The effects of alkyl substitution on the aggregation of π-conjugated dyes: spectroscopic study and modelling.

A family of dithienosilole-based dyes with alternating donor and acceptor conjugated groups, decorated with linear or branched alkyl chains at different positions on the backbone, have been obtained and investigated in different aggregation states. These dyes are characterized by almost panchromatic absorption and by near-IR emission, with good quantum yields in a variety of solvents with different polarity. We demonstrate that the nature and position of the alkyl substituents strongly govern the self-assembly of the dyes, whose packing is also sensitive to external stimuli, such as grinding and water addition. Thanks to computational results and theoretical modelling, we are able to interpret the results based on two possible preferential packings, characterized by distinct spectroscopic behaviour, whose abundance can be tuned according to the nature and position of the alkyl chains, as well as via external stimuli.

Acetylacetonate Ruthenium Nitrosyls: A Gateway to Nitric Oxide Release in Water under Near-Infrared Excitation by Two-Photon Absorption.

A fundamental challenge for phototriggered therapies is to obtain robust molecular frameworks that can withstand biological media. Photoactivatable nitric oxide (NO) releasing molecules (photoNORMs) based on ruthenium nitrosyl (RuNO) complexes are among the most studied systems due to several appealing features that make them attractive for therapeutic applications. Nevertheless, the propensity of the NO ligand to be attacked by nucleophiles frequently manifests as significant instability in water for this class of photoNORMs. Our approach to overcome this limitation involved enhancing the Ru-NO π-backbonding to lower the electrophilicity at the NO by replacing the commonly employed 2,2'-bipyridine (bpy) ligand by an anionic, electron-rich, acetylacetonate (acac). A versatile and convenient synthetic route is developed and applied for the preparation of a large library of RuNO photoNORMs with the general formula [RuNO(tpy)(acac)]2+ (tpy = 2,2':6',2″-terpyridine). A combined theoretical and experimental analysis of the Ru-NO bonding in these complexes is presented, supported by extensive single-crystal X-ray diffraction experiments and by topological analyses of the electron charge density by DFT. The enhanced π-back-bonding, systematically evidenced by several techniques, resulted in a remarkable stability in water for these complexes, where significant NO release efficiencies were recorded. We finally demonstrate the possibility of obtaining sophisticated water-stable multipolar NO-delivery platforms that can be activated in the near-IR region by two-photon absorption (TPA), as demonstrated for an octupolar complex with a TPA cross section of 1530 GM at λ = 800 nm and for which NO photorelease was demonstrated under TPA irradiation in aqueous media.

Redox-Switchable Behavior of Transition-Metal Complexes Supported by Amino-Decorated N-Heterocyclic Carbenes.

The coordination chemistry of the N-heterocyclic carbene ligand IMes(NMe2)2, derived from the well-known IMes ligand by substitution of the carbenic heterocycle with two dimethylamino groups, was investigated with d6 [Mn(I), Fe(II)], d8 [Rh(I)], and d10 [Cu(I)] transition-metal centers. The redox behavior of the resulting organometallic complexes was studied through a combined experimental/theoretical study, involving electrochemistry, EPR spectroscopy, and DFT calculations. While the complexes [CuCl(IMes(NMe2)2)], [RhCl(COD)(IMes(NMe2)2)], and [FeCp(CO)2 (IMes(NMe2)2)](BF4) exhibit two oxidation waves, the first oxidation wave is fully reversible but only for the first complex the second oxidation wave is reversible. The mono-oxidation event for these complexes occurs on the NHC ligand, with a spin density mainly located on the diaminoethylene NHC-backbone, and has a dramatic effect on the donating properties of the NHC ligand. Conversely, as the Mn(I) center in the complex [MnCp(CO)2 ((IMes(NMe2)2)] is easily oxidizable, the latter complex is first oxidized on the metal center to form the corresponding cationic Mn(II) complex, and the NHC ligand is oxidized in a second reversible oxidation wave.

On the Spin-State Dependence of Redox Potentials of Spin Crossover Complexes.

Resistance switching properties of nanoscale junctions of spin crossover molecules have received recently much interest. In many cases, this property has been traced back to the variation of molecular orbital energies upon spin transition. However, one can also expect a substantial reorganization of the molecular structure due to charge localization, which calls for a better understanding of the relationship between the redox potential and the spin state of the molecule. To investigate this issue, we carried out a detailed density functional theory and variable temperature cyclic voltammetry investigation of the benchmark compound [Fe(HB(1,2,4-triazol-1-yl)3)2] in solution. We show that, for a correct thermodynamical picture, it is necessary to take into account the charge transfer-induced electronic and structural reorganization as well as spin equilibria in the oxidized and reduced species.

