Parent Ligand Research Articles

Unexpected structural complexity of d-block metallosupramolecular architectures within the benzimidazole-phenoxo ligand scaffold for crystal engineering aspects

Design of metallosupramolecular materials encompassing more than one kind of supramolecular interaction can become deceptive, but it is necessary to better understand the concept of the controlled formation of supramolecular systems. Herein, we show the structural diversity of the bis-compartmental phenoxo-benzimidazole ligand H3L1 upon self-assembly with variety of d-block metal ions, accounting for factors such as: counterions, pH, solvent and reaction conditions. Solid-state and solution studies show that the parent ligand can accommodate different forms, related to (de)protonation and proton-transfer, resulting in the formation of mono-, bi- or tetrametallic architectures, which was also confirmed with control studies on the new mono-compartmental phenoxo-benzimidazole H2L2 ligand analogue. For the chosen architectures, structural variables such as porous character, magnetic behaviour or luminescence studies were studied to demonstrate how the form of H3L1 ligand affects the final form of the supramolecular architecture and observed properties. Such complex structural variations within the benzimidazole-phenoxo-type ligand have been demonstrated for the first time and this proof-of-concept can be used to integrate these principles in more sophisticated architectures in the future, combining both the benzimidazole and phenoxide subunits. Ultimately, those principles could be utilized for targeted manipulation of properties through molecular tectonics and crystal engineering aspects.

Syntheses and characterization of novel antimony (III) and bismuth (III) derivatives containing β-enamino ester along with antimicrobial evaluation, DFT calculation, and cytotoxic study.

Four novel antimony (III) and bismuth(III) complexes of the kind Cl-Sb-O-C(OR)-CH(CH3 )C-NH-(CH2 )2 -NH-C(CH3 )CH:C(OR)-O [where R = -CH3 , M = Sb (1a); R = -C2 H5 , M = Sb (1b); R = -CH3, M = Bi (1c); R = -C2 H5 , M = Bi (1d)] were successfully prepared by reacting antimony(III)chloride and bismuth(III)chloride with sodium salt of β-enamino esters in 1:1 stoichiometry, which were further structurally characterized by physicochemical and IR, 1 H, 13 C NMR spectral and mass spectrometry. Structural analysis revealed that all four derivatives of both antimony and bismuth display octahedarl geometry which has been optimized through computational studies. These derivatives along with their parent ligands were subsequently assayed in vitro for antibacterial (Bacillus subtilis, Pseudomonas aeruginosa) and antifungal (Aspergillus niger and Candida albicans) activities. Synthesized complexes were more efficacious in terms of biological activities as compared to parent ligands Further synthesized compounds were evaluated for their in vitro cytotoxic activity against lung cancer cell line A549 using MTT method. IC50 value for all four complexes was determined and all of them are found active. Computational studies of the representative complexes have been done using B3LYP/631-G* basis sets to provide optimized geometry.

Comprehensive investigation of Co(II), Ni(II) and Cu(II) complexes derived from a novel Schiff base: Synthesis, characterization, DNA interactions, ADME profiling, molecular docking, and in-vitro biological evaluation

Here, anisidine-based ligand (HL) and its cobalt (1a), nickel (1b) and copper (1c) complexes were synthesized and characterized by various spectroscopic techniques such as NMR, mass, IR, UV–visible, magnetic moments, ESR and TGA. The synthesized [Ni(L)2] and [Cu(L)2] complexes demonstrated square planar geometry around the metal centers, while the cobalt complex [Co(L)2(H2O)2] adopted six coordinated octahedral geometries. The DNA interaction studies of the complexes revealed an intercalative mode of binding, as evidenced by UV absorption, emission, and viscosity experiments, and the binding constant (Kb) follows the order of 1c > 1a > 1b. When exposed to oxidative and photolytic methods, the complexes demonstrated better efficacy in cleaving double-stranded pBR322 DNA compared to their parent Schiff base. When tested for cytotoxicity against A549 and MCF7 cell lines, complexes showed more activity than their parent ligand. In-vitro studies of the complexes' antimicrobial and antioxidant properties shown that they are far more effective than the parent ligand. Further, the biological efficiency of the ligand (HL) and complexes were verified by computational methods, including molecular docking (against protein data bank PDB ID: 2ADO.pdb) and pharmacokinetic studies, both the ligand (HL) and complexes have demonstrated significant potency. This promising result indicated their potential as therapeutic agents for treating pathogen-induced deformities.

