Novel non-peptide uracil-derived human gonadotropin-releasing hormone receptor antagonists.

Gonadotropin-releasing hormone (GnRH) is the main regulator of the reproductive system, acting on gonadotropic cells by binding to the GnRH1 receptor (GnRH1R). Traditionally, therapies targeting this receptor have relied on peptide modulators, which required subcutaneous or intramuscular injections. Due to the limitations of the parenteral administrations, there is a growing interest in developing oral small molecule modulators of GnRH1R as more convenient therapeutic alternatives.

Formation of extended polyiodides at large cation templates.

By studying the structures of (μ-1,4,10,13-tetrathia-7,16-diazacyclooctadecane)bis[iodidopalladium(II)] diiodide penta(diiodine), [PdI(CHNS)](I)·5I or [PdI([18]aneNS)](I)·(I), and 4,7,13,16,21,24-hexaoxa-1,10-diazoniabicyclo[8.8.8]hexacosane triiodide iodide hemipenta(diiodine) dichloromethane monosolvate, CHNO·I·I·2.

A hit expansion of 3-benzamidopyrazine-2-carboxamide: Toward inhibitors of prolyl-tRNA synthetase with antimycobacterial activity.

This study presents an exploration of the chemical space around derivatives of 3-benzamidopyrazine-2-carboxamides, previously identified as potent antimycobacterial compounds with predicted binding to mycobacterial prolyl-transfer RNA synthetase. New urea derivatives (Series-1) were generally inactive, probably due to their preference for cis-trans conformation (confirmed by density functional theory calculations and experimentally by nuclear overhauser effect spectroscopy NMR). Series-2 (3-benzamidopyrazine-2-carboxamides with disubstituted benzene ring) demonstrated that substituents larger than fluorine are not tolerated in the ortho position of the benzene ring.

Synthesis and Characterization of New Triazole-Bispidinone Scaffolds and Their Metal Complexes for Catalytic Applications.

Bispidines are a family of ligands that plays a pivotal role in various areas of coordination chemistry, with applications in medicinal chemistry, molecular catalysis, coordination polymers synthesis, and molecular magnetism. In the present work, triazole moieties were introduced using the CuAAC click-reaction, with the aim of expanding the number of coordination sites on the bispidine core. The 1,2,3-triazole rings were thus synthesized on propargyl-derived bispidines after reaction with different alkyl azides.

Elagolix Sodium Salt and Its Synthetic Intermediates: A Spectroscopic, Crystallographic, and Conformational Study.

Elagolix sodium salt is the first marketed orally active non-peptide gonadotropin-releasing hormone receptor antagonist (GnRHR-ant) for the management of hormone dependent diseases, such as endometriosis and uterine fibroids. Despite its presence on the market since 2018, a thorough NMR analysis of this drug, together with its synthetic intermediates, is still lacking. Hence, with the aim of filling this literature gap, we here performed a detailed NMR investigation, which allowed the complete assignment of the H, C, and N NMR signals.

Substituent-Guided Cluster Nuclearity for Tetranuclear Iron(III) Compounds with Flat {Fe(μ-O)} Butterfly Core.

The tetranuclear iron(III) compounds [Fe(μ-O)(μ-L)] (-) were obtained by reaction of FeCl with the shortened salen-type NO tetradentate Schiff bases -(salicylidene)--Z-phenylmethanediamine HL (Z = NO, Cl and OMe, respectively), where the one-carbon bridge between the two iminic nitrogen donor atoms guide preferentially to the formation of oligonuclear species, and the position of the substituent Z on the central phenyl ring selectively drives towards Fe bis-oxido clusters. All compounds show a flat almost-symmetric butterfly-like conformation of the {Fe(μ-O)} core, surrounded by the four Schiff base ligands, as depicted by both the X-ray molecular structures of and and the optimized geometries of all derivatives as obtained by UM06/6-311G(d) DFT calculations. The strength of the antiferromagnetic exchange coupling constants between the iron(III) ions varies among the three derivatives, despite their magnetic cores remain structurally almost unvaried, as well as the coordination of the metal ions, with a distorted octahedral environment for the two-body iron ions, Fe, and a pentacoordination with trigonal bipyramidal geometry for the two-wing iron ions, Fe.

