Parent Ligand Research Articles

Low-Temperature Metallomesogen Model Structures and Mixtures as Potential Materials for Application in Commercial Liquid Crystal Devices

The present work was the preliminary study of phase diagrams and miscibilities of low-temperature metallomesogen (MOM) model structures based on rod-like palladium (Pd) alkyl/alkoxy-azobenzene metal complexes and their mixtures with commercial liquid crystal materials for potential application. The initial results indicated the accessible temperature range and mesgenic miscibility between parent ligand, MOMs and commercial liquid crystal mixtures. The eutectic ligand/MOM composition with other MOMs and commercial nematic liquid crystal materials exhibited complete mesogenic miscibility and wide low-temperature mesogenic stability for eventual utilization in commercial liquid crystal devices.

Novel Co(II), Cu(II) and Zn(II) complexes derived from thiazole containing Schiff base ligands: Green synthesis, antimicrobial and anti-cancer studies

Six novel metal complexes of Co(II), Cu(II), and Zn(II) were synthesized using a microwave-assisted method. These complexes were derived from Schiff base ligands prepared through the condensation of 4-(p-fluorophenyl)-5-methyl-2-aminothiazole with 3-methoxysalicyldehyde (L1) and 2-hydroxynaphthaldehyde (L2). Characterization techniques, including UV–vis, IR, NMR, and HR-MS confirm the tridentate nature of Co(II), Zn(II), and bidentate nature of Cu(II) complexes. Elemental and thermogravimetric analysis showed 1:2 (M: L) stoichiometry in metal complexes. Meanwhile, magnetic susceptibility and powder X-ray diffraction express the geometry and crystal systems of complexes. The antimicrobial analysis of the synthesized compounds indicates Cu(II) complexes have greater potency against gram-positive bacterial and fungal strains while Zn(II) complexes show a greater zone of inhibition against gram-negative bacterial strains. Moreover, MIC values of the most potent complexes [Cu(L2)2] and [Zn(L2)2] range from 190-375 µg/mL. Furthermore, ligands and their complexes have been tested for anticancer potential against MDA-MB 231 and A549 cell lines by MTT assay. [Zn(L1)2] and [Zn(L2)2] complexes were found to have potent activity with IC50 values of 16.7 µM, 24.1 µM, and 8.7 µM, 13.4 µM respectively on MDA-MB-231 and A549 cell lines compared to other complexes and parent ligands. Molecular docking study performed using the PyRx 0.8 (with RF-Score V2 scoring function) program against EGFR (PDB: 5XGM) showed strong binding interactions which supports the experimental results.

New Organoruthenium(II) Complexes Containing Andrographolide‐Appended Hydrazide Derivatives: Synthesis, Spectral Characterization, Anticancer Evaluation

ABSTRACTA new set of andrographolide‐appended hydrazide derivatives (AFC, AGC, and ATC) were prepared from the reaction of andrographolide with furan‐2‐carboxylic acid hydrazide (AFC), pyridine‐3‐carboxylic acid hydrazide (AGC), and thiophene 2‐carboxylic acid hydrazide (ATC), and their corresponding ruthenium(II) complexes (Ru‐AFC, Ru‐AGC, and Ru‐ATC) were synthesized by the direct reaction of [RuCl2(η6‐p‐cymene)]2 with ligands in dichloromethane under stirring condition. The compounds were analyzed by elemental analysis, IR, UV‐Vis, 1H NMR, and ESI‐MS spectrometric techniques, and the obtained spectral data revealed that the ligands coordinated to Ru(II) ion through their enone oxygen and amine nitrogen. Antioxidant activities of the ligands and complexes were calculated against DPPH•, ABTS•+, O2−, and NO• free radicals and their results were compared with standard antioxidants. The cytotoxic activity of the synthesized ligands and complexes toward A549 and HeLa cell lines was evaluated using MTT method (MTT = 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide). Among the compounds, the complex Ru‐AGC showed better cytotoxic effect against A549 and HeLa cancer cells with IC50 values of 4.75 ± 0.17 and 6.32 ± 0.26 μM, respectively. Further, the nontoxic nature of the compounds was confirmed by using human umbilical vein endothelial (HUVEC) cells. The apoptosis was inspected with AO/EB and DAPI staining methods; further, the percentages of the apoptotic and necrotic cells were determined by flow cytometry. Overall, the biological activities of our ruthenium(II)‐arene complexes were found to be more potent than their parent ligands due to chelation, and among the complexes, Ru‐AGC showed better activity due to the presence of pyridine ring in the N‐terminal position of the ligand. The obtained results highlighted the strong possibility to develop highly active ruthenium complexes as anticancer agents.