Synthesis, structural elucidation, Hirshfeld surface analysis and cytotoxicity studies of homometallic dinuclear Cu(II), Ni(II) and Zn(II) Schiff base complexes derived from m-phenylenediamine

A polydentate Schiff base ligand, L was synthesized via condensation reaction between o-vanillin (OVan) and trimethyl-m-phenylenediamine [(Me)MPD]. Its Cu(II), Ni(II), and Zn(II) dinuclear complexes were prepared through complexation with corresponding acetate salts. The compounds were characterized via CHN elemental analyzer, molar conductivity, magnetic susceptibility, TGA, IR, 1H and 13C NMR. The crystal structure of the ligand, L and zinc(II) complex, Zn2L2 were elucidated by using single crystal x-ray diffraction. The crystal structure of Zn2L2 showed that the two Zn(II) metal atoms serve as bridges between the two units of the ligand through ONNO donor atoms leading to the formation of a centrosymmetric cyclic dinuclear complex. Based on the single x-ray crystallography, the zinc atoms exhibit a distorted tetrahedral geometry. Hirshfeld surface analysis was performed to determine the intermolecular interactions in the crystal structures. From this analysis, it revealed that H···H interaction for L (55%) and Zn2L2 (62.7%) was the dominant intermolecular interaction in the total area of Hirshfeld surface. The ν(CN) and ν(CO) peaks in IR spectra of the ligand L appeared at 1615 cm−1 and 1255 cm−1, respectively. The peaks shifted to lower and higher frequency by Δν of 4–12 cm−1 in the complexes. The new peaks assignable to ν(MN) and ν(MO) were observed at 514–562 cm−1 and 422–436 cm−1, respectively, indicating the coordination of the metal centers to the azomethine N and phenolic O. The Cu(II) and Ni(II) complexes are paramagnetic with μeff of 1.90 and 2.89 B.M., respectively. The thermal gravimetric analysis revealed the presence of three lattice water molecules in Cu(II) complex. The cytotoxicity studies of all compounds were carried out against colon cancer cell lines (HCT116). The parent ligand was found to be less cytotoxic than its metal complexes. Cu(II) showed the highest activity with IC50 of 0.73 ± 0.21 μM, better than the standard 5-FU.

New copper (II) complexes derived from azo pyridone dyes: Structure characterization, thermal properties, and molecular docking studies

Two azo dye ligands, bearing different substituents (chlorine atom or methoxy group) in the para‐position of the phenyl ring, were employed for the synthesis of two Cu(II) chelates. Full structural affirmation of complexes was assessed. X‐ray diffraction measurements revealed that the coordination geometry for Cu atoms in both complexes is square‐pyramidal with a ligand:metal ratio of 2:1 where dyes behave as monobasic bidentate ligands. Thermogravimetric analyses of the complexes and their starting dyes were performed to study their thermal stabilities and decomposition behavior confirming the thermal stability of both dyes and complexes. Antioxidative activity of the complexes has been assigned and compared with their parent ligands revealing that the presence of the electron–donor, methoxy group, in the phenyl ring, in both dye and complex, is responsible for the activity (IC50 values of 1.54 for the dye and 1.30 mM for the complex). It should be stated that the complexation of the methoxy‐substituted dye leads to enhanced antioxidative activity concurrent to a standard antioxidant molecule of ascorbic acid, making this molecule a promising antioxidant agent. Docking study with vascular endothelial growth factor receptor 2 and Aurora kinase A proteins indicate that complexes exhibit higher binding affinities to proteins than the starting ligand dyes. The most promising structure exhibiting the best docking potential toward both proteins is the complex‐bearing methoxy group. The presented results represent a promising start for further investigations of these compounds as potential therapeutic candidates for the treatment of various types of cancer.

