Dicationic Derivatives Research Articles

Synthesis, Structure, Electrochemical Properties, and Antioxidant Activity of Organogermanium(IV) Catecholate Complexes.

A series of novel organogermanium(IV) catecholates 1-9 of the general formula R'2Ge(Cat), where R' = Ph, Et, have been synthesized. Compounds were characterized by 1H, 13C NMR, IR spectroscopy, and elemental analysis. The molecular structures of 1-3, 6, and 8 in crystal state were established using single-crystal X-ray analysis. The complexes are tetracoordinate germanium(IV) compounds containing a dioxolene ligand in a dianion (catecholato) form. Electrochemical transformations of target germanium(IV) complexes have been studied by cyclic voltammetry. The electro-oxidation mechanism of complexes 1-5, 7, and 10 (the related complex Ph2Ge(3,5-Cat) where 3,5-Cat is 3,5-di-tert-butylcatecholate) involves the consecutive formation of mono- and dicationic derivatives containing the oxidized forms of redox-active ligands. The stability of the generated monocations depends both on the hydrocarbon groups at the germanium atom and on the substituents in the catecholate ring. Compounds 6, 8, and 9 are oxidized irreversibly under the electrochemical conditions with the formation of unstable complexes. The radical scavenging activity and antioxidant properties of new complexes were estimated in the reaction with DPPH radical, ABTS radical cation, and CUPRACTEAC assay. It has been found that compounds 8 and 9 with benzothiazole or phenol fragments are more active in DPPH test. The presence of electron-rich moieties in the catecholate ligand makes complexes 5 and 7-9 more reactive to ABTS radical cation. The value of CUPRACTEAC for organogermanium(IV) catecholates varies from 0.23 to 1.45. The effect of compounds 1-9 in the process of lipid peroxidation of rat liver (Wistar) homogenate was determined in vitro. It was found that most compounds are characterized by pronounced antioxidant activity. A feature of complexes 1, 3, and 5-9 is the intensification of the antioxidant action with the incubation time. In the presence of additives of complexes 3, 5, 6, and 8, an induction period was observed during the process of lipid peroxidation.

Synthesis, TDDFT Calculations and Biological Evaluation of Dicationic Porphyrins as Groove Binders and Antimicrobial Agents

AbstractA2B2 porphyrin bearing 2/3‐thienyl and 2‐pyridyl moieties (P1a, P3a) and its dicationic derivatives (P2a, P4a) were synthesized in reasonably good yield. The corresponding Copper (II) (P1‐4 b) and Zinc (II) metallated (P1‐4 c) analogs were obtained by conventional methods. The synthesized compounds were characterized by various spectroscopic techniques, electrochemical studies and thermogravimetric analysis. The Copper (II) porphyrin, P1b is structurally characterized by single‐crystal X‐ray structure analysis. The ground state electronic structure and geometry optimizations are carried out by DFT calculations. The computed TD‐DFT results validate the observed optical bands and spectral features. DNA interaction studies of trans‐dicationic porphyrins were performed using spectroscopic titrations, docking studies, and gel electrophoresis experiments. All porphyrins interact with the calf thymus DNA by outside groove binding mode with self‐stacking, and the highest intrinsic binding constant of 1.29 ± 0.14×106 M‐1 is observed for P4a. Molecular docking studies reveal that the binding energy of porphyrins with DNA is around −10 kcal/mol. The antimicrobial properties of the dicationic derivatives (P2,4 a, b, c) were investigated against E. Coli and S. aureus under light and dark conditions, and the growth inhibitory effect is found to be negligible when unilluminated.

Phosphonium-ammonium-based di-cationic ionic liquids as antibacterial over the ESKAPE group

Emergence of antibioresistance is currently a major threat of public health worldwide. Hence there is an urge need of finding new antibacterial material. Herein, we report a simple and eco-friendly method to synthesize homo and heterodicationic ionic liquids based on quaternary phosphonium and ammonium salt. In order to investigate the structure activity relationship (SAR) we measured the MICs of a series of 16 derivatives with structural variations (nature of cations and counter-ions, size of linker and alkyl side chains as well as structural symmetry) over a range of Gram-positive and Gram-negative bacterial strains from the ESKAPE group. Some of the tested structures exhibit high antimicrobial activities (MIC = 0.5 mg/L) and are active over a wide range of bacteria from Gram-positive to Gram-negative. Overall, these results reveal the strong potential of di-cationic derivatives as antibacterial agents and the determination of activities from structural features gives decisive information for future synthesis of such di-cationic structures for biocidal purpose.