Unveiling Anti-Malarial, Antimicrobial, Antioxidant Efficiency and Molecular Docking Study of Synthesized Transition Metal Complexes Derived From Heterocyclic Schiff Base Ligands.

Malaria, a persistent and ancient adversary, continues to impact vast regions worldwide, afflicting millions and severely affecting human health and well-being. Recently, despite significant progress in combating this parasitic disease, malaria remains a major global health concern, especially in areas with limited resources and vulnerable populations. Consequently, identifying and developing effective agents to combat malaria and its associated dysfunctions is essential therefore the two new Schiff base ligands incorporated Co(II), Ni(II), Cu(II) and Zn(II) ions were synthesized and thoroughly characterized. The synthesized compounds were assessed for in vitro anti-malarial and antimicrobial efficacy, compounds (9, 10) demonstrated highest potential with IC50=1.08±0.09 to 1.18±0.04 μM against P. falciparum and MIC=0.0058 μmol/mL against C. albicans and E. coli, respectively. The complexes (5, 6) were effectively reduce mitigate oxidative stress with lowest IC50 value of 2.69±0.12 to 2.87±0.09 μM. Moreover, the biological findings were reinforced by a molecular docking investigation involving the potential compounds (2, 7-10) against dihydroorotate dehydrogenase and sterol 14-alpha demethylase proteins which exposed complex's excellent biological response than their parent ligands. ADMET profiling was used to confirm the compounds' oral drug-like features. This research offers promising prospects for future multi-functional drug innovations targeting malaria, pathogenic infections, and oxidative stress.

Investigation of antileishmanial, antioxidant activities, CT-DNA interaction and DFT study of novel cobalt(II) complexes derived from mesogenic aromatic amino acids based Schiff base ligands.

In the present work, new Co(II) complexes were synthesized from mesogenic aromatic amino acids based Schiff base ligands, HL1 [Methyl 2-((2-hydroxy-4-(tetradecyloxy)benzylidene)amino)-3-phenylpropanoate] and HL2 [Methyl 2-((2-hydroxy-4-(tetradecyloxy)benzylidene)amino)-3-(1H-indol-2-yl)propanoate]. The compounds were thoroughly characterised using different elemental, thermogravimetric and spectroscopic studies. The in-vitro antileishmanial efficacy of the compounds against Leishmania donovani was evaluated by MTT assay and the antioxidant activity was performed by Mensor's method. The cell viability percentage and IC50 values for both the antileishmanial and antioxidant studies revealed that the cobalt(II) complexes are comparable to the standard, amphotericin B and ascorbic acid, respectively, signifying the potential applications of the biogenic compounds. The CT-DNA interaction experiments study using photophysical techniques indicated that the cobalt(II) complexes exhibited pronounced interactions as compared to the parent ligand. The parent ligands were found to possess mesogenicity as evidenced from the polarizing optical microscope (POM) and differential scanning calorimetry (DSC). The optical band gap of the compounds, as estimated from the Tauc plot of the UV-Vis spectra, lies within the domain of optoelectronic material properties, which was further supported through Density Functional Theory (DFT) study. Moreover, DFT methods have been used to explore the ground state geometry and DFT based reactivity descriptorsof the two synthesised ligands, HL1 and HL2 along with their corresponding Co(II) complexes, Co(L1)2 and Co(L2)2. Reactivity descriptors obtained from Conceptual Density Functional Theory (CDFT) analysis reveal that Co(L1)2 is the most stable and Co(L2)2 is the most electrophilic.

Folding a Molecular Strand into a Trefoil Knot of Single Handedness with Co(II)/Co(III) Chaperones.