Synthesis, characterisation, and solution behaviour of Ag(I) bis(phenanthroline-oxazine) complexes and the evaluation of their biological activity against the pathogenic yeast Candida albicans

Three Ag(I) bis(phenanthroline-oxazine) complexes with varying lipophilicity were synthesised and characterised. The solution stoichiometry of 1:2 Ag(I):ligand was determined for each complex by the continuous variation Job’s plot method using NMR spectroscopy. NMR studies were also carried out to investigate the fluxional behaviour of the Ag(I) complexes in solution. The biological activity of the silver(I) complexes and the corresponding ligands towards a clinical strain of Candida albicans MEN was studied using broth microdilution assays. Testing showed the choice of media and the duration of incubation were key determinants of the inhibitory behaviour towards Candida albicans, however, the difference between freshly prepared and pre-prepared solutions was insignificant in minimal media. The activity of the metal-free ligands correlated with the length of the alkyl chain. In minimal media, the methyl ester phenanthroline-oxazine ligand was effective only at 60 μM, limiting growth to 67% of the control, while a 60 μM dose of the propyl ester analogue limited fungal growth at < 20% of the control. MIC50 and MIC80 values for the propyl and hexyl ester analogues were calculated to be 45 and 59 µM (propyl), and 18 and 45 µM (hexyl). Moreover, in a study of activity as a function of time it was observed that the hexyl ester ligand maintained its activity for longer than the methyl and propyl analogues; after 48 h a 60 μM dose held fungal growth at 24% of that of the control. Complexation to Ag(I) was much more effective in enhancing biological activity of the ligands than was increasing the ester chain length. Significantly no difference in activity between the three silver(I) complexes was observed under the experimental conditions. All three complexes were substantially more active than their parent ligands against Candida albicans and AgClO4 and the three silver(I) bis(phen-oxazine) complexes have MIC80 values of < 15 μM. The ability of the silver(I) complexes to hold fungal growth at about 20% of the control even after 48 h incubation at low dosages (15 μM) showcases their superiority over the simple silver(I) perchlorate salt, which ceased to be effective at dosages below 60 μM at the extended time point.

Copper(II) Complexes Derived from Schiff Bases Containing 4-Methylbenzylamine as a Core Unit: Cytotoxicity, pBR322-DNA Studies, Biological Assays, and Quantum Chemical ParametersCopper(II) Complexes Derived from Schiff Bases Containing 4-Methylbenzylamine as a Core Unit: Cytotoxicity, pBR322-DNA Studies, Biological Assays, and Quantum Chemical Parameters.

Bivalent copper complexes, [Cu(SB1)2] 1 (SB1 = (2-(4-methylbenzylimino)methyl)-5-methylphenol, [Cu(SB2)2] 2 (SB2 = (2-(4-methylbenzylimino)methyl)-4-bromolphenol), and [Cu(SB3)2] 3 (SB3 = (2-(4-methylbenzylimino)methyl)-4,6-dibromophenol) were synthesized using the Schiff bases prepared from 4-methylbenzylamine (p-tolylmethanamine). These were characterized using a variety of spectro-analytical methods. For all copper complexes, a square planar geometry was determined through spectral analyses. Utilizing molecular orbital energies, the stability of the copper complexes was calculated from quantum chemical characteristics. The kinetic and thermal degradation parameters were calculated from the thermograms. Studies on DNA binding interactions, such as UV absorption and emission, have shown that the manner of DNA binding is intercalative, and the binding constant (Kb) order is 3 > 2 > 1. Under oxidative and photolytic techniques, the copper complexes outperform the parent Schiff bases in their ability to cleave double-stranded pBR322 DNA. When tested for cytotoxicity on the KB3 and MCF7 cell lines, complexes displayed greater activity than their parent ligands. Studies on the complexes' in-vitro antibacterial and antioxidant activity showed that they are significantly more powerful than the parent ligands.

