Series Of Ligands Research Articles

Understanding the high electronic quantum similarity of a series of ligands used as inhibitors of the SARS-CoV-2 virus by molecular mechanics and density functional theory approaches

Background A coronavirus identified in 2019, SARS-CoV-2, has caused a pandemic of respiratory illness, called COVID-19. Most people with COVID-19 experience mild to moderate symptoms and recover without the need for special treatments. The SARS‑CoV‑2 RNA‑dependent RNA polymerase (RdRp) plays a crucial role in the viral life cycle. The active site of the RdRp is a very accessible region, so targeting this region to study the inhibition of viral replication may be an effective therapeutic approach. For this reason, this study has selected and analysed a series of ligands used as SARS-CoV-2 virus inhibitors, namely: Darunavir (Daru), Dexamethasona (Dexame), Dolutegravir (Dolu), Fosamprenavir (Fosam), Ganciclovir (Gan), Insoine (Inso), Lopinavir (Lop), Ritonavir (Rito) and Tipranavir (Tipra). Methods These ligands were analyzed using molecular docking, molecular quantum similarity using four similarity indices like overlap, Coulomb and their Euclidean distances. On the other hand, these outcomes were supported with chemical reactivity indices defined within a conceptual density functional theory framework. Results The results show the conformations with the highest root-mean-square deviation (RMSD), have π-π stacking interaction with residue LYS621, ARG555 and ASP623, CYS622, ASP760, among others. In the molecular quantum similarity, the highest indices have been obtained in the electronic similarity in comparison with the structural similarity. Conclusions These studies allow the identification of the main stabilizing interactions using the crystal structure of SARS‑CoV‑2 RNA‑dependent RNA polymerase. In this order of ideas, this study provides new insights into these ligands that can be used in the design of new COVID-19 treatments. The studies allowed us to find an explanation supported in the Density Functional Theory about the chemical reactivity and the stabilization in the active site of the ligands.

Sadphos as Adaptive Ligands in Asymmetric Palladium Catalysis.

ConspectusPalladium catalysis, as one of the most important strategies in asymmetric synthesis, has continuously attracted the attention of organic chemists. With the development of chiral ligands, increasingly challenging reactions and substantial progress in asymmetric catalysis are being realized.Since 2014, we have focused on exploiting a series of sulfinamide phosphine ligands called "Sadphos," including Ming-Phos, Xu-Phos, Xiao-Phos, Xiang-Phos, TY-Phos, PC-Phos, GF-Phos, and WJ-Phos. These ligands can be easily prepared in two to four steps using commercial materials. These new types of ligands have shown remarkable performance in transition-metal-catalyzed reactions, especially in Pd-catalyzed transformations. X-ray diffraction analysis, mechanistic studies, and density functional theory calculations have revealed that Sadphos ligands can coordinate with the Pd0 and PdII species in the Pd0/P, Pd0/P,S, or PdII/P,O modes.This Account summarizes our recent efforts toward palladium-catalyzed enantioselective reactions using Sadphos ligands. These ligands were found to be privileged and very crucial to promote the reactions by increasing the reactivity and enantioselectivity. Ming-Phos is an effective ligand in Pd-catalyzed asymmetric coupling and intramolecular Heck reactions, providing highly enantioselective trisubstituted allenes, axially chiral anilides, gem-diarylmethine silanes, and disubstituted dihydroisoquinolinones. Incorporation of an electron-rich cyclohexyl group in the phosphine moiety afforded Xu-Phos, which showed a unique effect in a series of asymmetric transformations, including reductive Heck, dearomative Mizoroki-Heck, tandem Heck/Suzuki coupling, carboiodination, carboamination, and cross-coupling reactions. Using a similar strategy, our group synthesized more electron-rich TY-Phos and Xiang-Phos ligands bearing t-butyl and 1-adamantyl group at P atoms, respectively. Regarding stereoelectronic features, these two characteristic ligands were the best choice to satisfy the requirements of the palladium-catalyzed fluoroarylation of gem-difluoroalkenes, intermolecular α-arylation of aldehydes, carboetherification of alkenyl oximes, and carboheterofunctionalization of 2,3-dihydrofurans. Compared with the aforementioned Sadphos ligands, the attractive features of Xiao-Phos, including high nucleophilicity originating from the CH2PPh2 group and the ortho-substituent effect at the side of the aryl ring, are presumably responsible for its efficiency. The Pd/Xiao-Phos catalyst system shows good performance in a series of cross-coupling reactions of secondary phosphine oxides, affording P-stereogenic products bearing multiple types of molecular skeletons. The modification of the basic Sadphos backbone by introducing a xanthene skeleton motivated us to design and synthesize monophosphines, named PC-Phos and GF-Phos. PC-Phos is effective in various reactions, including arylation of sulfenate anions, denitrogenative cyclization of benzotriazoles, and dearomatization of indoles. The practicability of GF-Phos was validated in the Pd-catalyzed asymmetric three-component coupling of N-tosylhydrazones, aryl halides, and terminal alkynes, as well as in the cross-coupling of N-tosylhydrazones and vinyl iodides with pendent amines. In addition, ferrocene-derived WJ-Phos was employed in the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction, affording axially chiral biaryl monophosphine oxides in excellent enantiomeric excesses.