We report the synthesis of a right-handed (Δ-stereochemistry of strand crossings) trefoil knot from a single molecular strand containing three pyrazine-2,5-dicarboxamide units adjacent to point-chiral centers and six pyridine moieties. The oligomeric ligand strand folds into an overhand (open-trefoil) knot through the assistance of coordinatively dynamic Co(II) "chaperones" that drive the formation of a three-metal-ion circular helicate. The entangled structure is kinetically locked by oxidation to Co(III) and covalently captured by ring-closing olefin metathesis to generate a trefoil knot of single topological handedness. The stereochemistry of the strand crossings in the metal-coordinated overhand knot is governed by the stereochemistry of the point-chiral carbon centers in the ligand strand. The overhand and trefoil knots were characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. Removal of the metal ions from the knot, followed by hydrogenation of the alkene, yielded the wholly organic trefoil knot. The metal-free knot and parent ligand were investigated by circular dichroism (CD) spectroscopy. The CD spectra indicate that the topological stereochemistry of the knot has a greater effect on the asymmetry of the chromophore environment than do the point-chiral centers of the strand.

Crystal structure, Hirshfeld surface analysis, molecular modeling, electrochemical properties, and potential medicinal activity of a novel binuclear Co(II) complex

A quinoxaline‐based ligand, 6,7‐dimethyl‐2,3‐di(2‐pyridyl)quinoxaline (Me2dpq), and its unique binuclear Co(II)‐Me2dpq complex were prepared and analyzed using single crystal X‐ray diffraction and several spectroscopy techniques. Hirshfeld surface analyses were also used to clarify the Me2dpq ligand and the Co(II)‐Me2dpq crystal packing. The Co(II)‐Me2dpq complex crystallized in triclinic P‐1 space group and exhibited a distorted trigonal bipyramidal geometry around the cobalt(II) ion. Each Co(II) ion coordinated to a Me2dpq ligand through two N donor centers from pyridyl and quinoxaline rings along with a terminal Cl and two bridged Cl atoms. The binding properties of the ligand and its complex with CT‐DNA were studied by several techniques, namely UV–Vis spectroscopy, fluorescence quenching, viscosity measurements, thermal denaturation, and gel electrophoresis. The CT‐DNA binding interaction tests demonstrated that both the Co(II)‐Me2dpq complex and its parent ligand bind to DNA in an intercalative way. The antioxidant studies of the novel Co(II)‐Me2dpq complex illustrated significant activity against DPPH• and radicals. The in vitro cytotoxic effect of Me2dpq ligand and its Co(II)‐complex on MCF‐7 and Hep‐G2 tumor cell lines was evaluated by using the MTT assay. The studies showed that the Co(II)‐Me2dpq complex had superior activity toward the tested cell lines. Molecular docking studies of synthesized compounds were employed to figure out the way they would associate with a biologically macromolecular target B‐DNA (PDB: 1BNA). Thus, this study is anticipated to provide novel opportunities for the successful utilization of the synthesized compounds in many medical domains.

Unique Use of Dibromo-L-Tyrosine Ligand in Building of Cu(II) Coordination Polymer-Experimental and Theoretical Investigations.

Although the crystals of coordination polymer {[CuCl(μ-O,O'-L-Br2Tyr)]}n (1) (L-Br2Tyr = 3,5-dibromo-L-tyrosine) were formed under basic conditions, crystallographic studies revealed that the OH group of the ligand remained protonated. Two adjacent [CuCl(L-Br2Tyr)] monomers, bridged by the carboxylate group of the ligand in the syn-anti bidentate bridging mode, are differently oriented to form a polymeric chain; this specific bridging was detected also by FT-IR and EPR spectroscopy. Each Cu(II) ion in polymeric compound 1 is coordinated in the xy plane by the amino nitrogen and carboxyl oxygen of the parent ligand and the oxygen of the carboxyl group from the symmetry related ligand of the adjacent [Cu(L-Br2Tyr)Cl] monomer, as well as an independent chlorine ion. In addition, the Cu(II) ion in the polymer chain participates in long-distance intermolecular contacts with the oxygen and bromine atoms of the ligands located in the adjacent chains; these intramolecular contacts were also supported by NCI and NBO quantum chemical calculations and Hirshfeld surface analysis. The resulting elongated octahedral geometry based on the [CuCl(L-Br2Tyr)] monomer has a lower than axial symmetry, which is also reflected in the symmetry of the calculated molecular EPR g tensor. Consequently, the components of the d-d band obtained by analysis of the NIR-VIS-UV spectrum were assigned to the corresponding electronic transitions.