Synthetic and structural investigations of bis(N-alkyl-benzoselenadiazolium) cations.

The synthesis, and spectroscopic and structural characterization of bridged dicationic derivatives of benzo-2,1,3-selenadiazoles are reported. The chloride salt of [H4C6NSeN-CH2-CH2-NSeNC6H4]2+ crystallizes forming a macrocyclic structure in which two cations are bridged by SeCl chalcogen bonds (ChBs), with a third chloride at the centre of the macrocycle. The structure of [1,2-(H4C6NSeN)2-C6H10]Cl2 consists of two selenadiazolium cations linked by a chiral cyclohexane and capped by SeCl ChBs. Tetrafluoroborate salts of a xylene bridge crystallize in two pseudopolymorphs in which the cations form SeF ChBs in an anti- or syn-conformation. The triflate salt of ethylene-bridged cations dimerizes through the formation of the [Se-N]2 supramolecular synthon with SeO ChBs capping the second selenium atom. In contrast, [H4C6NSeN-CH2-CH2-CH2-NSeNC6H4](CF3SO3)2 only forms SeO ChBs.

Metal coordination to a dimetallaoctatetrayne.

The reactions of the ditungstaoctatetrayne [(Tp*)(CO)2W([triple bond, length as m-dash]CC[triple bond, length as m-dash]CC[triple bond, length as m-dash]CC[triple bond, length as m-dash])W(CO)2(Tp*)] with several metal complexes have been investigated. Addition of [Co2(CO)8] occurs across the internal C[triple bond, length as m-dash]C bonds, whereas [AuCl(SMe2)] initially delivers 'AuCl' across the W[triple bond, length as m-dash]C carbyne bonds before undergoing further reaction to oxidise the tungsten and replace the carbonyl ligands with chloride in [(Tp*)Cl2W([triple bond, length as m-dash]CC[triple bond, length as m-dash]CC[triple bond, length as m-dash]CC[triple bond, length as m-dash])WCl2(Tp*)] with retention of the ditungstaoctatetrayne bridge. Reaction with [AuCl(PR3)] (R = Ph, Cy) in the presence of AgPF6 prevents this oxidation and adds [AuPR3]+ across the W[triple bond, length as m-dash]C bonds to give dicationic derivatives. Finally, the reaction with [Pt(nbe)3] (nbe = norbornene, bicyclo[2.2.1]hept-2-ene) and 1,5-cyclooctadiene (COD) adds a 'Pt(COD)' unit to one or both tungsten-carbon bonds, allowing both the mono- and diplatinum complexes to be isolated.

Ionic liquids as potential enhancers for transdermal drug delivery

The aim of this study was to verify the effect of several cyclic onium based ionic liquids (ILs), including mono- and dicationic derivatives of 1,4-diazabicyclo[2.2.2]octane (DABCO), a dialkyl morpholinium salt and a Brønsted acidic IL, as enhancers of the in vitro transdermal permeation and skin retention of diltiazem through and into hairless rat skin. The drug was used as both the hydrochloride salt (DZHCl) and the free base (DZB) to highlight the relationship between the enhancement effect and the physico-chemical characteristics of the active agent. Permeation tests were carried out using Gummer-type diffusion cells and excised rat skin with a 0.005M aqueous solution of diltiazem hydrochloride or diltiazem free base with and without the addition of 1% w/w ionic liquids. At the end of the permeation experiments with diltiazem hydrochloride, a suitable extraction procedure allowed for the determination of the drug content retained in the skin. Depending on the ionic liquid structure, a significant enhancement in diltiazem hydrochloride levels in the receiving phase was observed, and the transdermal permeation of the diltiazem free base was markedly increased by treatment with all of the ionic liquids. N-dodecyldabco bromide was the best enhancer for both salified and free base drug forms, even though it showed a certain toxicity. On the other hand, N-methyl-N-decylmorpholinium bromide showed a good balance between enhancer activity and cytotoxicity.

