Werkzeuge zur Modellierung von Siliciumbornitrid-Keramiken : Entwicklung von Mehrkörperpotenzialen und Berechnung zur NMR-chemischen Verschiebung

Die Schrift schildert die Entwicklung von Zugängen zur Modellierung amorpher Hochleistungskeramiken im System Silicium/Stickstoff/Bor(/Wasserstoff) Es geht dabei um zwei komplementäre Herangehensweisen: (a) der Parameterisierung von klassischen (d.h. die Elektronenstruktur nicht explizit behandelnden) Wechselwirkungspotenzialen und (b) dem Finden, Quantifizieren und Validieren von Struktur-Eigenschaftsbeziehungen bzgl. der chemischen Verschiebung. Ersteres stellt für Si/B/N-Systeme, Zweiteres für die Modellierung amorpher Festkörper prinzipiell eine Novität dar. Für das System Si/B/N(/H) wurden verschiedene interatomare Modellpotenziale zur Bestimmung von Energie, Kräften etc. parameterisiert. Es handelt sich dabei um drei unterschiedlich schnell auszuwertende Parametersätze. Alle Potenziale werden hinsichtlich ihrer analytischen Form, der Anpassung und Leistungsfähigkeit detailliert dargestellt; neuartige analytische Ausdrücke werden besprochen. Auf Seiten der Beziehungen NMR Struktur konnte zu Beginn vermittels einer Konnektivitätsanalyse und Untersuchungen an (bis zur Konvergenz der Eigenschaften) wachsenden Clustern die 15N-chemische Verschiebung im hexagonalen Bornitrid vorhergesagt werden. Auf diesen Ergebnissen aufbauend wurde eine systematische Untersuchung der Abhängigkeit 15N und 11B-chemischer Verschiebungen in Bor - und Siliciumnitriden durch Strukturvariationen ermöglicht und durchgeführt. Ein perspektivischer Vorschlag zum Vereinen von sowohl Energiefunktionen als auch der NMR-Struktur-Eigenschaftsbeziehungen in einer KostenfunktionThis work documents the development and capabilities of tools for modelling the structure of amorphous high-demand ceramics in the system silicon/boron/nitrogen(/hydrogen). The thesis is concerned with two complementary approaches: (a) aparameterisation of classical interatomic interaction potentials (i.e. electrons are not treated explicitly) and (b) the establishment, quantification and validation of structure-property relationships for the chemical shift delta. The first point represents a novelty within the Si/B/N system, the second is presented in the framework of a general, new access to model amorphous solids. For the system Si/B/N(/H) different model potentials have been developed which are the basis for an efficient determination of energies, forces on atoms etc. There are three parameter sets which differ in their expressions/approximations and are thus evaluated at different computational speeds. All potentials including their extraction, powers, and limits are described in detail, new expressions are discussed. On the side of NMR-property relationships, a prediction of the 15N-chemical shift could be extablished; the method is based on an analysis of connectivities on growing clusters until the convergence of delta. Starting from these results, a systematic investigation of the 15N- and 11B-chemical shift dependency with structure has been conducted. A proposal bearing the character of a proposal to unify the two approaches within a single cost function closes the thesis

Modeling Si/B/N/(C) Ceramic Materials

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Crystal structures, binding interactions, and ADME evaluation of brain penetrant N-substituted indazole-5-carboxamides as subnanomolar, selective monoamine oxidase B and dual MAO-A/B inhibitors

Tzvetkov NT, Stammler H-G, Neumann B, Hristova S, Antonov L, Gastreich M. Crystal structures, binding interactions, and ADME evaluation of brain penetrant N-substituted indazole-5-carboxamides as subnanomolar, selective monoamine oxidase B and dual MAO-A/B inhibitors. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. 2017;127:470-492.The pharmacological and physicochemical analysis of structurally optimized N-alkyl-substituted indazole-5-carboxamides, developed as potential drug and radioligand candidates for the treatment and diagnosis of Parkinson's disease (PD) and other neurological disorders, is reported. Recent efforts have been focused on the development of subnanomolar potent, selective MAO-B (N1-alkyl-substituted compounds 12a-14a and 15) and dual active MAO-A/B (N2-methylated compounds 12b-14b) inhibitors with nanomolar potency towards MAO-B and moderately active against MAO-A enzyme, respectively. The most promising drug-like derivatives in both series were N-(3-chloro-4-fluoropheny1)-1-methy1-1Hindazole-5-carboxamide (13a, NTZ-1441, IC50 hMAO-B 0.662 nM, >15000-fold selective versus MAO-A) and N-(3-chloro-4-fluorophenyl)-2-methyl-2H-indazole-5-carboxamide (13b, NTZ-1442, IC50 hMAO-B 8.08 nM, IC50 hMAO-A 0.56 mu M, SI = 70). Moreover, compounds 13a and 13b were predicted to cross both the gastrointestinal tract (at pH 2.0, 5.5, and 7,4) and the blood-brain barrier (BBB) in vitro with appropriate drug-like properties required for CNS active drugs. Combined single X-ray/molecular modeling studies provided insights into the enzyme inhibitor interactions within both MAO isoforms and the rationale for their inhibitory activity with controlled MAO-A/B selectivity despite their small structural differences. The binding modes of 12a,b and 13a,b confirmed that the major interactions with hMAO-B were established via the flexible carbonyl group of the carboxamide linkage and the electron donating nitrogens N1 or N2 of the indazole moiety, allowing further exploration of the alkyl side chain for next step lead optimization efforts. (C) 2017 Elsevier Masson SAS. All rights reserved