Synthesis, crystal structure, and in vitro biological evaluation of bismuth (III) complexes incorporating pyrazinohydrazide‐derived Schiff bases

Two new Schiff‐base bismuth (III) complexes were prepared by an equivalent reaction between Schiff‐base ligand and Bi (NO3)3•5H2O with the assistance of Mannitol. The chemical structures of the two complexes were characterized by spectroscopic studies (FT‐IR, NMR, and MS), elemental analysis, and single‐crystal X‐ray diffraction. The ligand‐to‐metal ion ratio was found to be 1:1 in the complexes. During the formation of the complexes, Schiff bases changed from the amidic forms to the iminol forms, and the resulting tautomers could coordinate with bismuth (III) ions to produce dinuclear BiIII complexes(1a and 2a). Structural analyses showed that each Bi (III) ion held a distorted capped octahedron geometry with a seven‐coordinate mode in two complexes. Screening in vitro biological activities revealed that two bismuth (III) complexes exhibited much higher antimicrobial and cytotoxic activity than their parent ligands. The cytotoxic activity of the complex(1a) was close to that of the known anticancer drug (Doxorubicin) by evaluating against SGC7901 cells, with the IC50 value 0.59 μM. The complex(1a) could effectively induce SGC7901 cell apoptosis and its oral acute toxicity for LD50 value was found to be 576 mg kg−1. The content of bismuth (III) in mitochondria was higher than that in the nucleus.

Zinc(II) coordination compound with N′-(pyridin-2-ylmethylene)nicotinohydrazide: Synthesis, crystal structure, computational and cytotoxicity studies

In this work, we report on the synthesis of a novel zinc(II) coordination compound [ZnL2] (1), which was readily obtained from the reaction of Zn(OAc)·2H2O and N′-(pyridin-2-ylmethylene)nicotinohydrazide (HL) in methanol. Recrystallization of 1 from dimethylformamide under ambient conditions allowed to produce yellow block-like crystals of 1·H2O. Complex 1·H2O was characterized by FT-IR and 1H NMR spectroscopy, while its optical properties were studied by UV–vis and spectrofluorimetry in methanol. The crystal structure of the title complex was revealed by single crystal X-ray diffraction and further explored in detail by the Hirshfeld surface analysis. Theoretical investigations based on the DFT calculations have also been applied to show the electronic properties of complex 1. The antitumor activities of the parent ligand HL and complex 1 were studied using Dalton's lymphoma malignant cancer model. Both compounds were found to induce concentration-dependent cytotoxicity and apoptotic cell death, leading to a decrease in cell viability, body weight, and tumor volume in mice with the superior activity of complex 1 over HL. Mice treated with complex 1 demonstrated an increase in life span with a survival period of 23 days. Finally, using a molecular docking approach, we have probed complex 1 to inhibit the recombinant mouse tumor-necrosis factor alpha (mTNF).

Cytotoxic sigma-2 ligands trigger cancer cell death via cholesterol-induced-ER-stress

Sigma-2-ligands (S2L) are characterized by high binding affinities to their cognate sigma-2 receptor, overexpressed in rapidly proliferating tumor cells. As such, S2L were developed as imaging probes (ISO1) or as cancer therapeutics, alone (SV119 [C6], SW43 [C10]) and as delivery vehicles for cytotoxic drug cargoes (C6-Erastin, C10-SMAC). However, the exact mechanism of S2L-induced cytotoxicity remains to be fully elucidated. A series of high-affinity S2L were evaluated regarding their cytotoxicity profiles across cancer cell lines. While C6 and C10 displayed distinct cytotoxicities, C0 and ISO1 were essentially non-toxic. Confocal microscopy and lipidomics analysis in cellular and mouse models revealed that C10 induced increases in intralysosomal free cholesterol and in cholesterol esters, suggestive of unaltered intracellular cholesterol trafficking. Cytotoxicity was caused by cholesterol excess, a phenomenon that contrasts the effects of NPC1 inhibition. RNA-sequencing revealed gene clusters involved in cholesterol homeostasis and ER stress response exclusively by cytotoxic S2L. ER stress markers were confirmed by qPCR and their targeted modulation inhibited or enhanced cytotoxicity of C10 in a predicted manner. Moreover, C10 increased sterol regulatory element-binding protein 2 (SREBP2) and low-density lipoprotein receptor (LDLR), both found to be pro-survival factors activated by ER stress. Furthermore, inhibition of downstream processes of the adaptive response to S2L with simvastatin resulted in synergistic treatment outcomes in combination with C10. Of note, the S2L conjugates retained the ER stress response of the parental ligands, indicative of cholesterol homeostasis being involved in the overall cytotoxicity of the drug conjugates. Based on these findings, we conclude that S2L-mediated cell death is due to free cholesterol accumulation that leads to ER stress. Consequently, the cytotoxic profiles of S2L drug conjugates are proposed to be enhanced via concurrent ER stress inducers or simvastatin, strategies that could be instrumental on the path toward tumor eradication.

