Physicochemical Profiling of Sartans: A Detailed Study of Ionization Constants and Distribution Coefficients

A detailed investigation of the ionization and lipophilicity profiles of selected sartans (valsartan, losartan, irbesartan, candesartan, candesartan cilexetil), a class of antihypertensives commonly used in therapy, is presented. The pK_a macroconstants were determined by integrated potentiometry, capillary electrophoresis, and UV spectrophotometry. The measured pK_a macroconstants were connected with the ionizable centers present in each molecule with the aid of model compounds. Potentiometric titrations with the GLpKa apparatus were performed to determine the distribution profile (log D vs. pH) of valsartan, while the shake‐flask procedure was used to characterize the distribution profile of the other compounds. Valsartan showed a lipophilicity profile consistent with the presence of two acidic centers. Losartan and irbesartan, which contain one acidic and one basic center, displayed the classical bell‐shaped profile of ordinary ampholytes. By contrast, a more complex situation emerged in the case of candesartan, due to the large number of ionization equilibria involved. The low solubility of candesartan cilexetil, together with the ease of hydrolysis of the ester moiety, prevented a successful investigation of its ionization and lipophilicity profiles.     

Mechanistic and Kinetic Investigations of ON/OFF (Photo)Switchable Binding of Carbon Monoxide by Chromium(0), Molybdenum(0) and Tungsten(0) Carbonyl Complexes with a Pyridyl-Mesoionic Carbene Ligand

This work tackles the photochemistry of a series of mononuclear Cr⁰, Mo⁰ and W⁰ carbonyl complexes containing a bidentate mesoionic carbene ligand of the 1,2,3-triazol-5-ylidene type. FTIR spectroscopy, combined with density functional theory calculations, revealed a clean photo-induced reaction in organic solvents (acetonitrile, pyridine, valeronitrile) to give mainly one photoproduct with monosubstitution of a carbonyl ligand for a solvent molecule. The highest photodissociation quantum yields were reached for the Cr⁰ complex under UV irradiation (266 nm). Based on previous investigations, the kinetics of the dark reverse reactions have now been determined, with reaction times of up to several hours in pyridine. Photochemical studies in the solid state (KBr matrix, frozen solution) also showed light-induced reactivity with stabilization of the metastable intermediate with a free coordination site at very low temperature. The identified reactive species emphasizes a mechanism without ligand–sphere reorganization.     

Solvent Effects in Halogen and Hydrogen Bonding Mediated Electrochemical Anion Sensing in Aqueous Solution and at Interfaces

Sensing anionic species in competitive aqueous media is a well-recognised challenge to long-term applications across a multitude of fields. Herein, we report a comprehensive investigation of the electrochemical anion sensing performance of novel halogen bonding (XB) and hydrogen bonding (HB) bis-ferrocene-(iodo)triazole receptors in solution and at self-assembled monolayers (SAMs), in a range of increasingly competitive aqueous organic solvent media (ACN/H₂O). In solution, the XB sensor notably outperforms the HB sensor, with substantial anion recognition induced cathodic voltammetric responses of the ferrocene/ferrocenium redox couple persisting even in highly competitive aqueous solvent media of 20 % water content. The response to halides, in particular, shows a markedly lower sensitivity to increasing water content associated with a unique halide selectivity at unprecedented levels of solvent polarity. The HB sensor, in contrast, generally displayed a preference towards oxoanions. A significant surface-enhancement effect was observed for both XB/HB receptive films in all solvent systems, whereby the HB sensor generally displayed larger responses towards oxoanions than its halogen bonding analogue.     

Thermally Activated Delayed Fluorescence and Phosphorescence Quenching in Iminophosphonamide Copper and Zinc Complexes

The synthesis of copper and zinc complexes of four variably substituted iminophosphonamide ligands is presented. While the copper complexes form ligand-bridged dimers, the zinc compounds are monomeric. Due to different steric demand of the ligand the arrangement of the ligands within the dimeric complexes varies. Similar to the structurally related iminophosphonamide complexes of alkali metals and calcium, the steady-state and time-resolved photoluminescence (PL) of four of the seven compounds studied here as solids in a temperature range of 5–295 K can be described within the scheme of thermally activated delayed fluorescence (TADF). Accordingly, they exhibit bright blue-green phosphorescence at low temperatures (<100 K), which turns into delayed fluorescence by increasing the temperature. However, unusually, the fluorescence is practically absent in two copper complexes which otherwise still conform to the TADF scheme. In these cases, the excited singlet states decay essentially non-radiatively and their thermal population from the corresponding low-lying triplet states efficiently quenches PL (phosphorescence). Three other copper and zinc complexes only exhibit prompt fluorescence, evidencing a wide variation of photophysical properties in this class of compounds. The excited states of the copper complex with especially pronounced phosphorescence quenching were also investigated by low-temperature time-resolved infrared spectroscopy and quantum chemical calculations.     