Heteroleptic Copper(I) Complexes Prepared from Phenanthroline and Bis-Phosphine Ligands: Rationalization of the Photophysical and Electrochemical Properties.

The electronic and structural properties of ten heteroleptic [Cu(NN)(PP)]+ complexes have been investigated. NN indicates 1,10-phenanthroline (phen) or 4,7-diphenyl-1,10-phenanthroline (Bphen); each of these ligands is combined with five PP bis-phosphine chelators, i.e., bis(diphenylphosphino)methane (dppm), 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)benzene (dppb), and bis[(2-diphenylphosphino)phenyl] ether (POP). All complexes are mononuclear, apart from those based on dppm, which are dinuclear. Experimental data-also taken from the literature and including electrochemical properties, X-ray crystal structures, UV-vis absorption spectra in CH2Cl2, luminescence spectra and lifetimes in solution, in PMMA, and as powders-have been rationalized with the support of density functional theory calculations. Temperature dependent studies (78-358 K) have been performed for selected complexes to assess thermally activated delayed fluorescence. The main findings are (i) dependence of the ground-state geometry on the crystallization conditions, with the same complex often yielding different crystal structures; (ii) simple model compounds with imposed C2 v symmetry ([Cu(phen)(PX3)2]+; X = H or CH3) are capable of modeling structural parameters as a function of the P-Cu-P bite angle, which plays a key role in dictating the overall structure of [Cu(NN)(PP)]+ complexes; (iii) as the P-Cu-P angle increases, the energy of the metal-to-ligand charge transfer absorption bands linearly increases; (iv) the former correlation does not hold for emission spectra, which are red-shifted for the weaker luminophores; (v) the larger the number of intramolecular π-interactions within the complex in the ground state, the higher the luminescence quantum yield, underpinning a geometry locking effect that limits the structural flattening of the excited state. This work provides a general framework to rationalize the structure-property relationships of [Cu(NN)(PP)]+, a class of compounds of increasing relevance for electroluminescent devices, photoredox catalysis, and solar-to-fuels conversion, which so far have been investigated in an unsystematic fashion, eluding a comprehensive understanding.

Ordered Layered Dendrimers Constructed from Two Known Dendrimer Families: Inheritance and Emergence of Properties.

A new concept is presented, namely the synthesis of dendrimers intrinsically composed in alternation of building blocks pertaining to two known families of dendrimers: phosphorhydrazone dendrimers and triazine-piperazine dendrimers. These mixed dendrimers with layered controlled architecture inherit their easy (31) P NMR characterization and their thermal stability from the phosphorhydrazone family, and their decreased solubility from the triazine-piperazine family. However, they have also their own and original characteristics. Both parent families are white powders, whereas the mixed dendrimers are yellow, orange, or red powders, depending on the generation. DFT calculations were carried out on model dendrons to understand these special color features. Remarkably, these dendrimers incorporating redox-active organic entities allow for the first time the monitoring of the growth of an organic dendrimer by electrochemistry while highlighting an even-odd generation behavior.

Ruthenium complexes with dendritic ferrocenyl phosphanes: synthesis, characterization, and application in the catalytic redox isomerization of allylic alcohols.

An efficient system for the catalytic redox isomerization of the allylic alcohol 1-octen-3-ol to 3-octanone is presented. The homogeneous ruthenium(II) catalyst contains a monodentate phosphane ligand with a ferrocene moiety in the backbone and provides 3-octanone in quantitative yields. The activity is increased by nearly 90 % with respect to the corresponding triphenyl phosphane ruthenium(II) complex. By grafting the catalyst at the surface of a dendrimer, the catalytic activity is further increased. By introducing different spacers between ferrocene and phosphorus, the influence on the electronic properties of the complexes is shown by evaluating the electrochemical behavior of the compounds.

Characterization of new specific copper chelators as potential drugs for the treatment of Alzheimer's disease.