New nanometric metal complexes based on thiazole derivative as potential antitumor and antimicrobial agents: Full structural elucidation, docking simulation and biological activity studies

Novel Mn(II), Ni(II), Zr(IV) and Cd(II) nanosized complexes of thiazole Schiff base derivative (HL) were synthesized for further medicinal applications. The inspected complexes were fully characterized using elemental and thermal analyses in addition to infrared spectroscopy (IR) and nuclear magnetic resonance (1HNMR). Electronic absorption spectra, X-ray powder diffraction (XRD), transmittance electron microscopy (TEM), molar conductance and magnetic moment were also measured and explained. The brought about data revealed that the ligand–metal chelation happened through the N atom of N = N group, and the ortho-dehydrogenated phenolic O atom to form the chelates where the metal binds with one molecule of the parent ligand. All applied spectroscopic and analytical techniques confirmed tetrahedral geometry in Mn(II) and Ni(II) complexes and octahedral geometry for Cd(II) and Zr(IV) complexes. The ligand, Mn(II), Ni(II), and Zr(IV) chelates' XRD patterns indicated an amorphous character where the Cd(II) complex's nature is crystalline. Transmission electron microscopy (TEM) images of the prepared compounds showed that the surface morphology is uniform and homogeneous. Also, the metal ions distribute through the complexes' surface in a nanosized nature. The metal complexes have been simulated by docking in the co-crystal structures of the liver cancer and breast cancer proteins with PDB IDs, 2JW2 and 3S7S, successively. Antibacterial, antifungal and anticancer activities for the ligand that has been produced and its complexes were achieved. The most encouraging antitumor results were acquired by Ni(II) chelate which exhibited an IC50 of 23.52 µg/ml contra MCF-7 cells (human breast cancer) which is lower than the reference 5-Fluorouracil (5-FU, IC50 = 28.00 µg/ml).

Ligand-dictated planar versus bent nickel(II) chelates of the Schiff bases: Synthesis, crystal structures, optical properties, DFT and molecular docking studies

Two nickel(II) coordination compounds [Ni(LI)2] (1) and [Ni(LII)2] (2) (HLI = N-cyclohexyl-3-methoxysalicylideneimine, HLII = N-cyclohexyl-3-ethoxysalicylideneimine) were synthesized with the aim to reveal and compare the influence of the electronically and structurally similar methyl (Me) and ethyl (Et) funcionalities in a close proximity to the chelate backbone of the corresponding parent ligand. It was established that a minor difference in the structure of the parent ligand (Me in LI vs. Et in LII) leads to a crucial difference in the geometry of a complex molecule: a planar structure of 1 with two cycloalkane functionalities directed on the opposite sides of a molecule, and a bent structure of 2 with two cycloalkane functionalities directed on the convex side of a molecule. The coordination core of both complexes is a NiN2O2 planar square, formed due to two trans-coordinated ligands LI and LII, respectively. Solutions of the title compounds in CH2Cl2, MeOH and EtOH absorb up to about 475 nm due to intraligand transitions and LMCT. The DFT-based calculations were also applied to shed light on the structural and optical features of 1 and 2. In silico prediction using a molecular docking approach showed that both complexes can potentially inhibit a number of the SARS-CoV-2 proteins. The so-called ligand efficiency scores for complex Nsp14_N7-MTase–1 are within the recommended ranges for a drug, while the same scores for complexes Nsp14_N7-MTase–2, PLpro–1 and Mpro–1 fall in the ranges for a Hit.