Role of the Solvent in the Reactivity of Bis-4-imidazoline-2-selone Derivatives toward I: An Experimental and Theoretical Approach.

The reactivity of 1,1'-bis(3-methyl-4-imidazolin-2-selone)methane () and 1,2-bis(3-methyl-4-imidazolin-2-selone)ethane () toward I has been explored in MeCN under different experimental conditions and compared with that in CHCl. The compounds [](I) (), [I](I) (), [(μ-Se)](I)·1/2HO (), [I](I)·2I (), and [](I)·MeCN () were obtained and characterized. X-ray diffraction analyses point out an ionic nature for these compounds, which is presumably favored by the polarity of the solvent used.

Synthesis and Conformational Analysis of Hydantoin-Based Universal Peptidomimetics.

The synthesis of a collection of enantiomerically pure, systematically substituted hydantoins as structural privileged universal mimetic scaffolds is presented. It relies on a chemoselective condensation/cyclization domino process between isocyanates of quaternary or unsubstituted α-amino esters and -alkyl aspartic acid diesters followed by standard hydrolysis/coupling reactions with amines, using liquid-liquid acid/base extraction protocols for the purification of the intermediates. Besides the nature of the α carbon on the isocyanate moiety, either a quaternary carbon or a more flexible methylene group, conformational studies (molecular modeling), in solution (NMR, circular dichroism (CD), Fourier transform infrared (FTIR)), and in solid state (X-ray) showed that the presented hydantoin-based peptidomimetics are able to project their substituents in positions superimposable to the side chains of common protein secondary structures such as α-helix and β-turn, being the open α-helix conformation slightly favorable according to molecular modeling, while the closed β-turn conformation preferred in solution and in solid state.

Photoactivated Nanoscale Temperature Gradient Detection Using X-ray Absorption Spectroscopy as a Direct Nanothermometry Method.

Nanoparticle-mediated thermal treatments have demonstrated high efficacy and versatility as a local anticancer strategy beyond traditional global hyperthermia. Nanoparticles act as heating generators that can trigger therapeutic responses at both the cell and tissue level. In some cases, treatment happens in the absence of a global temperature rise, damaging the tumor cells even more selectively than other nanotherapeutic strategies.

Selective Formation, Reactivity, Redox and Magnetic Properties of Mn and Fe Dinuclear Complexes with Shortened Salen-Type Schiff Base Ligands.

The reactivity of the shortened salen-type ligands Hsalmp, Hsalmen and Hsal(-X)ben with variable -substituent on the central aromatic ring (X = Bu, Me, H, F, Cl, CF, NO) towards the trivalent metal ions manganese(III) and iron(III) is presented. The selective formation of the dinuclear complexes [M(μ-salmp)], M = Mn (), Fe (), [M(μ-salmen)(μ-OR))], R = Et, Me, H and M = Mn (-) or Fe (-), and (M(μ-sal[-X]ben)(μ-OMe)), X = Bu, Me, H, F, Cl, CF, NO and M = Mn (-) or Fe (-), could be identified by reaction of the Schiff bases with metal salts and the base NEt, and their characterization through elemental analysis, infrared spectroscopy, mass spectrometry and single-crystal X-ray diffraction of ·2AcOEt, ·2CHCN and ·2DMF was performed. In the case of iron(III) and Hsalmp, when using NaOH as a base instead of NEt, the dinuclear complexes [Fe(μ-salmp)(μ-OR)(salim)], R = Me, H (,) could be isolated and spectroscopically characterized, including the crystal structure of ·1.

Tuneable solvent adsorption and exchange by 1D bispidine-based Mn(II) coordination polymers ligand design.

Here we report novel bispidine-based coordination polymers (CPs) 2·TCM, 3·TCM, 3·NB, 5·TCM and 5·TCM·NB, of compostition [Mn(Cl)2(L2)2·(TCM)2], [Mn(Cl)2(L3)2·(TCM)5], [Mn(Cl)2(L3)2·(NB)8], [Mn(Cl)2(L5)2·(TCM)4], [Mn(Cl)2(L5)2·(TCM)2·(NB)2], respectively (NB = nitrobenzene; TCM = chloroform). They were obtained starting from novel bispidine ligands L2 (dimethyl 7-isopropyl-3-methyl-9-oxo-2,4-di(pyridin-4-yl)-3,7-diazabicyclo[3.3.