The non-controlled redox-active metal ions, especially copper, in the brain of patients with Alzheimer disease (AD) should be considered at the origin of the intense oxidative damage in the AD brain. Several bis(8-aminoquinoline) ligands, such as 1 and PA1637, are able to chelate Cu(2+) with high affinity, and are specific chelators of copper with respect to iron and zinc. They are able to efficiently extract Cu(2+) from a metal-loaded amyloid. In addition, these tetradentate ligands are specific for the chelation of Cu(2+) compared with Cu(+). Consequently, the copper ion is easily released from the bis(8-aminoquinoline) ligand under reductive conditions, and can be trapped again by a protein having some affinity for copper such as human serum albumin (HSA) proteins. In addition, the copper is not efficiently released from [Cu(CQ)2] in reductive conditions. The catalytic production of H2O2 by [Cu(2+)-Aß(1-28)]/ascorbate is inhibited in vitro by the bis(8-aminoquinoline) 1, suggesting that 1 should be able to play a protective role against oxidative damages induced by copper-loaded amyloids.

Heteroleptic bis(cis-1,2-disubstituted ethylene-1,2-dithiolato)nickel complexes obtained by ligand-exchange reaction: synthesis and properties.

The ligand-exchange reaction has been investigated to synthesize nickel bis(dithiolene) complexes bearing one hydroxyl functional group aimed at being grafted thereafter onto polymer materials. This reaction leads easily to heteroleptic complexes with the ethylene-1,2-dithiolato core substituted by either alkyl or aryl moieties. Details on synthetic parameters are given. A direct link between the electronic properties of the obtained molecules and those of the parent complexes involved in the ligand-exchange reaction is highlighted and also demonstrates that this reaction is a powerful method for preparing nickel complexes with tailor-made frontier orbital energies.

Single electron reduction of NHC-CO2-borane compounds.

The carbon dioxide radical anion [CO2˙-] is a highly reactive species of fundamental and synthetic interest. However, the direct one-electron reduction of CO2 to generate [CO2˙-] occurs at very negative reduction potentials, which is often a limiting factor for applications. Here, we show that NHC-CO2-BR3 species - generated from the Frustrated Lewis Pair (FLP)-type activation of CO2 by N-heterocyclic carbenes (NHCs) and boranes (BR3) - undergo single electron reduction at a less negative potential than free CO2. A net gain of more than one volt was notably measured with a CAAC-CO2-B(C6F5)3 adduct, which was chemically reduced to afford [CAAC-CO2-B(C6F5)3˙-]. This room temperature stable radical anion was characterized by EPR spectroscopy and by single-crystal X-ray diffraction analysis. Of particular interest, DFT calculations showed that, thanks to the electron withdrawing properties of the Lewis acid, significant unpaired spin density is localised on the carbon atom of the CO2 moiety. Finally, these species were shown to exhibit analogous reactivity to the carbon dioxide radical anion [CO2˙-] toward DMPO. This work demonstrates the advantage provided by FLP systems in the generation and stabilization of [CO2˙-]-like species.

A mononuclear cobalt(III) carboxylate complex with a fully O-based coordination sphere: CoIII-O bond homolysis and controlled radical polymerisation from [Co(acac)2(O2CPh)].

The addition of benzoyl peroxide to [CoII(acac)2] in a 1 : 2 ratio selectively produces [CoIII(acac)2(O2CPh)], a diamagnetic (NMR) mononuclear CoIII complex with an octahedral (X-ray diffraction) coordination geometry. It is the first reported mononuclear CoIII derivative with a chelated monocarboxylate ligand and an entirely O-based coordination sphere. The compound degrades in solution quite slowly by homolytic CoIII-O2CPh bond cleavage upon warming above 40 °C to produce benzoate radicals and can serve as a unimolecular thermal initiator for the well-controlled radical polymerisation of vinyl acetate. Addition of ligands (L = py, NEt3) induces benzoate chelate ring opening and formation of both cis and trans isomers of [CoIII(acac)2(O2CPh)(L)] for L = py under kinetic control, then converting quantitatively to the cis isomer, whereas the reaction is less selective and equilibrated for L = NEt3. The py addition strengthens the CoIII-O2CPh bond and lowers the initiator efficiency in radical polymerisation, whereas the NEt3 addition results in benzoate radical quenching by a redox process. In addition to clarifying the mechanism of the radical polymerisation redox initiation by peroxides and rationalizing the quite low efficiency factor for the previously reported [CoII(acac)2]/peroxide-initiated organometallic-mediated radical polymerisation (OMRP) of vinyl acetate, this investigation provides relevant information on the CoIII-O homolytic bond cleavage process.