Reaction of P4 with in situ Formed cyclo‐Triphosphatriazenium Cation [(DmpNP)3Cl2]+ (Dmp = 2,6‐Dimethylphenyl)

AbstractThe controlled activation of white phosphorus, P4, provides a key entry point into many aspects of polyphosphorus chemistry. Herein, the reaction of cyclo‐diphosphadiazane derivative (DmpNPCl)2 (3a; Dmp = 2,6‐dimethylphenyl) and P4 in the presence of GaCl3 as Lewis acid for the targeted synthesis of mono‐ and dicationic phosphorus‐rich cage compounds [(DmpNP)2(P4)Cl][GaCl4] (8a[GaCl4]) and [(DmpNP)2(P4)2][Ga2Cl7]2 (9a[Ga2Cl7]2) is reported. Depending on the reaction conditions, formation of these types of cages, which are similar to those of the known cations [(DippNP)2(P4)Cl]+ (8b+) and [(DippNP)2(P4)2]2+ (9b2+; Dipp = 2,6‐diisopropylphenyl) is observed. However, due to the reduced steric requirements of the Dmp compared to the Dipp group, an interconversion process of the P2N2 framework of cyclo‐dichlorodiphosphadiazane 3a with the cyclo‐trichlorotriphosphatriazane 5a is observed, which leads also to the formation of mono‐ and dicationic derivatives [(DmpNP)3(P4)Cl2]+ (10a+) and [(DmpNP)3(P4)2Cl]2+ (11a2+) via cyclo‐triphosphatriazenium cation [(DmpNP)3Cl2]+ (4a+).

Triaryl/trialkylantimony(V) catecholates with electron-acceptor groups

A number of new antimony(V) complexes of type CatSbR3 (R = ethyl, o-tolyl, p-tolyl, p-fluorophenyl, p-chlorophenyl) with 4-chloro-3,6-di-tert-butyl-catecholato (4-Cl-3,6-DBCat), 6-chloro-, 6-bromo- and 6-nitro-3,5-di-tert-butyl-catecholato (6-X-3,5-DBCat, X = Cl, Br, NO2) redox-active ligands was synthesized and characterized. The molecular structures of (4-Cl-3,6-DBCat)Sb(o-Tol)3 (2), (6-Cl-3,5-DBCat)Sb(p-Tol)3 (7), (6-Br-3,5-DBCat)Sb(p-Tol)3 (8) in crystals were determined by single-crystal X-ray analysis. In the accordance with cyclic voltammetry data, the oxidation of complexes proceeds in two successive stages with a formation of mono- and dicationic derivatives. The modification of Ph groups at antimony with different substituents does not affect appreciably the redox potentials of complexes containing the electron-acceptor groups in redox-active ligand.

Dicationic derivatives of dinaphthotetraaza[14]annulene: synthesis, crystal structures and the preliminary evaluation of their DNA binding properties

Four new water-soluble, fluorescent derivatives of dinaphthotetraaza[14]annulene (DNTAA) have been synthesized varying in the structure, dimensions and spatial arrangements of their meso side groups. The products have been carefully characterized by elemental analyses, spectroscopy, crystal structures and quantum-chemical calculations employing DFT methodology. One representative product of the DNTAA series was tested for DNA binding using UV–vis titrations, CD and thermal denaturation experiments. Intercalation of ds-DNA was recognized as a dominant binding mode. In contrast to non-fluorescent phenylene analogues (DBTAA), reported previously, DNTAA derivative showed threefold fluorescence increase upon DNA binding, and offered intriguing new applications as a fluorescent DNA/RNA dye.

A cationic zinc hydride cluster stabilized by an N-heterocyclic carbene: synthesis, reactivity, and hydrosilylation catalysis.

The trinuclear cationic zinc hydride cluster [(IMes)3Zn3H4(THF)](BPh4)2 (1) was obtained either by protonation of the neutral zinc dihydride [(IMes)ZnH2]2 with a Brønsted acid or by addition of the putative zinc dication [(IMes)Zn(THF)](2+). A triply bridged thiophenolato complex 2 was formed upon oxidation of 1 with PhS-SPh. Protonolysis of 1 by methanol or water gave the corresponding trinuclear dicationic derivatives. At ambient temperature, 1 catalyzed the hydrosilylation of aldehydes, ketones, and nitriles. Carbon dioxide was also hydrosilylated under forcing conditions when using (EtO)3SiH, giving silylformate as the main product.