Local Structure and Magnetism of FeO Maghemite Nanocrystals: The Role of Crystal Dimension.

Here we report on the impact of reducing the crystalline size on the structural and magnetic properties of γ-FeO maghemite nanoparticles. A set of polycrystalline specimens with crystallite size ranging from ~2 to ~50 nm was obtained combining microwave plasma synthesis and commercial samples. Crystallite size was derived by electron microscopy and synchrotron powder diffraction, which was used also to investigate the crystallographic structure.

Synthesis, Characterization and Biological Activity of Novel Cu(II) Complexes of 6-Methyl-2-Oxo-1,2-Dihydroquinoline-3-Carbaldehyde-4n-Substituted Thiosemicarbazones.

Three new 6-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde-thiosemicarbazones-N-4-substituted pro-ligands and their Cu(II) complexes (, -NH; , -NHMe; , -NHEt) have been prepared and characterized. In both the X-ray structures of and , two crystallographically independent complex molecules were found that differ either in the nature of weakly metal-binding species (water in and nitrate in ) or in the co-ligand (water in and methanol in ). Electron Paramagnetic Resonance (EPR) measurements carried out on complexes and confirmed the presence of such different species in the solution.

Combined structural and theoretical investigation on differently substituted bispidine ligands: predicting the properties of their corresponding coordination polymers.

Pyridine-based bispidine ligands L1-L7, which differ in the substituent at the N7 position of the bispidine scaffold, have been studied by single crystal X-ray diffraction and density functional theory (DFT) calculations, also including solid-state algorithms. Qualitative description of the packing interactions and quantitative data on the stability of each ligand in the solid-state have been employed to draw reasonable predictions on the ligand potential for the formation of linear 1D coordination polymers (CPs) with Mn(ii)Cl and on their resulting dynamic properties, in terms of adsorption and solvent exchange capabilities. The basic assumption lies in the fact that volume and polarizability of the ligands would similarly affect packing energies in both molecular solids and CP materials.

Drugs/lamellae interface influences the inner structure of double-loaded liposomes for inhaled anti-TB therapy: An in-depth small-angle neutron scattering investigation.

With the aim of developing new drug carriers for inhalation therapy, we report here an in depth investigation of the structure of multilamellar liposomes loaded with two well-established anti-tubercular (anti-TB) drugs, isoniazid (INH) and rifampicin (RIF), by means of small-angle neutron-scattering (SANS) analysis. Unloaded, single drug-loaded and co-loaded liposomes were prepared using different amounts of drugs and characterized regarding size, encapsulation efficiency and drug release. Detailed information on relevant properties of the investigated host-guest structures, namely the steric bilayer thickness, particle dispersion, number of lamellae and drug localization was studied by SANS.

Intriguing C-HCu interactions in bis-(phenanthroline)Cu(i) redox mediators for dye-sensitized solar cells.

We have synthesized and characterized a series of bis-(phenanthroline)Cu(i) complexes of interest as redox mediators for dye-sensitized solar cells. This study led to the discovery of intriguing anagostic interactions between the hydrogen atom and the copper center as evidenced by X-ray diffraction studies on a single crystal. Remarkably, an anagostic interaction was found between a H atom of a methyl group and a copper site.

Novel coumarins and related copper complexes with biological activity: DNA binding, molecular docking and in vitro antiproliferative activity.

Coumarins show biological activity and are widely exploited for their therapeutic effects. Although a great number of coumarins substituted by heterocyclic moieties have been prepared, few studies have been carried out on coumarins containing pyridine heterocycle, which is known to modulate their physiological activities. We prepared and characterized three novel 3-(pyridin-2-yl)coumarins and their corresponding copper(II) complexes.

Spectroscopic, Structural, and Computational Characterization of Three Bispidinone Derivatives, as Ligands for Enantioselective Metal Catalyzed Reactions.

Three chiral derivatives of the alkaloid sparteine (bispidines), characterized by the 3,7-diazabicyclo[3.3.1]nonane moiety, were designed as efficient ligands in a number of enantioselective reactions due to their metal coordination properties.

Crystallographic and spectroscopic study on a known orally active progestin.

