Synthesis,characterization, and biological activities of a Cu(II) complex with the non-steroidal antiinflammatory drug flufenamic acid

[Cu^II(L)₂.C₁₂H₁₀N₂] with flufenamic acid (HL=C₁₄H₁₀F₃NO₂) and phenanthroline (C₁₂H₁₀N₂O) was synthesized and characterized by C, H and N elemental analysis, single-crystal X-ray diffraction and, IR spectra. The urease inhibitory and antibacterial activities of the complex were tested. The complex showed strong inhibitory activity against jack bean urease with an IC₅₀ value of 0.265 μM. Four bacteria, Bacillus subtilis, Escherichia coli, Staphylococcus aureus, and proteusbacillus vulgaris, were used in the antibacterial test. The complex showed strong inhibitory activity against the species with IC₅₀ values of 2.016, 35.037, 10.680, and 3.820 μM. The interactions of the complex with human serum albumin (HSA) were studied through fluorescence spectroscopy. By analyzing the experimental data, we concluded that the fluorescence quenching mechanism of the complex with serum albumin was static quenching. The binding mode of the complex with DNA through UV spectroscopy was electrostatic binding or groove.     

Expression,Purification, and Comparative Inhibition of Helicobacter pylori Urease by Regio-Selectively Alkylated Benzimidazole 2-Thione Derivatives

The urease enzyme has been an important target for the discovery of effective pharmacological and agricultural products. Thirteen regio-selectively alkylated benzimidazole-2-thione derivatives have been designed to carry the essential features of urease inhibitors. The urease enzyme was isolated from Helicobacter pylori as a recombinant urease utilizing the His-tag method. The isolated enzyme was purified and characterized using chromatographic and FPLC techniques showing a maximal activity of 200 mg/mL. Additionally, the commercial Jack bean urease was purchased and included in this study for comparative and mechanistic investigations. The designed compounds were synthesized and screened for their inhibitory activity against the two ureases. Compound 2 inhibited H. pylori and Jack bean ureases with IC₅₀ values of 0.11; and 0.26 mM; respectively. While compound 5 showed IC₅₀ values of 0.01; and 0.29 mM; respectively. Compounds 2 and 5 were docked against Helicobacter pylori urease (PDB ID: 1E9Y; resolution: 3.00 Å) and exhibited correct binding modes with free energy (ΔG) values of −9.74 and −13.82 kcal mol⁻¹; respectively. Further; the in silico ADMET and toxicity properties of 2 and 5 indicated their general safeties and likeness to be used as drugs. Finally, the compounds’ safety was authenticated by an in vitro cytotoxicity assay against fibroblast cells.     

Preparation and structural characterization of oxovanadium(V) complexes with Schiff bases and their inhibition studies on Helicobacter pylori urease

A series of structurally similar dinuclear oxovanadium(V) complexes, [VO₂L]₂ (L?=?L¹?=?2-[(2-methylaminoethylimino)methyl]phenolate (1); L?=?L²?=?2-[(2-ethylaminoethylimino)methyl]phenolate (2); L?=?L³?=?2-[(2-isopropylaminoethylimino)methyl]phenolate (3)), has been synthesized and characterized by physico-chemical methods and single-crystal X-ray diffraction. The V in each complex is octahedral, with three donors of L and one oxo defining the equatorial plane, and with two oxos occupying the axial positions. The complexes were tested for their urease inhibitory activities. The inhibition rate (%) of 1, 2, and 3 at 100?µmol?L^?1 on urease are 67?±?1, 53.5?±?0.9, and 44?±?1. The relationship between structures of the complexes and the urease inhibitory activities indicates that shorter terminal groups of the complexes have stronger activities against urease. Molecular docking study of the complexes with the Helicobacter pylori urease was performed.     

Chemical analysis of the semipurified extract of Paullinia cupana and evaluation of in vitro inhibitory effects against Helicobacter pylori

Abstract

Paullinia cupana Kunth, commonly known as guarana, is a native Brazilian plant species from the Amazon area that presents various biological effects, including antimicrobial action. The aim of this study was to chemically analyse the semipurified aqueous extract (AqF) of the plant and to evaluate the activity of crude (CE), ethyl-acetate (EAF), and AqF extracts against Helicobacter pylori. The chemical profile of AqF was determined based on solid analysis ¹³C-NMR, direct infusion mass spectrometry (ESI-MS), and MALDI-TOF. The ¹³C-NMR spectrum showed characteristics of flavan-3-ol and oligomeric proanthocyanidins. ESI-MS revealed the presence of procyanidin, caffeic acid and its derivatives. MALDI-TOF analysis detected procyanidins of up to 6 units and profisetinidins of up to 5 units. Whereas CE and EAF showed inhibitory activity against H. pylori, CE, EAF, and AqF presented not high inhibitory activity against urease. The results demonstrate the potential of P. cupana to control and prevent H. pylori infection.     