Binding and unbinding of potent melatonin receptor ligands: Mechanistic simulations and experimental evidence.

The labeled ligand commonly employed in competition binding studies for melatonin receptor ligands, 2-[125I]iodomelatonin, showed slow dissociation with different half-lives at the two receptor subtypes. This may affect the operational measures of affinity constants, which at short incubation times could not be obtained in equilibrium conditions, and structure-activity relationships, as the Ki values of tested ligands could depend on either interaction at the binding site or the dissociation path. To address these issues, the kinetic and saturation binding parameters of 2-[125I]iodomelatonin as well as the competition constants for a series of representative ligands were measured at a short (2 h) and a long (20 h) incubation time. Concurrently, we simulated by molecular modeling the dissociation path of 2-iodomelatonin from MT1 and MT2 receptors and investigated the role of interactions at the binding site on the stereoselectivity observed for the enantiomers of the subtype-selective ligand UCM1014. We found that equilibrium conditions for 2-[125I]iodomelatonin binding can be reached only with long incubation times, particularly for the MT2 receptor subtype, for which a time of 20 h approximates this condition. On the other hand, measured Ki values for a set of ligands including agonists, antagonists, nonselective, and subtype-selective compounds were not significantly affected by the length of incubation, suggesting that structure-activity relationships based on data collected at shorter time reflect different interactions at the binding site. Molecular modeling simulations evidenced that the slower dissociation of 2-iodomelatonin from the MT2 receptor can be related to the restricted mobility of a gatekeeper tyrosine along a lipophilic path from the binding site to the membrane bilayer. The enantiomers of the potent, MT2-selective agonist UCM1014 were separately synthesized and tested. Molecular dynamics simulations of the receptor-ligand complexes provided an explanation for their stereoselectivity as due to the preference shown by the eutomer at the binding site for the most abundant axial conformation adopted by the ligand in solution. These results suggest that, despite the slow-binding kinetics occurring for the labeled ligand, affinity measures at shorter incubation times give robust results consistent with known structure-activity relationships and with interactions taken at the receptor binding site.

Glyme-functionalized ligand based MOF: A comprehensive study on copper and zirconium frameworks

In this study, the synthesis of a series of novel glyme-modified ligands and their corresponding copper and zirconium metal-organic frameworks (MOF) has been successfully realized. In addition, while using copper salts, it was possible to yield a water-stable MOF. Besides, the utilization of zirconium salts resulted in the formation of MOF exhibiting a UiO-68 type structure. The thorough characterization of these MOF was performed using Single Crystal X-ray Diffraction (SCXRD), Powder X-ray Diffraction (PXRD), Fourier Transform Infrared Spectroscopy (FT-IR), Scanning Electron Microscopy (SEM), Thermogravimetric Analysis (TGA) and nitrogen adsorption-desorption isotherms.Furthermore, the CO2 adsorption capacity of these MOF was also evaluated. Despite the significant differences in their crystalline networks, all MOF exhibited appreciable CO2 adsorption capacities, ranging from 0.6 to 1.3 mmol g−1 at ambient pressure and 0 °C.