Incorporation of Three Extracyclic Arginine Residues into a Melanocortin Macrocyclic Agonist (c[Pro-His-DPhe-Arg-Trp-Dap-Lys(Arg-Arg-Arg-Ac)-DPro]) Decreases Food Intake When Administered Intrathecally or Subcutaneously Compared to a Macrocyclic Ligand Lacking Extracyclic Arginine Residues (c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro)

Of the three Food and Drug Administration-approved melanocortin peptide drugs, two possess a cyclic scaffold, demonstrating that cyclized melanocortin peptides have therapeutic relevance. An extracyclic Arg residue, critical for pharmacological activity in the approved melanocortin cyclic drug setmelanotide, has also been demonstrated to increase the signal when fluorescently labeled cell-penetrating cyclic peptides are incubated with HeLa cells, with the maximal signal observed with three extracyclic Arg amino acids. Herein, a branching Lys residue was substituted into two macrocyclic melanocortin peptide agonists to incorporate 0-3 extracyclic Arg amino acids. Incorporation of the Arg residues resulted in equipotent or increased agonist potency at the mouse melanocortin receptors in vitro, suggesting that these substitutions were tolerated in the macrocyclic scaffolds. Further in vivo evaluation of one parent ligand (c[Pro-His-DPhe-Arg-Trp-Dap-Ala-Pro]) and the three Arg derivative (c[Pro-His-DPhe-Arg-Trp-Dap-Lys(Ac-Arg-Arg-Arg)-Pro)] demonstrated that the three Arg derivative further decreased food intake compared to the parent macrocycle when the compounds were administered either via intrathecal injection or subcutaneous dosing. This suggests that three extracyclic Arg amino acids may be beneficial in the design of cyclic melanocortin ligands and that in vitro pharmacological profiling may not predict the in vivo efficacy of melanocortin ligands.

Mixed ligand 4‑hydroxy acetanilide-febuxostat complexes of Co(II),- Ni(II), Cu(II) and Zr(IV): Synthesis, structural characterization, DFT calculations, antibacterial, antioxidant and molecular docking studies

The synthesized mixed ligand metal complexes were achieved by a combination of febuxostat (2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid) (FEB) and paracetamol (4‑hydroxy acetanilide) (Para) together with crucial biologically relevant elements. These elements, including Co(II), Cu(II), Zr(IV), and Ni(II) chlorides, play important roles in various biological systems and mechanisms, such as antioxidant, antimicrobial systems, and contribute to diverse functions and structures. To identify chemical formulae and structures of synthesized complexes, physical-analytical, spectroscopic (XRD, FT-IR, ESR, 13C NMR, 1H NMR, and UV-visible), mass spectrometry (MS), TG-DTG studies were used and supported by computational approaches. FT-IR and 1H NMR data revealed that FEB chelated through sulfur of thiazole ring as a mono-negative bidentate type and deprotonated oxygen of carboxylate group, according to lack of characteristic band at 1677 cm−1 and signal at δ = 13.37 ppm (-OHCOOH), whereas Para chelated through nitrogen and oxygen of amide group as a neutral bidentate ligand. Magnetic moment and electronic spectra data revealed that complexes have an octahedral structure. The optical band gap (Eg) for our compounds was calculated and according to Eg values, all complexes were semi-conductors and fell into the class of solar materials compared with FEB and Para. XRD pattern showed the monoclinic polycrystalline structure for all compounds except the Zr(IV) complex was amorphous. Kinetic parameters of the thermal decomposition stages were calculated. DFT was utilized to confirm bonding mode for FEB and Para with metal ions and according to calculations of energy band gap (ΔE) of complexes, Cu(II) complex with smaller ΔE is more reactive but, Zr(IV) complex with higher ΔE is less reactive than FEB and Para. The antibacterial activity of FEB, Para, and their complexes were tested against two G-ve and three G+ve bacteria. Co(II) complex displayed remarkable effectiveness and high significance against all strains of bacteria, compared with other compounds tested. All compounds demonstrated antioxidant effects, Cu(II) and Zr(IV) show greater antioxidants than parent ligands with IC50 values 0.040 and 0.057 mg/mL. The binding pattern and active site of all compounds were put through molecular docking studies and compared with empirical biological data.