Synthesis, structural characterization, and antimicrobial evaluation of new mononuclear mixed ligand complexes based on furfural-type imine ligand, and 2,2′-bipyridine

The present investigation goal was to investigate the chemistry of four new mononuclear mixed ligand Fe(III), Co(II), Cu(II), and Cd(II) complexes constructed from furfural-type imine ligand (L), and the co ligand 2,2′-bipyridine in addition to assessing their antimicrobial activity against some bacterial, and fungi strains. The structure of the complexes was interpreted by different spectroscopic techniques such as MS, IR, 1H NMR, UV–Vis, elemental analysis, TG-DTG, conductivity, and magnetic susceptibility measurements. The correlation of all results revealed that ligand (L) acts as a neutral ONNO tetradentate whereas the co ligand acts as a neutral NN bidentate. The coordination of the ligands with the metal ions in a molar ratio of 1:1:1 leads to formation of an octahedral geometry around the metal ions. The octahedral geometry has been validated and optimized by DFT analysis. Conductivity data showed the electrolytic nature of all complexes. The thermal stability of all complexes was deduced in addition to evaluating some thermodynamic, and kinetic parameters using Coats–Redfern method. Furthermore, all complexes in comparison to their parent ligands were tested for their biological potency against some pathogenic bacterial, and fungi strains using the paper disk diffusion method. [CdL(bpy)](NO3)2 complex revealed the highest antimicrobial activity.

Cure-PROs: Next-generation targeted protein degraders.

e15101 Background: Many proteins, including transcription factors and scaffolding proteins, are not amenable to targeting by traditional small molecule inhibitors due to the lack of a well-defined binding pocket or active site. Proteolysis-Targeting Chimeras (PROTACs) are a new class of hetero-bifunctional molecules that bind both a target protein and an E3 ubiquitin ligase, bringing the two into proximity for appending ubiquitin, and subsequently marking the target protein for proteasomal degradation. Currently, thirteen PROTACs are in clinical trials for oncology indications. However, the clinical utility of PROTACs is challenged by their large size and long development timelines. Also, resistance mutations in the E3 ligase or transporter overexpression inevitably evolve. Thus, a new platform for small-molecule degraders that enables ultra-rapid drug development timelines, efficient cellular uptake, and can be developed to overcome innate and acquired drug resistance is needed. Methods: Coferons, developed in our laboratory, are small molecules that self-assemble upon binding to a target, where they form reversible covalent dimers through bio-orthogonal linker chemistries. We have combined features of the Coferon platform and PROTACs to generate CURE-PROs (Combinatorial Ubiquitination REal-time PROteolysis), consisting of one target protein ligand and one E3 ligase ligand that form reversible heterodimers that lead to targeted protein degradation within cells. By modifying known ligands for BRD4, and the E3 ubiquitin ligases Cereblon, VHL, and MDM2, with linkers able to reversibly join the BRD4 to the ligase ligands, we synthesized libraries of CURE-PRO monomers that can be combined to create thousands of CURE-PRO dimer combinations. We explored whether this platform could yield meaningful BRD4 degradation in vitro and in vivo. Results: Rapid combinatorial cell-based screening identified several BRD4-E3 ligase CURE-PRO combinations that induced greater than 50% BRD4 degradation, with the most promising CURE-PRO pairs achieving more than 95% protein degradation. Consistent with a PROTAC mechanism-of-action, successful CURE-PRO combinations confirmed significant protein degradation which was inhibited by proteasome inhibitors or competition with parent ligands. Significant BRD4 degradation was also observed in mice bearing bilateral human xenograft tumors, confirming CURE-PRO proof-of-mechanism in vivo. Conclusions: The combinatorial nature of our platform has the potential to significantly reduce synthesis time and effort to identify the optimal linker length and E3 ligase for each target protein. The CURE-PRO platform consists of expanding libraries of monomers for both additional oncoprotein targets as well as E3 ligases, which can be redeployed to shorten lead development timelines.