On the thermodynamics of aggregation toward phosphorescent metallomesogens: From electronic tuning to supramolecular design

AbstractTwo series with three Pt(II) complexes each (PtLPh‐n, PtLFpy‐n) bearing asymmetric tetradentate ligands as dianionic luminophores with variable alkyl chain lengths were synthesized. Hence, each ligand series is distinguished by one of its cyclometallating rings (phenyl vs. 2,6‐difluoropyrid‐3‐yl). Steady‐state and time‐resolved photoluminescence spectroscopic studies in diluted solutions at room temperature and in glassy matrices at 77 K show that the emissive state is mainly centered on the invariantly electron‐rich cyclometalated side while the second ring regulates the admixture of ligand‐centered and metal‐to‐ligand charge‐transfer character. Hence, the radiative rates can be controlled, as indicated by quantum‐mechanical calculations, which also explain the temperature‐dependent trend in the phosphorescence rate constants. Studies in condensed phases (single‐crystal X‐ray diffractometry, polarized optical microscopy, differential scanning calorimetry, steady‐state and time‐resolved photoluminescence micro(spectro)scopy) showed the development of a smectic A mesophase for the fluorinated species bearing the two longest alkyl chains. Nuclear magnetic resonance‐based studies on the thermodynamics of aggregation in solution confirm the marked enthalpic stabilization of aggregates mediated by the polar 2,6‐difluoropyrid‐3‐yl moiety (and to a lesser extent by dispersive forces between the alkyl chains). On the other hand, the negative entropy of aggregation is dominated by the restriction of degrees of freedom involving the peripheral alkyl moieties upon stacking, which becomes increasingly relevant for longer chains. All these factors control Pt···Pt coupling, a crucial interaction for the design of photofunctional mesogens based on Pt(II) complexes.

Tuning the Softness of the Pendant Arms and the Polyazamacrocyclic Backbone to Chelate the 203Pb/212Pb Theranostic Pair.

A series of macrocyclic ligands were considered for the chelation of Pb2+: 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), 1,7-bis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane-4,10-diacetic acid (DO2A2S), 1,5,9-tris[2-(methylsulfanyl)ethyl]-1,5,9-triazacyclododecane (TACD3S), 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetrazacyclotridecane (TRI4S), and 1,4,8,11-tetrakis[2-(methylsulfanyl)ethyl]-1,4,8,11-tetrazacyclotetradecane (TE4S). The equilibrium, the acid-mediated dissociation kinetics, and the structural properties of the Pb2+ complexes formed by these chelators were examined by UV-Visible and nuclear magnetic resonance (NMR) spectroscopies, combined with potentiometry and density functional theory (DFT) calculations. The obtained results indicated that DO4S, DO3S, DO3SAm, and DO2A2S were able to efficiently chelate Pb2+ and that the most suitable macrocyclic scaffold for Pb2+ is 1,4,7,10-tetrazacyclododecane. NMR spectroscopy gave insights into the solution structures of the Pb2+ complexes, and 1H-207Pb interactions confirmed the involvement of S and/or O donors in the metal coordination sphere. Highly fluxional solution behavior was discovered when Pb2+ was coordinated to symmetric ligands (i.e., DO4S and DO2A2S) while the introduction of structural asymmetry in DO3S and DO3SAm slowed down the intramolecular dynamics. The ligand ability to chelate [203Pb]Pb2+ under highly dilute reaction conditions was explored through radiolabeling experiments. While DO4S and DO3S possessed modest performance, DO3SAm and DO2A2S demonstrated high complexation efficiency under mild reaction conditions (pH = 7, 5 min reaction time). The [203Pb]Pb2+ complexes' integrity in human serum over 24 h was appreciably good for [203Pb][Pb(DO4S)]2+ (80 ± 5%) and excellent for [203Pb][Pb(DO3SAm)]2+ (93 ± 1%) and [203Pb][Pb(DO2A2S)] (94 ± 1%). These results reveal the promise of DO2A2S and DO3SAm as chelators in cutting-edge theranostic [203/212Pb]Pb2+ radiopharmaceuticals.

