Marco Lessi

The present work reports a straightforward approach for the mechanochemical oxidative nitroso Diels–Alder (DA) reaction for the rapid synthesis of oxadiazo[2.2.2]octenes and a mechanochemical [3+3] hetero‐Cope rearrangement to access the corresponding dioxazines within reduced reaction time (up to 1.5 min and 1.5 h, respectively), high yields and reproducibility toward different functional groups.

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder involving metabolic impairment, neuroinflammation, synaptic failure, and comorbidities. Hence, therapeutic development for AD is rapidly shifting from a single-target approach, centred on amyloid-beta (Aβ) reduction, to multi-target strategies. In this study, we investigated the neuroprotective profile of two acetanilide derivatives, SG-22 and SG-23, originated from the halogen-free thyronamine-like lead compound SG-2. Their efficacy was evaluated through an integrated approach combining in vitro cellular models, in vivo phenotypic screening in a Caenorhabditis elegans AD model, and comprehensive ADME-Tox profiling. In U87MG cells, both SG-22 and SG-23 effectively prevented Aβ_25–35-induced cytotoxicity and restored autophagy-related gene expression, including LC3, SIRT1, and SIRT6, while reducing mTOR and SIRT5 levels. Furthermore, all compounds exhibited anti-inflammatory effects in activated HMC3 microglial cells, reducing IL-6 and increasing IL-10 levels, with evidence suggesting partial involvement of TAAR1 signalling. ADME-Tox analyses revealed improved safety and metabolic profiles for the tested compounds, particularly SG-22, which showed reduced hERG liability and enhanced cytochrome P450 stability. However, in vivo studies demonstrated that only SG-2 and SG-23 improved motility and fitness in the C. elegans AD model, consistent with their ability to activate autophagy, whereas SG-22 was ineffective due to limited organismal uptake. Ultimately, the monoacetylated analogue SG-23 emerges as a promising candidate, balancing neuroprotective efficacy and drug-like properties, and supporting thyronamine-like analogues as multi-target agents for AD.

The multivariate approach allows to achieve a controlled degree of structural heterogeneity within metal-organic frameworks (MOFs), offering a powerful means to finely tune the properties of the framework at the molecular level. In this work, we apply this concept to the MIL-140A(Ce) framework to systematically introduce multiple fluorinated terephthalate linkers (F x -BDC ²⁻ ), enabling precise modulation of the cooperative CO ₂ adsorption behaviour through the control of the framework’s degree of fluorination. By simultaneously incorporating and varying the nature and content of F x -BDC ²⁻ co-linkers ( x = 1, 2, 3) while maintaining F4-BDC ²⁻ as a fixed component, we synthesised a large library of mixed-linker F4:F x _MIL-140A(Ce) materials, whose nature of solid solutions was demonstrated. Across the series, we found that cooperative CO ₂ adsorption occurs above a threshold degree of fluorination of the framework of 75%, independently of fluorine positional isomerism, as demonstrated by the series of o -, m -, and p F2-BDC ²⁻ co-linkers, and is not determined by the content of the perfluorinated linker. The implication of the fluorination threshold on CO ₂ /CH ₄ selectivity was also assessed, revealing that the onset of CO ₂ -induced cooperative adsorption above this threshold is associated with a dramatic increase in selectivity towards CO ₂ . Since the degree of fluorination of single-linker MOFs is intrinsically fixed, the mixed-linker strategy represents an effective route to continuously tune the framework’s composition, thereby enabling the establishment of a structural design principle to control the emergence of cooperative CO ₂ adsorption.

The structural chemistry of two‐dimensional Cu(II) coordination networks constructed from ring‐disubstituted bis(imidazolyl)benzene ligands has been investigated in order to elucidate the combined influence of ligand functionalization and counteranion identity on layer geometry, packing, and framework stability. The dimethyl‐substituted ligand ( bibMe ₂ ) affords three closely related layered frameworks when combined with copper(II) nitrate ( UdP‐8‐NO ₃ ), copper(II) perchlorate ( UdP‐8‐ClO ₄ ), or copper(II) tetrafluoroborate ( UdP‐8‐BF ₄ ), leading to new compounds of formula [Cu( bibMe ₂ ) ₂ (X) ₂ ]·nSolv (X = NO ₃ , ClO ₄ or BF ₄ ). UdP‐8‐NO ₃ and UdP‐8‐ClO ₄ were obtained both in single crystal and powder form. On the other hand, UdP‐8‐BF ₄ could only be isolated as a powder. UdP‐8‐NO ₃ and UdP‐8‐ClO ₄ are isoreticular at the local coordination level, showing a sql topology, but display markedly different layer arrangements, stacking modes, interlayer separations, and accessible void volumes. These structural differences translate into a pronouncedly different response to external stimuli, as revealed by PXRD‐based stability tests under humidity, vacuum, and variable temperature conditions. Extension to a methoxy‐disubstituted ligand ( bibOMe ₂ ) yields single crystals of a further two‐dimensional Cu(II) network describable with a formula [Cu( bibOMe ₂ ) ₂ (ClO ₄ ) ₂ ] ( UdP‐9‐ClO ₄ ). This compound could only be isolated as single crystals; therefore, no further characterization was carried out.