Synthesis, Physicochemical, and Antimicrobial Activity of Copper and Zinc Complexes with N, O - Bidentate Schiff Base

This paper is intended to prepare new antimicrobial complexes with proven efficiency. The Schiff base, through the condensation process of salicylaldehyde and p-toludine, and its Cu and Zn complexes were successfully synthesized. The Schiff base and its complexes were characterized using molar conductivity, Ultraviolet-visible (UV-Vis), atomic absorption spectroscopy (AAS), and Fourier transform infrared (FTIR) techniques. Accordingly, these characterizations not only confirmed that the synthesized Schiff base acted as N,O bidentate ligand (through azomethine nitrogen and phenoxide oxygen) and chelated with Cu(II) and Zn(II) in the metal-to-ligand ratio of 1:2 but also revealed the characteristic electronic-transition of π→π*/n→π* of the ligand, and ligand-metal charge transfer and d-d of the metal complexes. Moreover, both Cu and Zn complexes recorded weak molar conductance of 54.12 and 51.41 S cm2 mol-1, respectively. Further, their antibacterial activities were evaluated by disc diffusion assay against Staphylococcus aureus (gram-positive), Escherichia coli (gram-negative), and Bacillus cereus (gram-negative) bacteria. For all microbial, the metal complexes recorded higher activities than the parent ligand; such increased activity of the complexes may be due to the chelation of the metal ion in the complexes, which enhances the lipophylic character favoring its permeation through the lipid layer of the cell membrane. Such metal complexes can therefore be explored in the future as an option for decreasing the pathogenic potential of infecting bacteria.

Synthesis, characterization and in vitro antibacterial activity of di- and tri n-butyltin(IV) complexes of 3-amino-4 -chloridobenzohydroxamic acid

New di-and tri- n-butyl tin(IV) hydroxamate complexes of composition [n-Bu2Sn(C6H3(3-NH2)(4-Cl)CONHO)2](I) and [n-Bu3Sn(C6H3(3-NH2)(4-Cl)CONHO)] (II) have been synthesized by the reactions of n-Bu2SnCl2 and n-Bu3SnCl with potassium 3-amino-4-chlorido benzohydroxamate(KHL) in predetermined metal:ligand 1:2 and 1:1 molar ratios respectively in MeOH+THF solvent medium and characterized by physiochemical, spectroscopic (IR,1 H and 13 C NMR) studies and mass spectrometry. The bidentate nature of hydroxamate ligand involving bonding through carbonyl and hydroxamic oxygen atoms (O,O coordination) has been inferred from IR spectra. The distorted octahedral and trigonal bipyramidal geometry around tin for (I) and (II) respectively have tentatively been proposed. The electrochemical behavior of complexes studied by cyclic voltammetric technique has shown two electron tin metal centered reductions. The in vitro antibacterial activity of (I) and (II) assayed against pathogenic gram -ve bacteria E.coli , P.aeruginosa; gram +ve bacteria S.aureus, B.cereus by MIC method has revealed these to be promising antibacterial agents relative to parent ligand.

Focusing on the 5F-MDMB-PICA, 4F-MDMB-BICA synthetic cannabinoids and their primary metabolites in analytical and pharmacological aspects

Nowadays, more and more new synthetic cannabinoids (SCs) appearing on the illicit market present challenges to analytical, forensic, and toxicology experts. For a better understanding of the physiological effect of SCs, the key issue is studying their metabolomic and psychoactive properties.In this study, our validated targeted reversed phase UHPLC-MS/MS method was used for determination of urinary concentration of 5F-MDMB-PICA, 4F-MDMB-BICA, and their primary metabolites. The liquid-liquid extraction procedure was applied for the enrichment of SCs. The pharmacological characterization of investigated SCs were studied by radioligand competition binding and ligand stimulated [35S]GTPγS binding assays.For 5F-MDMB-PICA and 4F-MDMB-BICA, the median urinary concentrations were 0.076 and 0.312 ng/mL. For primary metabolites, the concentration range was 0.029–881.02* ng/mL for 5F-MDMB-PICA-COOH, and 0.396–4579* ng/mL for 4F-MDMB-BICA-COOH. In the polydrug aspect, the 22 urine samples were verified to be abused with 6 illicit drugs. The affinity of the metabolites to CB1R significantly decreased compared to the parent ligands. In the GTPγS functional assay, both 5F-MDMB-PICA and 4F-MDMB-BICA were acting as full agonists, while the metabolites were found as weak inverse agonists. Additionally, the G-protein stimulatory effects of the full agonist 5F-MDMB-PICA and 4F-MDMB-BICA were reduced by metabolites. These results strongly indicate the dose-dependent CB1R-mediated weak inverse agonist effects of the two butanoic acid metabolites.The obtained high concentration of main urinary metabolites of 5F-MDMB-PICA and 4F-MDMB-BICA confirmed the relevance of their routine analysis in forensic and toxicological practices. Based on in vitro binding assays, the metabolites presumably might cause a lower psychoactive effect than parent compounds.