Towards Multitargeted Ligands as Pain Therapeutics: Dual Ligands of the Cavα2δ-1 Subunit of Voltage-Gated Calcium Channel and the μ-Opioid Receptor.

The synthesis and pharmacological activity of a new series of dual ligands combining activities towards the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) and the μ-opioid receptor (MOR) as novel pain therapeutics are reported. A careful exploration of the pharmacophores related to both targets, which in principle had few common characteristics, led to the design of novel compounds exhibiting both activities. The construction of the dual ligands started from published Cavα2δ-1 ligands, onto which MOR ligand pharmacophoric elements were added. This exercise led to new amino-acidic substances with good affinities on both targets as well as good metabolic and physicochemical profiles and low potential for drug-drug interactions. A representative compound, (2S,4S)-4-(4-chloro-3-(((cis)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid, displayed promising analgesic activities in several in vivo pain models as well as a reduced side-effect profile in relation to morphine.

Ligand effect on Ru-centered species toward methane activation.

Ligands have been known to profoundly affect the chemical transformations of methane, yet significant challenges remain in shedding light on the underlying mechanisms. Here, we demonstrate that the conversion of methane can be regulated by Ru centered cations with a series of ligands (C, CH, CNH, CHCNH). Gas-phase experiments complemented by theoretical dynamic analysis were performed to explore the essences and principles governing the ligand effect. In contrast to the inert Ru+, [RuC]+, and [RuCNH]+ toward CH4, the dehydrogenation dominates the reaction of ligand-regulated systems [RuCH]+/CH4 and [RuCHCNH]+/CH4. In active cases, CH acts as active sites, and regulates the activation of CH4 assisted by the "seemingly inert" CNH ligand.

Control of polymer-protein interactions by tuning the composition and length of polymer chains.

Nanomoduling the 3D shape and chemical functionalities in a synthetic polymer may create recognition cavities for biomacromolecule binding, which serves as an attractive alternative to natural antibodies with much less cost. To obtain fundamental understanding and predict molecular design rules of the polymer antibody, we analyze the complex structure between the biomarker protein epithelial cell adhesion molecule (EpCAM) and a series of polymer ligands via molecular dynamics (MD) simulations. For monomeric ligands, strong enrichment of aromatic residues in protein binding sites is revealed, in line with the reported observations for natural antibodies. Yet, for linear polymers with a growing degree of polymerization, for the first time, a drastic change is revealed on the type of enriched protein residues and the location of protein binding sites, driven by the increasing steric hindrance effect that makes the adsorption of the polymer in the protein exterior feasible. Varying the polymer length and monomeric composition also significantly affects the ligand binding affinity. Here, we have captured three distinct dependences of the ligand binding free energy on the degree of polymerization: for NIPAm based hydrophilic polymers, TBAm dominated hydrophobic polymers and AAc dominated charged polymers. These results can be rationalized by the complex structure and the composition of protein residues at the binding interface. The entire analysis demonstrates unique binding features for polymer ligands and the possibility to modulate their binding sites and affinity by engineering the polymer structure.

Contrasting a series of bidentate amido phosphine oxide, sulfide, or selenide ligands and complexes of dimethyl aluminum and indium.