Self-assembly of symmetrical and dissymmetrical dicationic surfactants in the solid phase and in solution

The effect of the spacer structure (linear, cyclic, bicyclic) and dissymmetry of alkyl fragment in a series of dicationic gemini surfactants on the ability to form thermotropic liquid crystals and on the micellar properties was studied. Transitions crystal-thermotropic liquid crystals-isotropic solution were studied using differential scanning calorimetry and optical microscopy. The self-diffusion coefficients of micelles and monomers of the dicationic dialkyl derivatives of 1,4-diazabicyclo[2.2.2]octane in water were determined by pulsed field gradient NMR spectroscopy. The effect of the surfactant structure on the values of critical micelle concentrations, hydrodynamic radii, and aggregation numbers of micelles was analyzed.

Novel Acid-Activated Fluorophores Reveal a Dynamic Wave of Protons in the Intestine of Caenorhabditis elegans

Unlike the digestive systems of vertebrate animals, the lumen of the alimentary canal of Caenorhabditis elegans is unsegmented and weakly acidic (pH ~4.4), with ultradian fluctuations to pH > 6 every 45-50 s. To probe the dynamics of this acidity, we synthesized novel acid-activated fluorophores termed Kansas Reds. These dicationic derivatives of rhodamine B become concentrated in the lumen of the intestine of living C. elegans and exhibit tunable pKa values (2.3-5.4), controlled by the extent of fluorination of an alkylamine substituent, that allow imaging of a range of acidic fluids in vivo. Fluorescence video microscopy of animals freely feeding on these fluorophores revealed that acidity in the C. elegans intestine is discontinuous; the posterior intestine contains a large acidic segment flanked by a smaller region of higher pH at the posterior-most end. Remarkably, during the defecation motor program, this hot spot of acidity rapidly moves from the posterior intestine to the anterior-most intestine where it becomes localized for up to 7 s every 45-50 s. Studies of pH-insensitive and base-activated fluorophores as well as mutant and transgenic animals revealed that this dynamic wave of acidity requires the proton exchanger PBO-4, does not involve substantial movement of fluid, and likely involves the sequential activation of proton transporters on the apical surface of intestinal cells. Lacking a specific organ that sequesters low pH, C. elegans compartmentalizes acidity by producing of a dynamic hot spot of protons that rhythmically migrates from the posterior to anterior intestine.

Ansa-Cyclopentadienyl-Arene Tantalum Complexes: Structure and Reactivity of Neutral, Cationic, and Dicationic Derivatives

The cationic tantalum complex {[η6-Ar-CMe2-η5-C5H4]TaPr}[B(C6F5)4] (1; Ar = 3,5-Me2C6H3) serves as a starting material for a series of neutral, monocationic, and dicationic derivatives. The cationi...

Phosphorus(III) Cations Supported by a PNP Pincer Ligand and Sub‐Stoichiometric Generation of P4 from Thermolysis of a Nickel Insertion Product

Neutral, mono-, and dicationic phosphorus(III) compounds are accessible with a supporting PNP pincer ligand (PNP = [4-Me-2-iPr(2)P-C(6)H(3))(2)N]). Reaction of (PNP)H with PCl(3) and nBu(3)N furnished (PNP)PCl(2) (1), which displays a highly temperature-dependent structure in solution. Synthesis and characterization by NMR spectroscopy and X-ray crystallography of Cl/Br-scrambled derivatives, a monocationic derivative [(PNP)PCl][HCB(11)H(11)] (4), and the dicationic derivatives [(PNP)P][OTf](2) (5), [(PNP)P][B(C(6)F(5))(4)](2) (6), [(PNP)P][B(12)Cl(12)] (7) established that 1 not only undergoes several fluxional processes in solution but also possesses a temperature-dependent ground state structure. Reaction of 1 with a Ni(0) source initially leads to a phosphine-phosphinidene complex, followed by thermal generation of P(4).

The relative stabilities of cyclic dicationic derivatives of diphosphanes with three (3P) or four (4P) linked phosphorus atoms

Reaction of a diphosphane with a chlorophosphane in the presence of SnCl(2) or AlCl(3) leads to the formation of dicationic heterocycles with three (3P) or four (4P) linked phosphorus atoms. Some 3P derivatives with small alkyl substituents may also be prepared by direct alkylation of cyclic triphosphenium ions. Several new species were prepared in solution, some of which were isolated and characterised by single-crystal X-ray diffraction. Investigations into the factors favouring formation of 3P or 4P species are described.

