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A selective direct arylation of the different Csp2‐H bonds of imidazo[2,1‐b]thiazole with (hetero) aryl halides can be achieved simply by switching from a palladium catalyst system to the use of stoichiometric amounts of copper. The observed selectivity, also rationalized by DFT calculations, can be explained by a change in the mechanistic pathways between electrophilic palladation and base‐promoted C−H metalation. [ABSTRACT FROM AUTHOR]

A series of supported N‐heterocyclic carbene silver complexes (NHC‐Ag(I)) were prepared and characterized as catalysts for the borono‐Minisci reaction. After characterization, the synthesized catalysts were evaluated in batch mode to determine the reaction performance and kinetics. Interestingly, cyclic voltammetric analysis showed that the structure of both the complex and the ligand significantly influences the Ag(I)/Ag(II) redox potential and, in turn, the catalytic efficiency. Among the tested catalysts, the Si‐supported NHC‐Ag(I) 6 afforded the desired products in good to excellent yields in only 15 min, providing a complementary tactic to standard homogeneous approaches. [ABSTRACT FROM AUTHOR]

Arylation of heteroaromatic rings is one of the most important strategy for the chemical space exploration (e. g. applied in medicinal chemistry). In the last two decades C−H activation reactions emerged as powerful and more sustainable synthetic methods for this kind of functionalization if compared to the classical Pd‐catalysed cross‐coupling reactions (e. g. Suzuki, Stille, Negishi, Hiyama). A further step in the direction of greater sustainability has been done developing ligandless C−H activation procedures with higher appeal for industrial application. Among the various N‐based heterocycles exploited in medicinal chemistry, there is no reported ligandless C−H activation for 1H‐indazole core, although its potential pharmaceutical applications. In this work we describe a novel synthetic procedure for the direct arylation/heteroarylation of C‐3 position of 1H‐indazole which was optimized using the Design of Experiment (DoE) (yield up to 72 %) and confirmed a fulfilling robustness among various aryl/heteroaryl and indazole scopes. [ABSTRACT FROM AUTHOR]

The 5-hydroxytryptamine (5-HT1A) receptors represent an attractive target in drug discovery. In particular, 5-HT1Aagonists and partial agonists are deeply investigated for their potential role in the treatment of anxiety, depression, ischaemic brain disorder and more recently, of pain. On the other hand, 5-HT1Aantagonists have been revealed promising compounds in cognition disorders and, lately, in cancer. Thus, the discovery of 5HT1Aligands is nowadays an appealing research activity in medicinal chemistry. In this work, Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) were applied on an in-house library of 5-HT1Aligands bearing different chemical scaffolds in order to elucidate their affinity and selectivity for the target.Following this procedure, a number of structural modifications have been drawn for the development of much more effective 5-HT1AR ligands. [ABSTRACT FROM AUTHOR]

Alzheimer′s disease has recently emerged as a possible field of application for PDE4D inhibitors (PDE4DIs). The great structure similarity among the various PDE4 isoforms and, furthermore, the lack of the full length crystal structure of the enzyme, impaired the rational design of new selective PDE4DIs. In this paper, with the aim of exploring new insights into the PDE4D binding, we tackled the problem by performing a computational study based on docking simulations combined with molecular dynamics (D-MD). Our work uniquely identified the binding mode and the key residues involved in the interaction with a number of in-house catechol iminoether derivatives, acting as PDE4DIs. Moreover, the new binding mode was tested using a series of analogues previously reported by us and it was used to confirm their key structural features to allow PDE4D inhibition. The binding model disclosed within the current computational study may prove to be useful to further advance the design and synthesis of novel, more potent and selective, PDE4D inhibitors. [ABSTRACT FROM AUTHOR]

A selective direct arylation of the different Csp2-H bonds of imidazo[2,1-b]thiazole with (hetero) aryl halides can be achieved simply by switching from a palladium catalyst system to the use of stoichiometric amounts of copper. The observed selectivity, also rationalized by DFT calculations, can be explained by a change in the mechanistic pathways between electrophilic palladation and base-promoted C-H metalation., (© 2024 The Authors. ChemistryOpen published by Wiley-VCH GmbH.)

This note discusses the application of a Minisci-type reaction for the direct alkylation of azoles with carboxylic acids as radical precursors. Different reaction conditions were investigated to achieve high yield of the desired products, focusing on acid strength and solvent screening. Moreover, the reactivity of imidazoles with various carboxylic acids was investigated, showing good yield for most cases. The study reveals the potential of this approach for late-stage functionalization in drug discovery.

A new series of 3-(cyclopentyloxy)-4-methoxyphenyl derivatives, structurally related to our hit GEBR-4a (1) and GEBR-7b (2), has been designed by changing length and functionality of the chain linking the catecholic moiety to the terminal cycloamine portion. Among the numerous molecules synthesized, compounds 8, 10a, and 10b showed increased potency as PDE4D enzyme inhibitors with respect to 2 and a good selectivity against PDE4A4, PDE4B2, and PDE4C2 enzymes, without both cytotoxic and genotoxic effects. The ability to enhance cAMP level in neuronal cells was assessed for compound 8. SAR considerations, also confirmed by in silico docking simulations, evidenced that both chain and amino terminal function characterized by higher hydrophilicity are required for a good and selective inhibitor-catalytic pocket interaction.