1,4-Dihydropyridines (1,4-DHPs) are well established as antagonists of L-type Ca2+ channels, thereby exerting potent vasodilatory effects. Nifedipine is regarded as the prototypical representative of this pharmacological class. Calcium signalling plays a critical role in the inflammatory response by activating multiple pro-inflammatory enzymes and mediators. Consequently, modulation or inhibition of this signalling cascade represents a compelling therapeutic approach for the development of novel anti-inflammatory agents. The hydrazone moiety is known to display a wide spectrum of biological activities, among which, its anti-inflammatory potential is particularly significant. In the present study, we report the rational design and synthesis of a series of 1,4-DHP–hydrazone hybrid derivatives (HA-1,4-DHPs) as prospective inhibitors of two inflammation-associated serine proteases, thrombin and trypsin. The target compounds were synthesized in good yields using benzotriazole-based one-dimensional Cu(II) coordination materials as catalytic systems and subsequently subjected to comprehensive in-vitro biological evaluation. The experimental outcomes were analyzed in relation to structure–activity relationships (SAR), providing insights into the key structural determinants of biological efficacy. Moreover, in silico drug-likeness assessments highlighted favorable pharmacokinetic and physicochemical properties, underscoring the drug-ability of the synthesized hybrids. Collectively, the experimental and computational findings provide a robust foundation for further optimization and development of 1,4-DHP–hydrazone hybrids as potential anti-inflammatory agents.

We introduce the compound (E)-2-(2-(3,4-dihydroxystyryl)-4H-chromen-4-ylidene)malononitrile, termed Epirus-Yellow (EY), as the first dual mode optical sensor for the naked-eye colorimetric and near-infrared (NIR) fluorometric selective detection of Sn2+. Designed for point-of-care (POC) cellular imaging and food-safety monitoring, EY exhibits exceptional sensitivity for colorimetric (23.4 × 10-8mol/L) and NIR fluorimetric (25.7 × 10-8mol/L) sensing, with a near-instantaneous response and complete colorimetric transition within 400 s. 1D/2D119Sn,1H, and13C NMR, UV-Vis, FT-IR, thermogravimetric analysis, ICP-MS, and DFT calculations elucidated the underlying mechanism. DFT suggests EY's oxidation, forming a quinone that interacts with Sn(OH)₂ through hydrogen bonding, leading to fluorescence. EY's applicability was demonstrated through paper strip and office scanner-assisted color quantification, with a visual detection limit of 12.0 × 10-7mol/L. EY was successfully applied to the real-time estimation of Sn2+in food and water samples, underscoring its potential for on-site food safety monitoring. Finally, a smartphone-assisted analytical platform and mobile application (Epirus4Tin) were developed, enabling user-friendly, real-time, and digital quantification of Sn²⁺ in agro-food samples.

Abstract Manganese neurotoxicity, arising from environmental overexposure or inherited transporter disorders due to pathogenic variants in SLC30A10 and SLC39A14, leads to manganism, a debilitating Parkinsonian movement disorder. Alhtough chelation therapy can partially reverse neuropathology, current clinical practice relies on intravenous CaNa2EDTA, which is burdensome and poorly suited for long-term use. Consequently, there remains a significant unmet need for more effective, orally bioavailable chelators. This study aimed to establish and validate a pipeline for identifying and assessing novel ligands that attenuate manganese neurotoxicity and support preclinical translational development. Based on the structural features of manganese-based MRI contrast agents, we selected two chelators, N-picolyl-N,N′,N′-trans-1,2-cyclohexylenediaminetriacetic acid (H3PyC3A) and ethylenediaminetetraacetic acid−benzothiazole aniline (H4EDTA-BTA), and their methyl ester derivatives, Me3PyC3A and Me4EDTA-BTA. These were evaluated in vivo using zebrafish (slc39a14U801/U801) and mouse (Slc30a10KO/KO) models of manganese overload. H3PyC3A and Me3PyC3A demonstrated greater manganese-mobilizing efficacy than CaNa2EDTA, improving locomotor behavior in slc39a14U801/U801 zebrafish. In Slc30a10KO/KO mice, intravenous administration confirmed selective in vivo chelation of excess manganese over physiological concentrations of zinc and copper. Although oral bioavailability was low (<1%), long-term oral administration of H3PyC3A modestly reduced liver and brain Mn accumulation, suggesting an added benefit of oral administration via gastrointestinal chelation. This integrated in vitro to in vivo pipeline provides a robust and scaleable approach for the development of next-generation Mn chelators. Slc39a14U801 loss-of-function zebrafish enable high throughput identification of candidate compounds while Slc30a10KO/KO mice offer a clinically relevant disease model for pharmacokinetic profiling and proof-of-concept validation.

A Cu II Schiff-base chain and a rare high-nuclearity Mn II /Cu II cluster were synthesized, revealing a templating effect and demonstrating the value of preformed 3d-metal species in building novel heterometallic architectures.

