less than 99.00 %. No interference was observed from common pharmaceutical additives and the results were favorably compared with those obtained by a reference method. Conclusions: This work describes simple, sensitive, and reliable second derivative spectrofluorimetric method in addition to two multivariate calibration methods, principal component regression (PCR) and partial least square (PLS), for the determination of MLT in the presence of compound 10. KW - melatonin KW - commercial preparations KW - spectrofluorimetry KW - synthesis KW - contaminants Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134606 VL - 6 IS - 36 ER -