A series of EP(V)-imine phosphine-imine ligands (Dipp-NC(CH3)-(CH2)-PE(Ph2)) (Dipp = 2,6-diisopropylphenyl, E = O, S, Se) and corresponding dimethyl aluminum and indium complexes were prepared and characterized using multi-nuclear NMR spectroscopy and SC-XRD. Solution-state 1H and 31P NMR spectroscopy indicate a mixture of isomers in solution (C6D6, CDCl3, and CD3CN). Solid state structures of both the imine and (E)-enamine isomers of the oxygen-based ligand have been observed. These three ligands (L) were then deprotonated with M(CH3)3 (M = Al or In), with methane loss forming a 6-membered ring via bidentate chelation ((κ2-L)M(CH3)2). The indium/oxide complex also crystallized as a 12-membered ring.

Development of thiacrown ligands for encapsulation of mercury-197m/g into radiopharmaceuticals.

The theranostic pair mercury-197m and mercury-197g (197m/gHg, t1/2 = 23.8 h/64.14 h), through their γ rays and Meitner-Auger electron emissions, have potential use as constituents in radiopharmaceuticals to treat small metastatic tumours. However, the use of this pair of nuclear isomers in radiopharmaceuticals requires the development of suitable [197m/gHg]Hg2+ chelators as currently there is a lack of established ligands for radiometals in the field. Herein, this work studies the natHg/197m/gHg coordination of three thiacrown 18-membered N2S4 macrocycles with pendant arms of varying chemical "softness". Following the synthesis and characterization of the N2S4 ligand series (6,6'-((1,4,10,13-tetrathia-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinic acid (N2S4-Pa), 7,16-bis(pyridin-2-ylmethyl)-1,4,10,13-tetrathia-7,16-diazacyclooctadecane (N2S4-Py) and 7,16-bis(2-(methylthio)ethyl)-1,4,10,13-tetrathia-7,16-diazacyclooctadecane (N2S4-Thio)), Hg2+ complexes were studied through mass spectrometry, nuclear magnetic resonance (NMR) spectroscopy, and density functional theory (DFT) calculations, revealing successful complexation of all ligands with the Hg2+ ion. Radiolabeling studies demonstrated the effect of the pendant arm on [197m/gHg]Hg2+ coordination, as N2S4-Thio and N2S4-Py had the highest radiochemical yield, similar to that of previously reported N-benzyl-2-(1,4,7,10-tetrathia-13-azacyclopentadecan-13-yl)acetamide (NS4-BA), while N2S4-Pa had the lowest. The complex integrity of [197m/gHg][Hg(N2S4-Py)]2+ and [197m/gHg][Hg(N2S4-Thio)]2+ in both human serum and glutathione was notably lower compared to the [197m/gHg][Hg(NS4-BA)]2+ complex. However, the [197m/gHg][Hg(N2S4-Py)]2+ and [197m/gHg][Hg(N2S4-Thio)]2+ complexes remained above 70% intact over 82 h when competed against biologically relevant metals (ZnCl2, FeCl3, CuCl2, MgCl2 and CoCl2), suggesting the selectivity of the ligands for Hg2+. This study illustrates the importance of the macrocyclic backbone size and electron-donor groups of the donor pendant arms in the design of chelators for 197m/gHg-radiopharmaceuticals, as both affect the radiolabeling properties and complex inertness.

Hydrogen evolution driven by heteroatoms of bidentate N-heterocyclic ligands in iron(II) complexes.