Tuning of the emission efficiency and HOMO-LUMO band gap for ester-functionalized {Al(salophen)(H2O)2}+ blue luminophors.

A series of [AlL(H(2)O)(2)(NO(3))] complexes, with L standing for an ester substituted salophen-type ligand, has been synthesized, and the luminescence properties have been investigated. These derivatives differ by the nature of the ester-R group introduced at the C5 position of their salicylidene rings (i.e., phenyl, 7a,a'; naphthyl, 7b,b'; pentafluorophenyl, 7c,c'; and p-nitrophenyl, 7d) and by the bis-imino bridge (i.e., 1,2- phenylene, 7a-d; and 1,2-naphthalene, 7a'-c'). All the complexes are characterized by luminescence in the blue range, the chemical diversity having no effect on the emission wavelength (480-485 nm). However, the emission efficiency was found to be strongly dependent on the Schiff-base ligand with quantum yields ranging from ϕ = 22% to 44%, the highest values being for the salophen derivatives with the electron-withdrawing ester-R groups (7a, 34%; 7a', 23%; 7b, 31%; 7b', 22%; 7c, 40%; 7c', 29%, and 7d, 44%). Both the electrochemical data and DFT calculations show that the HOMO-LUMO band gap is modified as a function of the ester R group (from 2.92 to 3.16 eV, based on the redox potentials). The crystal structures for the N,N'-bis(5-(phenoxycarbonyl)salicylidene)-1,2-phenylenediamine and the N,N'-bis(5-(p-nitrophenoxycarbonyl)salicylidene)-1,2-phenylenediamine aluminum complexes (7a and 7d) are reported.

Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-a]pyridine Antileishmanial Pharmacophore.

An antileishmanial structure−activity relationship (SAR) study focused on positions 2 and 8 of the imidazo[1,2-a]pyridine ring was conducted through the synthesis of 22 new derivatives. After being screened on the promatigote and axenic amastigote stages of Leishmania donovani and L. infantum, the best compounds were tested against the intracellular amastigote stage of L. infantum and evaluated regarding their in vitro physicochemical and pharmacokinetic properties, leading to the discovery of a new antileishmanial6-chloro-3-nitro-8-(pyridin-4-yl)-2-[(3,3,3-trifluoropropylsulfonyl)methyl]imidazo[1,2-a]pyridine hit. It displayed low cytotoxicities on both HepG2 and THP1 cell lines (CC50 > 100 µM) associated with a good activity against the intracellular amastigote stage of L. infantum (EC50 = 3.7 µM versus 0.4 and 15.9 µM for miltefosine and fexinidazole, used as antileishmanial drug references). Moreover, in comparison with previously reported derivatives in the studied series, this compound displayed greatly improved aqueous solubility, good mouse microsomal stability (T1/2 > 40 min) and high gastrointestinal permeability in a PAMPA model, making it an ideal candidate for further in vivo studies on an infectious mouse model.

New 8-Nitroquinolinone Derivative Displaying Submicromolar in Vitro Activities against Both Trypanosoma brucei and cruzi.

An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC50 ≤ 13 µM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E° = -0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds.

Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties.

To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program.

8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi.

An antikinetoplastid pharmacomodulation study was done at position 8 of a previously identified pharmacophore in 3-nitroimidazo[1,2-a]pyridine series. Twenty original derivatives bearing an alkynyl moiety were synthesized via a Sonogashira cross-coupling reaction and tested in vitro, highlighting 3 potent (40 nM ≤ EC50 blood stream form≤ 70 nM) and selective (500 ≤ SI ≤ 1800) anti-T. brucei brucei molecules (19, 21 and 22), in comparison with four reference drugs. Among these hit molecules, compound 19 also showed the same level of activity against T. cruzi (EC50 amastigotes = 1.2 µM) as benznidazole and fexinidazole. An in vitro comet assay showed that nitroaromatic derivative 19 was not genotoxic. It displayed a low redox potential value (-0.68 V/NHE) and was shown to be bioactivated by type 1 nitroreductases both in Leishmania and Trypanosoma. The SAR study indicated that an alcohol function improved aqueous solubility while maintaining good activity and low cytotoxicity when the hydroxyl group was at position beta of the alkyne triple bond. Hit-compound 19 was also evaluated regarding in vitro pharmacokinetic data: 19 is BBB permeable (PAMPA assay), has a 16 min microsomal half-life and a high albumin binding (98.5%). Moreover, compound 19 was orally absorbed and was well tolerated in mouse after both single and repeated administrations at 100 mg/kg. Its mouse plasma half-life (10 h) is also quite encouraging, paving the way toward further efficacy evaluations in parasitized mouse models, looking for a novel antitrypanosomal lead compound.