6,17α-Dimethyl-4,6-pregnadiene-3,20-dione (medrogestone, 2) is for a long time known steroid endowed with progestational activity. In order to study its crystallographic and NMR spectroscopic properties with the aim to fill the literature gap, we prepared medrogestone following a traditional procedure. A careful NMR study allowed the complete assignment of the (1)H and (13)C NMR signals not only of medrogestone but also of its synthetic intermediates.

Dipeptide Nanotubes Containing Unnatural Fluorine-Substituted β(2,3)-Diarylamino Acid and L-Alanine as Candidates for Biomedical Applications.

The synthesis and the structural characterization of dipeptides composed of unnatural fluorine-substituted β(2,3)-diarylamino acid and L-alanine are reported. Depending on the stereochemistry of the β amino acid, these dipeptides are able to self-assemble into proteolytic stable nanotubes. These architectures were able to enter the cell and locate in the cytoplasmic/perinuclear region and represent interesting candidates for biomedical applications.

Copper(II)-Catalyzed Alkoxyhalogenation of Alkynyl Ureas and Amides as a Route to Haloalkylidene-Substituted Heterocycles.

A highly effective synthesis of haloalkylidene-substituted heterocycles by copper(II)-catalyzed cyclization of alkynyl ureas and secondary amides has been developed. The reaction, which involves a catalytic amount of CuCl2 and a stoichiometric amount of N-halosuccinimide, occurs selectively through an alkoxyhalogenation process. Alternatively, alkoxychlorination and alkoxybromination reactions can be performed working solely with stoichiometric CuCl2 and CuBr2, respectively.

Zinc(II)-methimazole complexes: synthesis and reactivity.

The tetrahedral S-coordinated complex [Zn(MeImHS)4](ClO4)2, synthesised from the reaction of [Zn(ClO4)2] with methimazole (1-methyl-3H-imidazole-2-thione, MeImHS), reacts with triethylamine to yield the homoleptic complex [Zn(MeImS)2] (MeImS = anion methimazole). ESI-MS and MAS (13)C-NMR experiments supported MeImS acting as a (N,S)-chelating ligand. The DFT-optimised structure of [Zn(MeImS)2] is also reported and the main bond lengths compared to those of related Zn-methimazole complexes.

Novel copper(II) complexes as new promising antitumour agents. A crystal structure of [Cu(1,10-phenanthroline-5,6-dione)2(OH2)(OClO3)](ClO4).

The cytotoxic properties of copper(II) complexes with 1,10-phenanthroline (phen) can be modified by substitution in the phen backbone. For this purpose, Cu(II) complexes with phen, 1,10-phenanthrolin-5,6-dione (phendione) and 1,10-phenanthrolin-5,6-diol (phendiol) have been synthesised and characterised. The crystal structure of [Cu(phendione)2(OH2)(OClO3)](ClO4) is discussed.

Reactivity of fluoro-substituted bis(thiocarbonyl) donors with diiodine: an XRD, FT-Raman, and DFT investigation.

The reactions of 1,3,8,10-tetrakis(4'-fluorophenyl)-4,5,6,7-tetrathiocino[1,2-b:3,4-b']diimidazolyl-2,9-dithione (4) and molecular diiodine afforded spoke adducts with stoichiometries 4·I2 and 4·3I2 , isolated in the compound 4·3I2·xCH2Cl2·(1-x)I2 (x=0.70), and characterized by single-crystal XRD and FT-Raman spectroscopy. The nature of the reaction products was investigated under the prism of theoretical calculations carried out at the DFT level.

Formation of T-shaped versus charge-transfer molecular adducts in the reactions between bis(thiocarbonyl) donors and Br2 and I2.

The reactions of 4,5,6,7-tetrathiocino-[1,2-b:3,4-b']-1,3,8,10-tetrasubstituted-diimidazolyl-2,9-dithiones (R(2),R'(2)-todit; 1: R=R'=Et; 2: R=R'=Ph; 3: R=Et, R'=Ph) with Br(2) exclusively afforded 1:1 and 1:2 "T-shaped" adducts, as established by FT-Raman spectroscopy and single-crystal X-ray diffraction in the case of complex 1·2Br(2). On the other hand, the reactions of compounds 1-3 with molecular I(2) provided charge-transfer (CT) "spoke" adducts, among which the solvated species 3·2I(2)·(1-x)I(2)·xCH(2)Cl(2) (x=0.94) and (3)(2)·7I(2)·xCH(2)Cl(2), (x=0.