Benzo- and Thienobenzo- Diazepines: Multi-target Drugs for CNS Disorders

Terpenoids are major subcomponents in aroma substances which harbor sedative physiological potential. We have demonstrated that various monoterpenoids such as the acyclic linalool enhance GABAergic currents in an allosteric manner in vitro upon overexpression of inhibitory α1β2 GABAA receptors in various expression systems. However, in plants or humans, i.e., following intake via inhalation or ingestion, linalool undergoes metabolic modifications including oxygenation and acetylation, which may affect the modulatory efficacy of the generated linalool derivatives. Here, we analyzed the modulatory potential of linalool derivatives at α1β2γ2 GABAA receptors upon transient overexpression. Following receptor expression control, electrophysiological recordings in a whole cell configuration were used to determine the chloride influx upon co-application of GABA EC10−30 together with the modulatory substance. Our results show that only oxygenated linalool metabolites at carbon 8 positively affect GABAergic currents whereas derivatives hydroxylated or carboxylated at carbon 8 were rather ineffective. Acetylated linalool derivatives resulted in non-significant changes of GABAergic currents. We can conclude that metabolism of linalool reduces its positive allosteric potential at GABAA receptors compared to the significant potentiation effects of the parent molecule linalool itself.

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“…Thus, GABA A Rs represent excellent drug targets for anticonvulsant and sedative agents (Middendorp et al, 2014; Mendonca Junior et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Metabolic Products of Linalool and Modulation of GABAA Receptors

et al. 2017

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“…Benzazepinones are an interesting class of natural products. 19 Notably, point chiral and achiral dibenzazepinones or dibenzodiazepines are present in some drugs, but atropisomeric dibenzazepinones have never been reported. The authors thus surmised that such original atropisomeric products could be readily obtained from bromo-aromatic amides, via Pd-catalyzed intramolecular C-H arylation, with a concomitant introduction of chiral information.…”

Section: Atropo-enantioselective Intramolecular Pd-catalyzed C-h Arylmentioning

confidence: 99%

Challenging Atroposelective C–H Arylation

Wencel‐Delord¹,

Colobert²

2020

SynOpen

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Atropisomeric molecules are privileged scaffolds, not only as ligands for asymmetric synthesis, but also as biologically active products and advanced materials. Although very attractive from a sustainability viewpoint, the direct construction of the stereogenic axis through asymmetric C–H arylation is very challenging and consequently only a few examples have been reported. This short review summarizes these very recent results on the atropo-enantio or diastereoselective synthesis of atropisomeric (hetero)biaryl molecules; transformations during which the Ar–Ar atropisomeric axis is formed during the C–H activation process.1 Introduction2 Atropo-enantioselective Intermolecular Pd-Catalyzed C–H Arylation of Thiophene Derivatives3 Atropodiastereoselective Intermolecular Pd-Catalyzed C–H Arylation towards Terphenyl Scaffolds Bearing Two Atropisomeric Axes4 Atropo-enantioselective Intramolecular Pd-Catalyzed C–H Arylation towards Atropisomeric Benzodiazepinones5 Atropo-enantioselective Intermolecular Pd-Catalyzed C–H Arylation of Heteroarenes6 Rh-Catalyzed Atropo-enantioselective C–H Arylation of Diazonaphthoquinones7 Conclusion

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“…Seven‐membered ring heterocycles are very important scaffolds in Medicinal Chemistry, being widely applied in commercialized drugs with action on the central nervous system . This versatile pharmacophore has been an interesting research topic for chemists and was also object of study for flow chemistry researchers.…”

Section: Heterocyclic Synthesismentioning

confidence: 99%

Flow Chemistry: Towards A More Sustainable Heterocyclic Synthesis

2019

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Flow Chemistry is a revolutionary field in Organic Chemistry. By changing the conventional methods and apparatus applied in the chemical synthesis, flow chemistry emerges as a game changer for organic synthesis laboratories, in both academia and industries. Considered as a sustainable practice, flow processes play an important role in the development of fine chemical products and in drug discovery development pro- [a] The main advantages of flow chemistry are that it allows the reaction to be carried out safely with high selectivity, high reproducibility and reduced energy consumption/carbon footprint. These features make this emerging technology for organic synthesis desirable for green and sustainable chemical synthesis, giving the chemist time for work planning and design, instead of using it in repetitive tasks, [5b,12] as expressed by the CHEM21 project by awarding a green flag for continuousflow reactions, in opposition to an amber flag for those performed under batch conditions. [13] Pedro Brandão received his MSc in Pharmaceutical Sciences from the Faculty of Pharmacy -University of Porto, in 2011. Pursuing his passion on studies in the field of Drug Discovery and Development, he is currently undergoing his PhD studies in Chemistry, in the field of Catalysis and Sustainability. His main focus of work is the discovery of new drug candidates through sustainable techniques. Marta Pineiro received her Ph.D. in Organic Chemistry in 2003 in the University of Coimbra, Portugal, and since 2002 has been enrolled at the University of Coimbra, being at present Auxiliary Professor. Her research interests are in the area of sustainable organic synthesis, microwave-assisted organic synthesis and synthesis and biological applications of tetrapyrrolic macrocycles. Teresa M. V. D. Pinho e Melo studied Chemistry at the University of Coimbra, where she graduated in 1985, got her M. 7191CPBA) as the oxidizing agent, avoiding the handling of this expensive and explosive reagent. [25] Recently, Morodo et al. explored the synthesis of two very important oxiranes (epichlorohydrin and glycidol) from biobased glycerol, under flow conditions. As depicted in Scheme 1, and using pimelic acid as the catalyst (10 mol-%), a sequential hydrochlorination/dichlorination process allows high conversion of glycerol (> 99 %) into 1,3-dichloro-2-propanol, followed by the quantitative conversion into a separable mixture of glycidol and epichlorohydrin (2:3). The separation of these two products is performed by an in-line membrane separation system, which allows the first product to be collected in the aqueous phase, while the second is collected in MTBE. This heterocycle can be further used as a synthetic precursor to relevant APIs bearing -amino alcohol moieties (e.g., propranolol, alprenolol and naftopidil). [26] Scheme 1. Sequential flow setup for the preparation of glycidol and epichlorohydrin, important APIs synthetic intermediates.Scheme 3. Synthesis and inline purification of a bicyclic aziridine (SGMR = silicon-glass microfluidic react...

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Benzo- and Thienobenzo- Diazepines: Multi-target Drugs for CNS Disorders

Cited by 35 publications

References 135 publications

Metabolic Products of Linalool and Modulation of GABAA Receptors

Metabolic Products of Linalool and Modulation of GABAA Receptors

Challenging Atroposelective C–H Arylation

Flow Chemistry: Towards A More Sustainable Heterocyclic Synthesis

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