Synthesis, characterization, thermal, anticancer studies, and density functional theory for potentially active pyrimidine‐based complexes

This work aimed to create and characterize some new bioactive chelates of bis azodye ligand, 5‐((2‐hydroxy‐4,6‐dioxo‐1,4,5,6‐tetrahydropyrimidin‐5‐yl)diazenyl)naphthalen‐1‐yl)diazenyl) pyrimidine 2,4,6 (1H,3H,5H)‐trione. Except for the Sm(III) chelate, which exhibited a (3M:1L) molar ratio, all chelates had a (2M:1L) stoichiometry. According to Fourier transform infrared spectroscopy (FT‐IR), azo groups were not included in chelating with all ions except Sm(III), where just one azo group was coordinated. With the Ni(II) and Zn(II) ions, the ligand behaved as OON‐tridentate moiety; with the Co(II) and Cu(II) ions, it behaved as ON‐bidentate moiety. Co(II) and Cu(II) chelates had square planar structure, and Ni(II) and Zn(II) chelates had square pyramidal geometry. The chelates had greater thermal stability than the uncoordinated ligand due to the chelate's structure. [Sm3(H4L)(OH)7(NO3)2.H2O].4.5EtOH exhibited the maximum thermal stability, which may be due to the large number of solvent molecules and the high number of chelate rings. With the exception of the Sm(III) chelate, all of the examined chelates were more cytotoxic against MCF‐7 and Hep‐G2 cells than their parent ligand. With the exception of the Zn(II) chelate, which demonstrated activity on Hep‐G2 rather than MCF‐7, the effects of each metal chelate on the two cells were nearly equivalent. All of the studied chelates, especially Zn(II) and Co(II), were potent as antioxidants more than the native ligand. To support experimental findings, density functional theory (DFT) studies were performed via the CAM‐B3LYP/LanL2DZ method, and the geometry of the ligand and its chelates had been validated.

Pivotal Role of Salicylates in Tuning the Formation and Reactivity of Mn(V)=O's

AbstractAn alternative and efficient route has been derived to generate the high valent [Mn(V)=O(m‐Cl‐salicylate)]+ intermediates with a series of non‐heme neutral ligand frameworks at 20 °C. The current method provides an advantage with feasibility in maintaining stoichiometric oxidant ratios along with the crucial variations of the salicylate moieties in tuning the reactivity of Mn(V)=O species. An in‐depth analysis of the Hammett studies revealed that the bound 5‐X‐salicylate (X=Cl, and NO2) drastically alters the corresponding Mn(V)=O's reactivity rates. In contrast, variations in the parent ligand frameworks resulted in consistent ρ values with increased lifetimes depicting the ligand's role in stabilization. Lastly, the complexes have been characterized to promote oxidative stress and prevent the proliferation of cancer cells effectively.

Semi-synthetic nanobody-ligand conjugates exhibit tunable signaling properties and enhanced transcriptional outputs at neurokinin receptor-1.

Antibodies have proven highly valuable for therapeutic development; however, they are typically poor candidates for applications that require activation of G protein-coupled receptors (GPCRs), the largest collection of targets for clinically approved drugs. Nanobodies (Nbs), the smallest antibody fragments retaining full antigen-binding capacity, have emerged as promising tools for pharmacologic applications, including GPCR modulation. Past work has shown that conjugation of Nbs with ligands can provide GPCR agonists that exhibit improved activity and selectivity compared to their parent ligands. The neurokinin-1 receptor (NK1R), a GPCR targeted for the treatment of pain, is activated by peptide agonists such as Substance P (SP) and neurokinin A (NKA), which induce signaling through multiple pathways (Gs , Gq and β-arrestin). In this study, we investigated whether conjugating NK1R ligands with Nbs that bind to a separate location on the receptor would provide chimeric compounds with distinctive signaling properties. We employed sortase A-mediated ligation to generate several conjugates consisting of Nbs linked to NK1R ligands. Many of these conjugates exhibited divergent and unexpected signaling properties and transcriptional outputs. For example, some Nb-NKA conjugates showed enhanced receptor binding capacity, high potency partial agonism, prolonged cAMP production, and an increase in transcriptional output associated with Gs signaling; whereas other conjugates were virtually inactive. Nanobody conjugation caused only minor alterations in ligand-induced upstream Gq signaling with unexpected enhancements in transcriptional (downstream) responses. Our findings underscore the potential of nanobody conjugation for providing compounds with advantageous properties such as biased agonism, prolonged duration of action, and enhanced transcriptional responses. These compounds hold promise not only for facilitating fundamental research on GPCR signal transduction mechanisms but also for the development of more potent and enduring therapeutics.