Manganese (Mn) overload is a characteristic of multiple disease entities, from acquired manganism upon environmental or occupational overexposure, to end-stage liver disease and certain genetic disorders. The latter include hypermanganesaemia with dystonia 1 and 2 caused by pathogenic variants in the genes encoding the Mn transporters SLC30A10 and SLC39A14. Excess Mn accumulates in the brain, particularly in the globus pallidus, leading to progressive dystonia-parkinsonism. Furthermore, Mn dyshomeostasis is a characteristic feature of common neurodegenerative disorders such as Parkinson's disease, whether as a cause or consequence needs to be determined, suggesting that Mn as an environmental toxicant may play a role in its aetiology. Therefore, there is a need for therapeutics that effectively chelate Mn and remove excess Mn from the brain. This review discusses the Mn chelators currently used in clinical practice, their advantages and disadvantages as well as their adverse effects. Na2CaEDTA is the primary chelating agent used to re-establish Mn homeostasis; however, its burdensome treatment regimen, need for intravenous administration, and lack of metal specificity make it a poor drug for clinical application. The development of novel, Mn-specific chelating agents is therefore a clinical priority. An ideal chelator would be orally bioavailable, soluble in both lipids and water to reach the sites of metal storage, chemically inert, and non-toxic whilst retaining chelating abilities at physiological pH. We discuss current progress in identifying novel Mn ligands that have been primarily developed as magnetic resonance imaging contrast agents.

We report a family of propeller-shaped polynuclear metal complexes whose overall chirality is dictated by a single stereogenic centre within their component amino alcohol-ligand. These topologically intriguing complexes are readily prepared in enantiomerically pure form and are shown here to catalyse the conjugate addition of barbituric acids and their derivatives to nitroalkenes, with a catalyst loading of 1 mol%. Although only low levels of enantioinduction are observed, control experiments indicate that the enantioselectivity is dictated by the overall topology of the complex and not governed by binding to the tetrametallic entity, heralding a potentially new mode of catalysis.

Halogen bonding is increasingly recognized as a further elaboration of supramolecular effects between coordination moieties. Here, we report two isostructural trigonal prismatic Er6 coordination clusters for which one has no halogen on the ligand (E)-N '-(2-hydroxy-3-ethoxybenzylidene)pyrazine-2-carbohydrazide (H2oepch) (1), whereas the other has a bromine on the o-vanillin component (E)-N '-(5-bromo-2-hydroxy-3-methoxybenzylidene)pyrazine-2-carbohydrazide (H2opch-Br) (2). This allows us to gauge the effect of the supramolecular interactions on network formation via halogen bonding. Furthermore, the topological analysis on the network in (2) reveals a completely novel and unexpectedly 7-connected uninodal network that has to conform with the symmetry imposed by the tetragonal space group P421 c. In addition, in-depth theoretical calculations were performed to investigate the strength of the halogen bonding interactions and reveal cooperative effects unprecedented for inorganic coordination clusters.

Copper catalyzed aldehyde-alkyne-amine (A3) couplings lead to multifunctional, racemic, propargylic amines, many on a multigram scale. As part of an industrial collaboration, a selection of linkers was purified by chiral HPLC to afford single enantiomers, the absolute configuration of which was determined by vibrational circular dichroism (vCD). To show medicinal chemistry applications, selected linkers were further derivatized into potential cellular probes and (+)-JQ1 containing PROTACs (proteolysis targeting chimeras), which degraded their target protein BRD4.

Five (1-5) Ag(i) compounds, derived from different N,N'-bidentate 1-heteroaryl benzotriazole ligands, were synthesised and characterised using SXRD, IR, UV-Vis, elemental analysis, ESI-MS, and NMR. Variations in ligands and counter-anions produced distinct structures and morphologies. Preliminary antimicrobial testing at the micromolar level, in DMSO, revealed that only compound 2, based on 1-(2-pyridyl)benzotriazole and triflate anion, exhibited interesting antimicrobial properties, thus marking the introduction of a new class of Ag(i) compounds in medicinal inorganic chemistry.

We synthesized and characterized known and new Cu(ii)-salen complexes and investigated their efficacy in yielding propargylamines (PAs) via an A(3) coupling reaction mechanochemically. Although the method appears simple, we explicitly describe synthetic obstacles that urge unavoidable solvent use to isolate the molecular entities in high purity. The recovered complexes retain structure and catalytic efficacy, and a library of twenty-four known and unknown PAs are isolated in very good to excellent yields. The scope and limitations of this method are presented.