Nongenotoxic 3-Nitroimidazo[1,2-a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity.

Twenty nine original 3-nitroimidazo[1,2-a]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC50 > 100 µM) alongside good antileishmanial activities (IC50 = 1-2.1 µM) against L. donovani, L. infantum, and L. major; and good antitrypanosomal activities (IC50 = 1.3-2.2 µM) against T. brucei brucei and T. cruzi, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine, and benznidazole (IC50 = 0.6 to 13.3 µM). Molecule 5, presenting a low reduction potential (E° = -0.63 V), was shown to be selectively bioactivated by the L. donovani type 1 nitroreductase (NTR1). Importantly, molecule 5 was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule 5 showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and nonmutagenic, making 5 a good candidate for further in vivo studies.

Efficient analoging around ethionamide to explore thioamides bioactivation pathways triggered by boosters in Mycobacterium tuberculosis.

Ethionamide is a key antibiotic prodrug of the second-line chemotherapy regimen to treat tuberculosis. It targets the biosynthesis of mycolic acids thanks to a mycobacterial bioactivation carried out by the Baeyer-Villiger monooxygenase EthA, under the control of a transcriptional repressor called EthR. Recently, the drug-like molecule SMARt-420, which triggers a new transcriptional regulator called EthR2, allowed the derepression a cryptic alternative bioactivation pathway of ethionamide. In order to study the bioactivation of a collection of thioisonicotinamides through the two bioactivation pathways, we developed a new two-step chemical pathway that led to the efficient synthesis of eighteen ethionamide analogues. Measurements of the antimycobacterial activity of these derivatives, used alone and in combination with boosters BDM41906 or SMARt-420, suggest that the two different bioactivation pathways proceed via the same mechanism, which implies the formation of similar metabolites. In addition, an electrochemical study of the aliphatic thioisonicotinamide analogues was undertaken to see whether their oxidation potential correlates with their antitubercular activity measured in the presence or in the absence of the two boosters.

Homo- and Heteropolymetallic Complexes of the Hybrid, Ambidentate N-Heterocyclic Carbene Ligand IMes-acac.

The anionic 5-acetylimidazol-2-ylidene-4-olate 1 -, named as "IMes-acac", is composed of fused diaminocarbene and acetylacetonato units in the same IMes-based imidazolyl ring. The bifunctional compound 1 - is shown to act as an effective, ditopic bridging ligand for transition metal centers. Several new complexes supported by this ligand were prepared, including the complex [RuCl(p-Cym)(κ2 O,O-1·H)](BF4) (2), which can be regarded as a metallated imidazolium salt, the homobimetallic complex [((COD)Rh)(RhCl(COD))(µ-1κ2 O,O:2κ1 C-1)] (4), the heterobimetallic complexes [((p-Cym)ClRu)(RhCl(COD))(µ-1κ2 O,O:2κ1 C-1)] (3), [((p-Cym)ClRu)(RhCl(CO)2)(µ-1κ2 O,O:2κ1 C-1)] (5), [((p-Cym)ClRu)(Cu(IPr))(µ-1κ2 O,O:2κ1 C-1)] (9), the anionic homoleptic Cu(I) complexes [Cu(κ1 C-1)2]K ([10]K) and [Cu(κ1 C-1)2](NEt4) ([10](NEt4)), and the heterotrimetallic complex [((p-Cym)RuCl)2(Cu)(µ-1κ2 O,O:3κ1 C-1)(µ-2κ2 O,O:3κ1 C-1)](PF6) (11). Preliminary studies on the possible preparation of supramolecular metallopolymers and electrochemical studies on the series of complexes are also reported.

Unveiling the redox-active character of imidazolin-2-thiones derived from amino-substituted N-heterocyclic carbenes.

IMes-derived thioureas in which the imidazolyl ring is directly substituted by one or two dimethylamino groups are redox-active, exhibiting one and two oxidized states, respectively. The structure, stability, and electronics of the oxidized species are investigated, emphasizing the decisive role of the amino substituents.