Single Two-Electron Transfers and Successive One-Electron Transfers in Biferrocenyl−Indacene Isomers

Novel biferrocenyl complexes of s- and as-dihydroindacenes have been prepared and the charge transfer properties of their mono- and dicationic derivatives, selectively generated by one-electron and...

Voltage‐dependent and ‐independent block of α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptor channels

Polyamine-containing toxins and synthetic dicationic derivatives of adamantane and phenylcyclohexyl selectively antagonize Ca(2+)-permeable α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor channels. These compounds demonstrate voltage-dependent open-channel block and are trapped by closed channels. In this study, we describe an alternative mechanism of non-competitive AMPA receptor inhibition caused by 9-aminoacridine and some of its derivatives. These compounds exhibit similar potency against Ca(2+)-permeable and Ca(2+)-impermeable AMPA receptors. The inhibition is largely voltage-independent, binding and unbinding do not require presence of agonist. We conclude that 9-aminoacridine binds to a shallow site in the AMPA receptor, which is located above the activation gate. A comparison of three-dimensional structures of the antagonists suggests that the 'V-like' shape of the hydrophobic headgroup favors voltage-dependent binding to the deep site in the channel pore, whereas the compounds possessing flat aromatic headgroups preferably bind to the shallow site. The characterization of the novel mechanism of AMPA receptor channel antagonism opens a way to develop a new family of pharmacological agents, which can be of scientific and practical importance.

Synthesis and Evaluation of Bis‐Thiazolium Salts as Potential Antimalarial Drugs

An innovative therapeutic approach based on the use of dicationic derivatives was previously designed to inhibit the biosynthesis of phosphatidylcholine in Plasmodium spp. Among these, bis-thiazolium salts were shown to block proliferation of the malaria parasite at concentrations in the low nanomolar range. However, due to unsuitable molecular properties such as the presence of the two polar heads and flexibility in the linker, these compounds have low oral bioavailability. To characterize the structural requirements of the linker that lead to more rigid analogues with fewer rotatable bonds but which retain antimalarial activity, a new series of compounds incorporating an aryl moiety and eventually oxygen atoms were prepared, and their biological activity was evaluated. Structure-activity relationships suggest that the optimal linker construct is an aromatic group with two n-butyl chains branched at the para position; two new leads (compounds 39 and 40) were selected for further development.

A new series of titanocene dichloride derivatives bearing chiral alkylammonium groups; assessment of their cytotoxic properties

A series of new, water soluble titanocene dichloride derivatives containing chiral alkylammonium groups have been synthesized and characterized and their cytotoxicities against the human lung cancer cell lines A549, H209 and H209/CP have been assessed. The potencies of the compounds vary greatly, with primary ammonium salts being particularly ineffective. However, mono- and dicationic derivatives containing chiral ephedrine-type functional groups are very effective, in particular the dicationic species.

Peculiarities of the structure and function of AMPA receptors revealed from the action of channel blockers

Dicationic derivatives of adamantine, phenylcyclohexyl and diphenyl are potent channel blockers of AMPA type ionotropic glutamate receptors. Our previous studies have revealed structural and molecular determinants of binding of AMPA receptor channel blockers. More detailed investigation of the mechanisms of the blocking action offers a clearer view of structure and activation mechanisms of the channels. The following conclusions were made in the present study: (i) extracellular drug application results in the open channel block, indicating that the binding site is guarded by the activation gate of the channel; (ii) drug binding does not prevent channel closure and blockers get trapped in the closed channels; (iii) blockers can permeate though the open channel and dissociate from the closed channel into the cytoplasm; (iv) intracellular application of the drugs causes the block of open and closed channel conformations; (v) blockers bind to a single site in the channel independent on the side of application. Analysis of the whole set of the data using molecular and kinetic models demonstrates that the channel activation gate controls the access to the binding site from the external but not from the internal side of the membrane. It means that the selectivity filter of the AMPA receptor channel is permeable to organic compounds even in the closed state. This conclusion significantly contributes to the notion of the activation mechanisms of ionotropic glutamate receptors.