Synthesis, structural and spectroscopic properties of Co(II), Ni(II) and Cu(II) complexes with 2-((2-chlorobenzylidene)amino) acetohydrazide hydrate and their Antimicrobial and antioxidant activities

The current study was purposed to prepare Co(II), Ni(II) and Cu(II) complexes with the ligands derived from 2-chlorobenzaldehyde, glycine and hydrazine hydrate. The obtained compounds were characterized by different physicochemical studies such as elemental analysis, atomic absorption, molar ratio analysis, electronic absorption (UV-Vis spectroscopy), magnetic properties, FTIR spectroscopy, 1H�NMR, 13C-NMR, conductance measurements and XRD. Antimicrobial and antioxidant activities were also calculated. The antibacterial activity was evaluated by the diffusion method against two Gram-positive and two Gram-negative bacteria, while antifungal activity was assessed against two fungal strains by using the agar method. The ligand with Schiff base and hydrazide groups and its complexes showed better biological activity. The results showed that the most metal complexes have much higher antibacterial and antifungal activity compared to the parent ligand. The antioxidant activity of 3.7453 mg of the ligand exhibited excellent activity as the activity of 1 mg of ascorbic acid which is used as a standard antioxidant.

Preparation, Structures and Antimicrobial Activity of Ni(II) Complexes on the Base of Enrofloxacin with Dicumarol Derivative

Objective: To synthesize Ni(II) complexes on the base of enrofloxacin with dicumarol derivative and to investigate their antioxidant and antimicrobial potentials. Methods: Ni(II) complexes have been synthesized by classical thermal methods by mixing aqueous metal solutions with ethanol ligands and enrofloxacin in a 1:1 molar ratio. A biologically strong ligand was prepared by refluxing a dicoumarol derivative in aldehyde and ethanol. The structures of the ligands and their nickel complexes were investigated and confirmed by elemental analysis, FT-IR, 1H-NMR, 13C-NMR and mass spectroscopy. The thermal behavior of newly synthesized mixed-ligand Ni(II) complexes was studied by thermogravimetric analysis. Ferric-reducing antioxidant power (FRAP) (antioxidant activity) of all complexes were measured. All the compounds were screened for their antimicrobial activity against E. coli; P. aeruginosa; S. pyogenes; C. albicans and A. niger using Luria Broth dilution method for MIC values. Both the ligand and its complex were screened for antioxidant and antimicrobial activity in vitro. Findings: Antioxidant and antimicrobial activities of complexes were found to be better than the parent ligands used for complex formation. MIC values for complex C5 (-CH3 derivative) were found to be between 40-70 mg/mL and FRAP values was 82.44 mmol/100g, indicative of its ferric reducing antioxidant power. These result show that complex C5 (-CH3 derivative) was found more potential as antimicrobial and antioxidant agent. Novelty : The coordination of metal complex with enrofloxacin (antibiotic) draws a scheme for the synthesis of new drug as well as increasing the activity of enrofloxacin that is currently in use. Current work supports that the activity of antibiotics could be increased by coordination of metal ion complex. There could be a possibility that these complexes allow to reduce the dose of drug introduced into the body. Keywords: Dicumarol; Antimicrobial; Antioxidant; Thermal Analysis; TGA

Synthesis, characterization, single crystal structure, biological evaluation of ONO donor hydrazones and their diorganotin(IV) complexes