While Pt is considered the best catalyst for the electrocatalytic hydrogen evolution reaction (HER), it is evident that non-noble metal alternatives must be explored. In this regard, it is well known that the binding sites for non-noble metals play a pivotal role in facilitating efficient catalysis. Herein, we studied Fe(II) complexes with bidentate 2-(2'-pyridyl)benzoxazole (LO), 2-(2'-pyridyl)benzthiazole (LS), 2-(2'-pyridyl)benzimidazole (LNH), and 2-2'-bipyridyl (Lpy) ligands - by adding trifluoroacetic acid (TFA) to their acetonitrile solution - in order to examine how their reactivity towards protons under reductive conditions could be impacted by the non-coordinating heteroatoms (S, O, N, or none). By applying this ligand series, we found that the reduction potentials relevant for HER correlate with ligand basicity in the presence of TFA. Moreover, DFT calculations underlined the importance of charge distribution in the ligand-based LUMO and LUMO+1 orbitals of the complexes, dependent on the heterocycle. Kinetic studies and controlled potential electrolysis - using TFA as a proton source - revealed HER activities for the complexes with LNH, LO, and LS of kobs = 0.03, 1.1, and 10.8 s-1 at overpotentials of 0.81, 0.76, and 0.79 V, respectively, and pointed towards a correlation between the kinetics of the reaction and the non-coordinating heteroatoms of the ligands. In particular, the activity was associated with the [Fe(LS/O/NH)2(S)2]2+ form (S = solvent or substrate molecule), and the rate-determining step involved the formation of [Fe(H-H)]+, during the weakening of Fe-H and CF3CO2-H bonds, according to the experimental and DFT results.

In an attempt to add ligands to the sixth (axial) position of vanadyl bis-acetylacetonate: A unique tetranuclear vanadyl species

We have explored the interaction of [(acac)2V=O] (acac = acetylacetone) with a series of potential ligands which were chosen because of their expected ability to attach themselves onto its sixth (axial) position. Furthermore, some of the species chosen were expected to have the capability of linking pairs of [(acac)2V=O] molecules, thus creating magnetically coupled substances whose behavior would be interesting to document by magnetic as well as structural methods. Some of the synthetic results were surprising in that unexpected products were obtained which we had not envisioned; specifically, herein we describe a tetranuclear vanadyl cluster (Crystal data for C38H51N4O17ClV4: orthorhombic, space group Pca21 (no. 29), a = 26.4698(3) Å, b = 13.5167(2) Å, c = 12.7659(2) Å, V = 4567.44(11) Å3, Z = 4, μ(CuKα) = 7.842 mm-1, Dcalc = 1.53 g/cm3, 41277 reflections measured (6.538° ≤ 2Θ ≤ 137.892°), 7841 unique (Rint = 0.0428, Rsigma = 0.0421) which were used in all calculations; the final R1 was 0.0675 (I > 2σ(I)) and wR2 was 0.1641 (all data)), which is unusual in several aspects of its composition as well as its stereochemistry.

Theoretical Study on ORR/OER Bifunctional Catalytic Activity of Axial Functionalized Iron Polyphthalocyanine.

Designing efficient ORR/OER bifunctional electrocatalysts is very significant for reducing energy consumption and environmental protection. Hence, we studied the ORR/OER bifunctional catalytic activity of iron polyphthalocyanine (FePPc) coordinated by a series of axial ligands which has different electronegative coordination atom (FePPc-L) (L = -CN, -SH, -SCH3, -SC2H5, -I, -Br, -NH2, -Cl, -OCH3, -OH, and -F) in alkaline medium by DFT calculations. Among all FePPc-L, FePPc-CN, FePPc-SH, FePPc-SCH3, and FePPc-SC2H5 exhibit excellent ORR/OER bifunctional catalytic activities. Their ORR/OER overpotential is 0.256 V/0.234 V, 0.278 V/0.256 V, 0.280 V/0.329 V, and 0.290 V/0.316 V, respectively, which are much lower than that of the FePPc (0.483 V/0.834 V). The analysis of the electronic structure of the above catalysts shows that the electronegativity of the coordination atoms in the axial ligand is small, resulting in less distribution of dz2, dyz, and dxz orbitals near Ef, weak orbital polarization, small charge and magnetic moment of the central Fe atom, and weak adsorption strength for *OH. All these prove that the introduction of axial ligands with appropriate electronegativity coordinating atoms can adjust the adsorption of catalyst to intermediates and modify the ORR/OER bifunctional catalytic activities. This is an effective strategy for designing efficient ORR/OER bifunctional electrocatalysts.

Design and Synthesis of D3R Bitopic Ligands with Flexible Secondary Binding Fragments: Radioligand Binding and Computational Chemistry Studies.