Herein, we report a general and practical electrochemical method for the synthesis of α-keto esters from malonic acid derivatives via α-carbonyl carbocations. Although these cations are typically unstable, they can be efficiently generated under Hofer-Moest-type conditions when stabilized by an α-acetoxy substituent. This metal- and supporting-electrolyte-free approach grants straightforward access to α-keto esters that are otherwise challenging to obtain using conventional methods.

Alternating current (AC) has recently been explored as a powerful electrolysis operating mode to access synthetic intermediates, avoiding overoxidation events and electrode passivation. In this work, we explore the applications of AC to the electrooxidative nitroso Diels-Alder reaction (nDA) through the in situ formation of acyl nitroso intermediates (dienophile). Further reaction with 1,2-dihydropyridine (DHP) derivatives (dienes) unlocked a sustainable regio- and stereoselective protocol for the synthesis of oxadiazo[2.2.2]octenes.

Understanding fundamental aspects of the adsorption behaviour of flexible metal-organic frameworks (MOFs) is key to develop improved sorbents for gas separations. The recently reported F4_MIL-140A(Ce) displays cooperative CO2 and H2O adsorption driven by concerted rotation of the aromatic rings of the tetrafluoroterephthalate linkers, giving rise to a step-shaped isotherm. Here, we shed light on the key role played by the degree of fluorination of the linker in such mechanism by synthesising novel Fx_MIL-140A(Ce) (x = 2 or 3) analogues and characterising them by gas sorption analysis, in situ powder X-ray diffraction, solid state nuclear magnetic resonance spectroscopy, in situ infrared spectroscopy and adsorption microcalorimetry. We found that the cooperative CO2 adsorption mechanism is switched off in Fx_MIL-140A(Ce), leading to Langmuir-type CO2 isotherms. Different from F4_MIL-140A(Ce), CO2 adsorption triggers no structural response in Fx_MIL-140A(Ce), due to the reduced steric hindrance of less fluorinated linkers that makes the CeIV open metal sites accessible already at low pressure, with no need for concerted aromatic ring rotation. In contrast, the adsorption of water induces similar cooperative structural rearrangements in Fx_MIL-140A(Ce) and the parent F4_MIL-140A(Ce), suggesting that auxiliary adsorbate-linker interactions play a role in inducing cooperative adsorption.

Sirtuin 1 (SIRT1) is an NAD⁺-dependent deacetylase implicated in various physiological and pathological processes, including cardiovascular diseases. The lead compound for SIRT1, resveratrol (1), as well as natural-derived and synthetic SIRT1-activating compounds demonstrated to exert cardioprotective effects. In the present work, we evaluated a small series of diarylimidazoles, of which 4 emerged, in in vitro enzymatic assays, as an activator of SIRT1 endowed with a similar potency compared with that of 1. Therefore, 4 was subjected to pharmacological investigation, where it was proven to reduce myocardial damage induced by ischemia/reperfusion injury in isolated rat hearts, thus demonstrating its cardioprotective properties. An in silico study suggested the binding mode of this derivative within SIRT1 in the presence of the p53-AMC-peptide. These promising results could pave the way to further expand and optimize this chemical class of new SIRT1 activators as potential cardioprotective agents.

Incorporating fluorine atoms into the organic linker is a widely adopted strategy to tune the properties of Metal-Organic Frameworks (MOFs). However, identifying a trend in how fluorine atoms modulate the structure of porous frameworks remains an unaddressed topic. We report a systematic investigation of how stepwise fluorination of 1,4-benzenedicarboxylic acid linkers (Fx-H₂BDC) influences the structural features of the Ce^IV-based UiO-66 architecture. The complete series of fluorinated Fx_UiO-66(Ce) materials (where x = 0, 1, 2, 3, 4) was synthesized using acetic acid as a crystallization modulator in a mixed DMF:H₂O solvent and fully characterized. ¹H and ¹⁹F liquid-state NMR spectroscopy of digested samples, supported by thermogravimetric analysis, confirmed that all fluorinated derivatives are defect-free, whereas the nonfluorinated analogue contains a small amount of missing-linker defects. N₂ adsorption measurements revealed a decreasing trend in BET surface areas with increasing fluorination. Rietveld refinements of high-resolution synchrotron powder X-ray diffraction data indicate a gradual expansion of the unit cell as the degree of fluorination increased, along with the elongation of the Ce^IV-O_carboxylate bonds, while the aromatic rings are progressively twisted out of the plane of the carboxylates and a water molecule is incorporated into the coordination sphere of Ce^IV.

Three isoreticular anion pillared metal-organic frameworks were synthesized using CuX₂ (X = BF₄^-, ClO₄^-, NO₃^-) salts and the 1,1'-(2-(trifluoromethyl)-1,4-phenylene)bis(1H-imidazole) ligand (bibCF₃). Single-crystal X-ray diffraction reveals that these peculiar materials, of the general formula [Cu(bibCF₃)₂X]·X, feature bidentate monovalent anions acting as pillars between square layers designed by metal ions and organic linkers and extraframework anions located in the channel-like pores. The materials display remarkable thermal and chemical stability and promising CO₂ adsorption performance, dependent on the nature of the anion.