We have synthesized a series of four ligands (H2L1 - H2L4) and their sixteen diorganotin(IV) complexes R''2SnL, [R'' = Me, Et, Bu, Ph]. The ligands were derived by condensation of 2-hydroxy-3-methylbenzohydrazide with different salicylaldehyde derivatives. The synthesized compounds were well characterized by various spectroscopic and physicochemical techniques like FT-IR, (1H, 13C, 119Sn) NMR, UV-Vis, SEM-EDAX, TGA, XRD, HRMS, molar conductance measurements and elemental analysis. The spectroscopic data suggested the tridentate nature (ONO) of hydrazones forming a pentacoordinated environment around the tin metal. Further, the X-ray crystallographic study of compound [Me2SnL4] (17) confirmed the anticipated results of tridentate (ONO) nature of ligands forming distorted trigonal bipyramidal geometry with the tin metal atom. The synthesized compounds were assessed for their in vitro antioxidant activity and compound [Ph2SnL1] (8) exhibited the best activity with IC50 value of 2.92 µM. In vitro antimicrobial potential of the synthesized compounds was evaluated against different microbial strains viz. S. aureus, B. subtilis, p. aeruginosa, E. coli, C. albicans, A. niger. The antimicrobial data inferred that the complexes exhibited better efficacy than their parent ligands and compound [Et2SnL4] (16) exhibited the highest activity having same MIC value of 0.0053 µmol/mL against S. aureus and A. niger. Furthermore, in silico ADME study of the compounds was also carried out and observation revealed that the compounds can be used as an orally active drugs.

Copper (II) complexes with some antibiotics: synthesis, FT-IR study and in vitro antibacterial activity

Copper (II) complexes with commercial antibiotics, amoxicillin (AMX), azithromycin (AZT) and ciprofloxacin (CFL) were synthesized and isolated as solids. Structures of the isolated products were determined by FTIR spectroscopy. Antibacterial activities were determined on reference bacterial strains from the ATCC collection by diffusion technique. The results show that AMX and CFL coordinate Cu (II) ion as bidentate O-donor ligand. AZT coordinates metal center as bidentate NO-donor ligand. A difference in the morphology of antibiotic crystals and the synthesized complexes was found. Complex of Cu (AMX)2 show complete absence of antibacterial activity, while the other com-plexes show the same or even lower activity than the parent ligands.

Ability of Azathiacyclen Ligands To Stop Cu(Aβ)-Induced Production of Reactive Oxygen Species: [3N1S] Is the Right Donor Set.

Alzheimer's disease (AD) is an incurable neurodegenerative disease that leads to the progressive and irreversible loss of mental functions. The amyloid beta (Aβ) peptide involved in the disease is responsible for the production of damaging reactive oxygen species (ROS) when bound to Cu ions. A therapeutic approach that consists of removing Cu ions from Aβ to alter this deleterious interaction is currently being developed. In this context, we report the ability of five different 12-membered thiaazacyclen ligands to capture Cu from Aβ and to redox silence it. We propose that the presence of a sole sulfur atom in the ligand increases the rate of Cu capture and removal from Aβ, while the kinetic aspect of the chelation was an issue encountered with the 4N parent ligand. The best ligand for removing Cu from Aβ and inhibiting the associated ROS production is the 1-thia-4,7,10-triazacyclododecane [3N1S]. Indeed the replacement of more N by S atoms makes the corresponding Cu complexes easier to reduce and thus able to produce ROS on their own. In addition, the ligand with three sulfur atoms has a weaker affinity for CuII than Aβ, and is thus unable to remove Cu from CuAβ.

Novel Benzimidazole Derived Imine Ligand and Its Co(III) and Cu(II) Complexes as Anticancer Agents: Chemical Synthesis, DFT Studies, In Vitro and In Vivo Biological Investigations.