Copper is an abundant, low cost, and redox-plural (0/I/II/III) transition element, and frequently, its salts or complexes are used for efficient molecular transformations of natural products, bioactive molecules, agrochemicals, and organic functional materials, thus representing an ideal candidate for developing sustainable metal-based catalytic protocols. Current, green, and sustainable process development trends involve alternate energy inputs (e.g. microwaves and sources used in mechanochemistry and photochemistry) and produce functional chemicals with the utmost level of waste minimisation. This work details recent sustainable copper-based methodologies that yield organic scaffolds of high pharmaceutical importance, such as but not limited to propargylamines, pyrroles, and dihydropyridines.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Many small molecule bioactive and marketed drugs are chiral. They are often synthesised from commercially available chiral building blocks. However, chirality is sometimes incorrectly assigned by manufacturers with consequences for the end user ranging from: experimental irreproducibility, wasted time on synthesising the wrong product and reanalysis, to the added cost of purchasing the precursor and resynthesis of the correct stereoisomer. Further on, this could lead to loss of reputation, loss of funding, to safety and ethical concerns due to potential in vivo administration of the wrong form of a drug. It is our firm belief that more stringent control of chirality be provided by the supplier and, if needed, requested by the end user, to minimise the potential issues mentioned above. Certification of chirality would bring much needed confidence in chemical structure assignment and could be provided by a variety of techniques, from polarimetry, chiral HPLC, using known chiral standards, vibrational circular dichroism, and x-ray crystallography. A few case studies of our brushes with wrong chirality assignment are shown as well as some examples of what we believe to be good practice.

The use of flexible molecular systems in solution, without strictly controlling their behaviour, has frequently been productive. Their potential could increase by a more holistic view of the reaction(s) process(es) in which they are involved. In this perspective, we introduce a broader approach - "Chemical Chartographisis" - and discuss three projects in detail to illustrate its potential. The topics involve bimetallic 3d/4f species and coordination compounds built from benzotriazole-based and (a)symmetric salan ligands and focus on catalytic and, in less detail, biological-related examples.

Two propeller-shaped chiral CoIII3YIII complexes built from fluorinated ligands are synthesized and characterized by single-crystal X-ray diffraction (SXRD), IR, UV-vis, circular dichroism (CD), elemental analysis, thermogravimetric analysis (TGA), electron spray ionization mass spectroscopy (ESI-MS), and NMR (1H, 13C, and 19F). This work explores the sensing and discrimination abilities of these complexes, thus providing an innovative sensing method using a 19F NMR chemosensory system and opening new directions in 3d/4f chemistry. Control experiments and theoretical studies shed light on the sensing mechanism, while the scope and limitations of this method are discussed and presented.

We synthesised and characterised the racemic and chiral versions of two Zn salan fluorine-based complexes from commercially available materials. The complexes are susceptible to absorbing H2O from the atmosphere. In solution (DMSO-H2O) and at the millimolar level, experimental and theoretical studies identify that these complexes exist in a dimeric-monomeric equilibrium. We also investigated their ability to sense amines via19F NMR. In CDCl3 or d6-DMSO, strongly coordinating molecules (H2O or DMSO) are the limiting factor in using these easy-to-make complexes as chemosensory platforms since their exchange with analytes requires an extreme excess of the latter.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Glassy carbon, in general, is made by the pyrolysis of polymeric materials and has been the subject of research for at least fifty years. However, as understanding its microstructure is far from straightforward, it continues to be an area of active research. Glassy carbon adopts different allotropes depending on the hybridizations of the C–C bond, that is, sp, sp2, or sp3. Furthermore, a variety of short-range ordering effects can interact with each other and this, along with the effects of microporosity, grain boundaries, and defects, render this a fascinating material. Following the nanoarchitectonics concept of bottom-up creation of functional materials, we use methane rather than a polymer to form glassy carbon. Here we show that tubular glassy carbon microneedles with fullerene-like tips form when methane undergoes pyrolysis on a curved alumina surface. X-ray diffraction of these glassy carbon tubules shows long-range order with a d-spacing of 4.89 Å, which is indicative of glassy carbon. Raman spectroscopy shows the material to be graphitic in nature, and SEM shows the fullerene-like structure of the material. This work provides new insights into the structure of glassy carbons relevant to the application of glassy carbons as a biomaterial, for example, as a new form of carbon-based microneedles. Since metallic needles can introduce toxic/allergenic species into susceptible subjects, this alternative carbon-based microneedle form has great potential as a replacement biomedical material for metallic needles in the field of neural engineering and as acupuncture needles.

The multicomponent reaction of aldehydes, amines, and alkynes, known as A(3) coupling, yields propargylamines, a valuable organic scaffold, and has received significant interest and attention in the last years. In order to fully realise the potential of the metal-based catalytic protocols that facilitate this transformation, we summarise substrates, in situ and well-characterised synthetic methods that provide this scaffold and attempt a monumental classification considering several variables (Metal, Coordinating atom(s), Ligand type and name, in-situ or well-characterised, co-catalyst, catalyst and ligand Loading (mol%), solvent, volume, atmosphere, temperature, microwave, time, yield, selectivity (e.e. d.r.), substrate name, functionality, loading (amines, aldehydes, alkynes), and use of molecular sieves). This pioneering work creates a valuable database that contains 2376 entries and allows us to produce graphs and better visualise their impact on the reaction.