Synthesis, characterization, Hirshfeld surface analysis, antioxidant and selective β-glucuronidase inhibitory studies of transition metal complexes of hydrazide based Schiff base ligand

The synthesis of N′-[(4-hydroxy-3-methoxyphenyl)methylidene] 2-aminobenzohydrazide (H-AHMB) was performed by condensing O-vanillin with 2-aminobenzohydrazide and was characterized by FTIR, high resolution ESI(+) mass spectral analysis, 1H and 13C-NMR. The compound H-AHMB was crystallized in orthorhombic Pbca space group and studied for single crystal diffraction analysis. Hirshfeld surface analysis was also carried out for identifying short interatomic interactions. The major interactions H…H, O…H and C…H cover the Hirshfeld surface of H-AHMB. The metal complexes [M(AHMB)n] where M = Co(II), Ni(II), Cu(II) and Zn(II) were prepared from metal chlorides and H-AHMB ligand. The bonding was unambigously assigned using FTIR and UV/vis analysis. The synthesized ligand H-AHMB and its metal complexes were studied for β-glucuronidase enzyme inhibition. Surprisingly the metal complexes were found more active than the parent ligand and even the standard drug. Zn-AHMB shown IC50 = 17.3 ± 0.68 µM compared to IC50 = 45.75 ± 2.16 µM shown by d-saccharic acid-1,4-lactone used as standard. The better activity by Zn-AHMB implying zinc based metallodrug for the treatment of diseases associated with β-glucuronidase enzyme. The DPPH radical scavenging activities were also studied for all the synthesized compounds. The Co-AHMB complex with IC50 = 98.2 ± 1.78 µM was the only candidate to scavenge the DPPH free radicals.

Palladium(ii), platinum(ii), and silver(i) complexes with 3-acetylcoumarin benzoylhydrazone Schiff base: Synthesis, characterization, biomolecular interactions, cytotoxic activity, and computational studies.

New Pd(ii) (C1), Pt(ii) (C2), and Ag(i) (C3) complexes derived from 3-acetylcoumarin benzoylhydrazone (HL) Schiff base were synthesized and characterized by FTIR, 1H NMR, UV-visible spectroscopies along with elemental analysis (C, H, N), magnetic, molar conductivity measurements, and DFT calculations. The obtained results suggested that the ligand had different behaviors in the complexes: mono-negative tridentate (C1) and neutral tridentate (C2) as an ONO-donor and neutral bidentate (C3) as an ON-donor. Quantum chemistry calculations were performed to validate the stability of the suggested geometries and indicated that all the complexes possess tetra-coordinated metal ions. The binding affinity of all the compounds toward calf thymus (ctDNA), yeast (tRNA), and bovine serum albumin (BSA) was evaluated by absorption/emission spectral titration studies, which revealed the intercalative binding to ctDNA and tRNA and static binding upon complex formation with BSA. Molecular insights into the binding affinity of the characterized complexes were provided through conducting molecular docking analysis. Moreover, the cytotoxic activity (in vitro) of the compounds was screened against human cancerous cell lines and a non-cancerous lung fibroblast (WI38) one using cis-platin as a reference drug. The IC50 and selective index (SI) values indicated the higher cytotoxic activity of all the metal complexes compared to their parent ligand. Among all the compounds, the complex C2 showed the highest activity. These results confirmed the improvement of the anticancer activity of the ligand by incorporating the metal ions. In addition, flow cytometry results showed that complexes C1 and C2 induced cell cycle arrest at S and G1/S, respectively.