Hydrazides as substrates in drug synthesis and pharmacological tools

Hydrazydy oraz maleimidy stanowią ważne substraty w syntezie wielu leków oraz narzędzi farmakologicznych. Przykładem łączącym ugrupowanie hydrazydowei maleimidowe w swojej strukturze oraz drodze syntezy jest lek przeciwwirusowy - Tecovirimat. Większość aktualnie opisanych metod syntezy maleimidów wykorzystuje drastyczne warunki reakcji. Alternatywą dla tych metod może być synteza izomaleimidów, przebiegająca w niskiej temperaturze, a następnie konwersja do N-podstawionych maleimidów za pomocą niskotemperaturowego przegrupowania Mumma.Celem niniejszej pracy było zbadanie możliwości zastosowania niskotemperaturowego przegrupowanie Mumma w syntezie N-podstawionych maleimidów. Przedmiotem badań były związki stanowiące intermediaty w syntezie Tecovirimatu oraz związki o potencjalnym zastosowaniu w funkcjonalizacji reszt cysteinowych. Zakres prac obejmował optymalizację syntezy 5-[(5-azydopentylo)imino]furan-2-onu, 5 hydrazydów, 6 pochodnych izomaleimidowych oraz 7 pochodnych maleimidowych. W ramach niniejszej pracy zsyntezowano 18 związków, w tym 2 nieopisane dotychczas w literaturze. Otrzymano 3 z 7 planowanych pochodnych maleimidowych, wykorzystując niskotemperaturowe przegrupowanie Mumma. Wśród 3 w ten sposób otrzymanych pochodnych maleimidowych dla 1 związku stanowiącego intermediat w syntezie Tecovirimatu uzyskano wydajność 2-krotnie wyższą od opisanej,w dokumentacji patentowej. Zoptymalizowano również syntezę -[(5-azydopentylo)imino]furan-2-onu, uzyskując wysokie wydajności i prostą procedurę.Hydrazides and maleimides are important substrates in the synthesis of many drugs and pharmacological tools. An example combining hydrazide and maleimide groups in its structure and synthesis route is the antiviral drug Tecovirimat. Most of the currently described methods of maleimide synthesis encompaass harsh reaction conditions. As an alternative to these methods, isomaleimides can be synthesised at low temperature and then converted to N-substituted maleimides by low-temperature Mumm rearrangement.The aim of this work was to investigate the application of low temperature Mumm rearrangement in the synthesis of N-substituted maleimides. The subject of the study were compounds being intermediates in the synthesis of Tecovirimat and compounds with potential application in functionalization of cysteinę residues. The scope of the work included optimization of the synthesis of 5-[(5-azopentyl)imino]furan-2-one, 5 hydrazides, 6 isomaleimide derivatives and 7 maleimide derivatives. As a part of the present work, 18 compounds were synthesized, including 2 not yet reported in the literature. Three of the seven planned maleimide derivatives were obtained using low-temperature Mumm rearrangement. Among the 3 maleimide derivatives obtained in this way, for 1 compound being an intermediate in the synthesis of Tecovirimat, a two-fold yield increase compared to the one described in the patent documentation was obtained. The synthesis of -[(5-azopentyl)imino]furan-2-one was also optimised, obtaining high yields and a simple procedure

A preliminary report on the verifying research at the fortified settlement from the Early Iron Age in Chotyniec

The article presents the results of the trial excavations carried out in 2016 at the fortified settlement in Chotyniec, Jarosław district. It is an object which has been known and mentioned in archaeological literature for a long, but without its precise chronological affiliation, due to the lack of excavations. However, it was most often combined with the Middle Ages. The conducted research requires significant adjustments. All the sources and contextual records allow us to link this large fortified settlement in Chotyniec with the Early Iron Age and the forest steppe variant of the Scythian cultural circle. This unique site will be researched in the next excavation seasons

1-(Arylsulfonyl-isoindol-2-yl)piperazines as 5-HT6R Antagonists: Mechanochemical Synthesis, In Vitro Pharmacological Properties and Glioprotective Activity

International audienceIn addition to the canonical Gs adenylyl cyclase pathway, the serotonin type 6 receptor (5-HT 6 R) recruits additional signaling pathways that control cognitive function, brain development, and synaptic plasticity in an agonist-dependent and independent manner. Considering that aberrant constitutive and agonist-induced active states are involved in various pathological mechanisms, the development of biased ligands with different functional profiles at specific 5-HT 6 R-elicited signaling pathways may provide a novel therapeutic perspective in the field of neurodegenerative and psychiatric diseases. Based on the structure of SB-258585, an inverse agonist at 5-HT 6 R-operated Gs and Cdk5 signaling, we designed a series of 1-(arylsulfonyl-isoindol-2-yl)piperazine derivatives and synthesized them using a sustainable mechanochemical method. We identified the safe and metabolically stable biased ligand 3g, which behaves as a neutral antagonist at the 5-HT 6 R-operated Gs signaling and displays inverse agonist activity at the Cdk5 pathway. Inversion of the sulfonamide bond combined with its incorporation into the isoindoline scaffold switched the functional profile of 3g at Gs signaling with no impact at the Cdk5 pathway. Compound 3g reduced the cytotoxicity of 6-OHDA and produced a glioprotective effect against rotenone-induced toxicity in C8-D1A astrocyte cell cultures. In view of these findings, compound 3g can be considered a promising biased ligand to investigate the role of the 5-HT 6 R-elicited Gs and Cdk5 signaling pathways in neurodegenerative diseases

Overcoming undesirable hERG affinity by incorporating fluorine atoms: A case of MAO-B inhibitors derived from 1 H-pyrrolo-[3,2-c]quinolines

International audienceThe incorporation of the fluorine motif is a strategy widely applied in drug design for modulating the activity, physicochemical parameters, and metabolic stability of chemical compounds. In this study, we attempted to reduce the affinity for ether-à-go-go-related gene (hERG) channel by introducing fluorine atoms in a group of 1H-pyrrolo[3,2-c]quinolines that are capable of inhibiting monoamine oxidase type B (MAO-B). A series of structural modifications guided by in vitro evaluation of MAO-B inhibition and antitargeting for hERG channels were performed, which led to the identification of 1-(3-chlorobenzyl)-4-(4,4-difluoropiperidin-1-yl)-1H-pyrrolo[3,2-c]quinoline (26). Compound 26 acted as a reversible MAO-B inhibitor exhibiting selectivity over 45 targets, enzymes, transporters, and ion channels, and showed potent glioprotective properties in cultured astrocytes. In addition, the compound demonstrated good metabolic stability in rat liver microsomes assay, a favorable safety profile, and brain permeability. It also displayed procognitive effects in the novel object recognition test in rats and antidepressant-like activity in forced swim test in mice. The findings of the study suggest that reversible MAO-B inhibitors can have potential therapeutic applications in Alzheimer's disease