The emerging interest in the field of coordination chemistry and their biological applications has created a novel impact in the field of chemical biology. With this motivation, in this work we have synthesized a novel benzimidazole derived imine ligand, 2-((E)-((1H-benzo[d]-2-yl)methylimino)methyl)-4-fluorophenol (HBMF) and its Co(III) and Cu(II) complexes. The metal complexes (C1-C4) were synthesized in 2:1 (HBMF: metal ion) and 1:1:1 (HBMF: metal ion: 1,10-phen) ratios. Structural elucidations of all the synthesized compounds were performed using FT-IR, UV-Visible, NMR, Mass spectroscopy and elemental analysis techniques. A combination of first principles calculations and molecular dynamics simulations was applied to computationally investigate the structural, reactive, and spectroscopic properties of the newly synthesized HBMF ligand and its complexes with copper and cobalt metal ions. Quantum-mechanical calculations in this study were based on the density functional theory (DFT), while molecular dynamics (MD) simulations were based on the OPLS4 force field. The DFT calculations were used to obtain the reactive and spectroscopic properties of the ligand and its complexes, while molecular dynamics (MD) simulations were used to address the ligand's reactivity with water. Further, the in vitro anti-proliferative activity of the compounds was tested against the A549, Ehrlich-Lettre ascites carcinoma (EAC), SIHA and NIH3T3 cell lines. The biological results depicted that the compound C4, with molecular formula C27H23Cl2CoFN5O3 exhibited profound anti-proliferative activity against the EAC cell line with a significant IC50 value of 10 µm when compared to its parent ligand and other remaining metal complexes under study. Various assays of hematological parameters (alkaline phosphate, creatinine, urea, RBC and WBC) were performed, and significant results were obtained from the experiments. Furthermore, the effect of C4 on neovascularization was evaluated by stimulating the angiogenesis with rVEGF165, which was compared with non-tumor models. The EAC cells were cultured in vivo and administrated with 50 and 75 mg/kg of two doses and tumor parameters were evaluated.

Synthesis and Characterization of a Cannabinoid Type 2 Receptor Photoactivated Prodrug

AbstractG protein‐coupled receptor (GPCR) ligand prodrugs that can be released on demand with spatiotemporal control are powerful chemical tools that can assist in elucidating the consequences of GPCR activation or blockade at precise locations and times both in vitro and in vivo. Cannabinoid receptor prodrugs are of interest from both a drug delivery perspective and as tools to unravel the potential for differential signaling responses to be produced from cannabinoid receptor populations in distinct subcellular locations. Herein, the development and characterization of a cannabinoid type 2 receptor agonist prodrug is described, based on a 4‐diethylamino‐coumarylidenemalononitrilemethyl (DEACM‐MN) photo caging moiety linked via a carbonate to a chromenopyrazole cannabinoid ligand. This prodrug showed rapid photolysis with 450–455 nm light and good stability in biologically relevant buffer. The formation of various coumarin products alongside drug release was studied in different conditions. Radioligand binding assays were conducted with the prodrug, which revealed a significantly decreased human cannabinoid type 2 receptor binding affinity than the active chromenopyrazole parent ligand.

Synthesis, spectral, Hirshfeld surface analysis and biological evaluation of a Schiff base copper(II) complex: Towards a copper(II) based human anti-glioblastoma agent

Schiff base ligand 4-{(Z)-[(2-hydroxynaphthalen-1-yl)methylidene]amino}-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (HNMDP) was synthesized from 2-hydroxynaphthaldehyde and 4-aminoantipyrine. Since the ligand bears the suitable donor sites HCN (azomethine), hydroxyl and lactone carbonyl moieties it was reacted with Cu2+ to yield respective metal complex. The products were investigated by elemental analyses and IR spectroscopic techniques. Cu-NMDP crystallizes in the Ibam space group and forms a peculiar coordination polymer based on disordered acetate groups acting as bridging ligands producing distorted square planar geometry around copper. The molecular structure confirms the anticipated sites of coordination to be all involved in metal ion binding. The short interatomic interactions in the crystal structures were evaluated by mapping the Hirshfeld surface process using pseudo-mirrored 2D fingerprint plots. The major short interatomic interactions H···H, O···H and C···H cover the Hirshfeld surfaces. The interaction of the Schiff base ligand and its copper complex with human glioblastoma (malignant aggressive brain cancer) cells A172 and LN229 was studied. The copper complex on its own was found to be more active than its parent ligand. The Cu-NMDP IC50 values 5.698 µM after 72 h for A172 and 13.38 µM after 72 h for LN229 compared to HNMDP imply the copper based metallodrug to be a candidate for the chemotherapy of glioblastoma.