A series of bitopic ligands based on Fallypride with a flexible secondary binding fragment (SBF) were prepared with the goal of preparing a D3R-selective compound. The effect of the flexible linker ((R,S)-trans-2a-d), SBFs ((R,S)-trans-2h-j), and the chirality of orthosteric binding fragments (OBFs) ((S,R)-trans-d, (S,R)-trans-i, (S,S)-trans-d, (S,S)-trans-i, (R,R)-trans-d, and (R,R)-trans-i) were evaluated in in vitro binding assays. Computational chemistry studies revealed that the interaction of the fragment binding to the SBF increased the distance between the pyrrolidine nitrogen and ASP1103.32 of the D3R, thereby reducing the D3R affinity to a suboptimal level.

Oligodentate Aminotriazole Ligands for CuAAC and Copper‐Mediated Monooxygenation of Phenols: Influence of Denticity, Chain Length and N‐Alkylation on Catalytic Activity

AbstractCopper complexes supported by a series of ligands containing different N‐donor groups were prepared, and the influence of the ligand design on the catalytic activity towards (i) the conversion of monophenols to o‐quinones and (ii) the CuAAC reaction was investigated. Increasing the number of methyltriazole moieties attached to an amine from one (TTA) over two (BTTA) to three (TTTA) decreases the catalytic mono‐phenolase activity of derived Cu complexes. By contrast, replacing the methylene group between the apical and the outer N‐donors of TTA with an ethylene bridge in TTEA increases the activity whereas alkylation of the amino group (dmTTEA, prlTTEA) has no positive effect on the catalytic activity. When employing the complexes in the CuAAC reaction, opposite trends in catalytic activity are observed. The results are interpreted in the context of the respective mechanistic pathways.

Design and synthesis of acyclic bis-triazole ligands: Complexation with metal ions, DFT calculations, and biological activity

Triazole-derived heterocyclic compounds have significant biological activities and pharmaceutical stability. A new series of acyclic bis-triazole ligands 16–20 with ester end groups were designed. The synthesized ligands were evaluated for their complexation ability with transition metals (Cu2+, Hg2+, Pb2+, and Zn2+). The molar conductivity of bis-1,2,3-triazole ligand-metal complexes was measured in acetonitrile at a temperature range 288.15–308.15 K. Furthermore, the thermodynamic quantities (∆H°, ∆S°, and ∆G°) were determined using the van't Hoff equation and the computational stability constants of the resulting 1:1 complexes were determined based on 1:1 stoichiometry. Meanwhile, the optimized geometry of ligands and ligand-metal complexes was computationally calculated using density fraction theory (DFT). Moreover, the antioxidant potential, in DPPH and ABTS assays, as well as the antibacterial activity of the bis-1,2,3-triazole ligands were evaluated. Ligands 16, 19, and 20 complexed with Hg2+ as well as ligand 17 with Cu2+, Hg2+, and Pb2+ showed a continuous decrease in molar conductivity on complexation, however, ligand 18 complexed with Cu2+, Hg2+, Pb2+, and Zn2+ begins to level off at a mole ratio of 1:1 (ligand:metal) indicating the formation of stable complexes. Noteworthy, ligand 17 formed a 1:2 and 2:1 ligand-to-metal ratio with Hg2+ and Pb+2 cations, respectively. The formation reactions of all ligand-metal complexes were exothermic and spontaneous indicating a strong triazole-metal interaction based on ∆H° and ∆G° values. Bis-triazole ligands 16–20 revealed antioxidant activity with IC50 values ranging from 89.0 to 156.1 µg/ml in DPPH and 91.3–167.2 µg/ml in ABTS assays. Ligands 16–19 exhibited antibacterial activity against the Gram-positive Bacillus cereus with MICs ranging from 150 to 250 µg/ml. The synthesized bis-triazole ligands have a potential application in the pharmaceutical and food industries. Moreover, the selectivity of ligands 16, 19, and 20 to Hg2+ could be useful for removing such a metal from industrial wastewater containing a variety of toxic heavy metals and ISE construct.