Indazole- and Indole-5-carboxamides: Selective and Reversible Monoamine Oxidase B Inhibitors with Subnanomolar Potency

Indazole- and indole-carboxamides were discovered as highly potent, selective, competitive, and reversible inhibitors of monoamine oxidase B (MAO-B). The compounds are easily accessible by standard synthetic procedures with high overall yields. The most potent derivatives were <i>N</i>-(3,4-dichlorophenyl)-1-methyl-1<i>H</i>-indazole-5-carboxamide (<b>38a</b>, PSB-1491, IC₅₀ human MAO-B 0.386 nM, >25000-fold selective versus MAO-A) and <i>N</i>-(3,4-dichlorophenyl)-1<i>H</i>-indole-5-carboxamide (<b>53</b>, PSB-1410, IC₅₀ human MAO-B 0.227 nM, >5700-fold selective versus MAO-A). Replacement of the carboxamide linker with a methanimine spacer leading to (<i>E</i>)-<i>N</i>-(3,4-dichlorophenyl)-1-(1<i>H</i>-indazol-5-yl)­methanimine (<b>58</b>) represents a further novel class of highly potent and selective MAO-B inhibitors (IC₅₀ human MAO-B 0.612 nM, >16000-fold selective versus MAO-A). In <i>N</i>-(3,4-difluorophenyl-1<i>H</i>-indazole-5-carboxamide (<b>30</b>, PSB-1434, IC₅₀ human MAO-B 1.59 nM, selectivity versus MAO-A >6000-fold), high potency and selectivity are optimally combined with superior physicochemical properties. Computational docking studies provided insights into the inhibitors’ interaction with the enzyme binding site and a rationale for their high potency despite their small molecular size

Magnet for the Needle in Haystack: “Crystal Structure First” Fragment Hits Unlock Active Chemical Matter Using Targeted Exploration of Vast Chemical Spaces

Fragment-based drug discovery (FBDD) has successfully led to approved therapeutics for challenging and “undruggable” targets. In the context of FBDD, we introduce a novel, multidisciplinary method to identify active molecules from purchasable chemical space. Starting from four small-molecule fragment complexes of protein kinase A (PKA), a template-based docking screen using Enamine’s multibillion REAL Space was performed. A total of 93 molecules out of 106 selected compounds were successfully synthesized. Forty compounds were active in at least one validation assay with the most active follow-up having a 13,500-fold gain in affinity. Crystal structures for six of the most promising binders were rapidly obtained, verifying the binding mode. The overall success rate for this novel fragment-to-hit approach was 40%, accomplished in only 9 weeks. The results challenge the established fragment prescreening paradigm since the standard industrial filters for fragment hit identification in a thermal shift assay would have missed the initial fragments

Carboxamides vs. methanimines: Crystal structures, binding interactions, photophysical studies, and biological evaluation of (indazole-5-yl)methanimines as monoamine oxidase B and acetylcholinesterase inhibitors.

Tzvetkov NT, Stammler H-G, Georgieva MG, et al. Carboxamides vs. methanimines: Crystal structures, binding interactions, photophysical studies, and biological evaluation of (indazole-5-yl)methanimines as monoamine oxidase B and acetylcholinesterase inhibitors. European journal of medicinal chemistry. 2019;179::404-422.A comprehensive study was performed for the first time to compare two structurally related substance classes, namely indazole-5-carboxamides (11-16) and (indazole-5-yl)methanimines (17-22). Both chemical entities are potent, selective and reversible MAO-B inhibitors and, therefore, may serve as promising lead structures for the development of drug candidates against Parkinson's disease (PD) and other neurological disorders. Compounds 15 (Ki = 170 pM, SI = 25907) and 17 (Ki = 270 pM, SI = 16340) were the most potent and selective MAO-B inhibitors in both series. To investigate the multi-target inhibitory activity, all compounds were further screened for their potency against human AChE and BuChE enzymes. Compound 15 was found to be the most potent and selective AChE inhibitor in all series (hAChE IC50 = 78.3 ± 1.7 muM). Moreover, compounds 11 and 17 showed no risk of drug-induced hepatotoxicity and a wider safety window, as determined in preliminary cytotoxicity screening. Molecular modeling studies into the human MAO-B enzyme-binding site supported by a HYDE analysis suggested that the imine linker similarly contributes to the total binding energy in methanimines 17-22 as the amide spacer in their carboxamide analogs 11-16. Amplified photophysical evaluation of compounds 17 and 20, including single X-ray analysis, photochemical experiments, and quantum-chemical calculations, provided insights into their more favourable isomeric forms and structural features, which contribute to their biologically active form and promising drug-like properties. Copyright © 2019 Elsevier Masson SAS. All rights reserved