Rapid assembly of the polyhydroxylated beta-amino acid constituents of microsclerodermins C, D, and E

A very short and efficient synthesis of protected derivatives of APTO and AETD, the complex polyhydroxylated beta-amino acid residues present in microsclerodermins C, D, and E, is described. The targets are obtained in only five steps, in 23% and 16% overall yields, respectively. The key transformation involves the completely diastereoselective two-carbon homologation of appropriately selected intermediate chiral sulfinimines.     

Aromatic-carbohydrate interactions: an NMR and computational study of model systems

The interactions of simple carbohydrates with aromatic moieties have been investigated experimentally by NMR spectroscopy. The analysis of the changes in the chemical shifts of the sugar proton signals induced upon addition of aromatic entities has been interpreted in terms of interaction geometries. Phenol and aromatic amino acids (phenylalanine, tyrosine, tryptophan) have been used. The observed sugar-aromatic interactions depend on the chemical nature of the sugar, and thus on the stereochemistries of the different carbon atoms, and also on the solvent. A preliminary study of the solvation state of a model monosaccharide (methyl beta-galactopyranoside) in aqueous solution, both alone and in the presence of benzene and phenol, has also been carried out by monitoring of intermolecular homonuclear solvent-sugar and aromatic-sugar NOEs. These experimental results have been compared with those obtained by density functional theory methods and molecular mechanics calculations.     

Rapid cooling experiments and use of an anionic nuclear probe to sense the spin transition of the 1D coordination polymers [Fe(NH2trz)3]SnF6n x H2O (NH2trz=4-amino-1,2,4-triazole)

[Fe(NH₂trz)₃]SnF₆ ? n H₂O (NH₂trz=4‐amino‐1,2,4‐triazole; n=1 ( 1 ), n=0.5 ( 2 )) are new 1D spin‐crossover coordination polymers. Compound 2 exhibits an incomplete spin transition centred at around 210 K with a thermal hysteresis loop approximately 16 K wide. The spin transition of 2 was detected by the Mössbauer resonance of the ¹¹⁹Sn atom in the SnF₆^2? anion primarily on the basis of the evolution of its local distortion. Rapid‐cooling ⁵⁷Fe Mössbauer and superconducting quantum interference device experiments allow dramatic widening of the hysteresis width of 2 from 16 K up to 82 K and also shift the spin‐transition curve into the room temperature region. This unusual behaviour of quenched samples on warming is attributed to activation of the molecular motion of the anions from a frozen distorted form towards a regular form at temperatures well above approximately 210 K. Potential applications of this new family of materials are discussed.     

Synthesis and structural characterization of copper–molybdenum–sulfur and copper–tungsten–sulfur cluster complexes (n-Bu4N)[OMS3Cu3Br2L2] with heterocyclic thiones as ligands

Reaction of (NH₄)₂[WOS₃] or (NH₄)₂[MoO₂S₂], n-Bu₄NBr, CuCl and Imt in acetone solvent afforded air- and moisture-stable clusters (n-Bu₄N)[MOS₃Cu₃(Imt)₂Br₂] (M = W or Mo, Imt = imidazolidine-2-thione). These compounds have been characterized by IR, UV–Vis, ¹H and ¹³C NMR spectra and single-crystal X-ray diffraction. They are crystallographically isostructural, with Imt and [MOS₃]²⁻ acting as monodentate and bidentate S-donor ligands, respectively. In the anions, the three Cu atoms have different coordination environments, one being distorted tetrahedral with Imt and Br as terminal ligands, the other two being approximately trigonal planar with Imt as a terminal ligand for one and Br as a terminal ligand for the other. W and Mo have approximately tetrahedral coordination geometry, with a terminal O and three triply-bridging S atoms. The NH groups of the Imt ligands serve as donors in intramolecular N–H?Br and in intermolecular N–H?Br and N–H?O hydrogen bonds, linking the anions to form layers with the cations in cavities.     

Fluorine in medicinal chemistry

It has become evident that fluorinated compounds have a remarkable record in medicinal chemistry and will play a continuing role in providing lead compounds for therapeutic applications. This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.