Ligand Promoted Pd-Catalyzed High para-Selective C-H Olefination.

Achieving high para-selective C-H functionalized products of benzoic acid derivatives using a designed template is still a daunting challenge because the carbonyl group also could coordinate with metal to activate the ortho-C-H bond. Herein, we report the ligand promoted high para-selective C-H olefination of benzoic acid derivatives; we screened a series of ligands increasing the ratio of p:others from 62:38 to 96:4. This work may find application in the construction of para-substituted benzoic acid derivatives.

Discovery of a far-red carbazole-benzoindolium fluorescent ligand that selectively targets mitochondrial DNA and suppresses breast cancer growth

G-quadruplex (G4) formation was considered to be more prevalent in the mitochondrial DNA (mtDNA) of cancer cells compared with normal cells. Stabilization of these G4s may induce mtDNA instability and cause mitochondrial dysfunction and subsequent cell death, which may be treated as a new strategy for cancer treatment. However, few ligands were developed to target mtG4s, leaving a huge room to improve. In this study, we designed and synthesized a series of carbazole-based ligands, among which, BKN-1 was identified as the most promising mitochondrial targeting fluorescent ligand with far-red emission. Then, we demonstrated that BKN-1 may robustly interact with mtG4s via a variety of biophysical, biological experiments. Subsequently, we proved that BKN-1 may cause mtDNA loss, disrupt mitochondrial integrity, decrease ATP level and trigger unbalanced ROS, thereby leading to apoptosis and autophagy. Finally, we verified that BKN-1 had good anti-tumor activity in both cellular and in vivo models. Altogether, this study provided a dual-function ligand that may not only track the formation of mtG4s but also induce mitochondrial dysfunction, which may be developed into an applicable chemical tool for investigating the structure and function of mtG4s, and moreover, an effective therapeutic agent for cancer interference.

Synthesis, spectroscopic elucidation, density functional theory calculation, and molecular docking studies of a novel series of tetradentate macrocyclic Schiff base ligands and their Zn(II) complexes and investigations of their antimicrobial, anti‐inflammatory, and anticancer activities

In the present work, novel Schiff base macrocyclic Zn(II) complexes [Zn(N8O4MacL1)Cl2–Zn(N8O4MacL3)Cl2] were synthesized by the reaction of ZnCl2 and macrocyclic ligands (N8O4MacL1–N8O4MacL3) derived from the condensation of ligand (L) and dicarboxylic acids [HOOC‐(CH2)n‐COOH]. The structural confirmation of the newly synthesized compounds was accomplished through various analytical techniques, including elemental analysis, infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), UV–visible spectroscopy, and powder X‐ray diffraction (XRD) studies. The spectral data provided evidence that the macrocyclic ligands acted as tetradentate ligands, forming coordination bonds with Zn(II) ions through the nitrogen atom of the imine (>C=N) group. The coordination complexes exhibited an octahedral geometry around the zinc ion, with two chloro groups covalently attached. Density functional theory (DFT) studies of the synthesized Schiff base macrocyclic compounds were carried out to determine their structural and electronic properties. The antimicrobial potential of the macrocyclic compounds was examined against a panel of pathogenic microbes, including four bacterial strains (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Xanthomonas campestris) and two fungal strains (Fusarium oxysporum and Candida albicans). Then, the newly synthesized Schiff based macrocyclic compounds were evaluated for their anti‐inflammatory activity using an egg albumin method. The synthesized compounds were subjected to further evaluation to assess their potential as anticancer agents against MCF‐7 (human breast adenocarcinoma cell line), HCT‐116 (human colon cancer cell line), and A549 (human alveolar adenocarcinoma epithelial cell line). In addition, molecular docking studies were conducted to explore the potential interactions between the synthesized compounds and the target proteins VEGFR2 (PDB ID 1YWN), EGFR (PDB ID 1M17), and DNA gyrase B (PDB ID 4URO). It was found that there was a high correlation between the experimental results and the docking calculations.