Synthesis and biological evaluation of Cu(II), Zn(II), and Ni(II) 3-(4-nitrophenyl)acrylic acid complexes with diamines as potential urease inhibitors

Five new Cu(II), Zn(II), and Ni(II) 3-(4-nitrophenyl)acrylic acid complexes were synthesized and evaluated for inhibitory activity on jack bean urease. All five complexes were structurally determined by single crystal X-ray analysis. Compared with the positive reference acetohydroxamic acid (IC₅₀?=?13.25?μM), Cu(II) complexes 3 and 4 showed the strongest inhibitory activity against jack bean urease (IC₅₀?=?1.23 and 1.17?μM). Ni(II) and Zn(II) complexes also exhibited inhibitory activities (IC₅₀?=?10.09–13.10?μM).     

Synthesis,structure, urease inhibitory,and cytotoxic activities of two complexes with protocatechuic acid derivative and phenanthroline

Two complexes, [Cu^II(L¹)(phen)₂](ClO₄) (1) and [Ni^II₂(L¹)₂(phen)₂(MeOH)₂](ClO₄)₂ (2), with HL¹, a ligand derived from protocatechuic acid (=2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid) and phen (=1,10-phenanthroline) were synthesized and characterized by C, H, and N elemental analysis, UV–vis, FT-IR, and single-crystal X-ray diffraction, which revealed that 1 is mononuclear and 2 is dinuclear. Both complexes crystallized in monoclinic space group C2/c. The urease inhibitory activity and in vitro cytotoxic activity of 1 and 2 were tested. The complexes showed strong inhibitory activity against jack bean urease and significantly suppressed the growth of A549, L929, and SW620 cell lines.     

Synthesis,crystal structures,and urease inhibition studies of two new Schiff-base copper complexes derived from n-butylamine

Two Schiff-base copper(II) complexes, bis(N-n-butyl-5-chlorosalicylaldiminato) copper(II) (1) and bis(N-n-butyl-4-methoxysalicylaldiminato) copper(II) (2), were synthesized and their solid-state structures were determined by X-ray crystallography. Complex 1 displays a distorted square-planar geometry, while 2 possesses square-planar geometry. Copper(II) complexes 1 and 2 showed strong inhibitory activity against jack bean urease (IC₅₀?=?2.7, 3.5?µmol?L^?1), compared with acetohydroxamic acid (IC₅₀?=?63.00?µmol?L^?1). A molecular modeling study was carried out via the DOCK program to gain understanding of the potent inhibitory activity of these copper species against jack bean urease.     

Synthesis,In Silico Studies,and Evaluation of Syn and Anti Isomers of N-Substituted Indole-3-carbaldehyde Oxime Derivatives as Urease Inhibitors against Helicobacter pylori

Gastrointestinal tract infection caused by Helicobacter pylori is a common virulent disease found worldwide, and the infection rate is much higher in developing countries than in developed ones. In the pathogenesis of H. pylori in the gastrointestinal tract, the secretion of the urease enzyme plays a major role. Therefore, inhibition of urease is a better approach against H. pylori infection. In the present study, a series of syn and anti isomers of N-substituted indole-3-carbaldehyde oxime derivatives was synthesized via Schiff base reaction of appropriate carbaldehyde derivatives with hydroxylamine hydrochloride. The in vitro urease inhibitory activities of those derivatives were evaluated against that of Macrotyloma uniflorum urease using the modified Berthelot reaction. Out of the tested compounds, compound 8 (IC₅₀ = 0.0516 ± 0.0035 mM) and compound 9 (IC₅₀ = 0.0345 ± 0.0008 mM) were identified as the derivatives with potent urease inhibitory activity with compared to thiourea (IC₅₀ = 0.2387 ± 0.0048 mM). Additionally, in silico studies for all oxime compounds were performed to investigate the binding interactions with the active site of the urease enzyme compared to thiourea. Furthermore, the drug-likeness of the synthesized oxime compounds was also predicted.     

Synthesis,structures, and urease inhibition of nickel(II), zinc(II), and cobalt(II) complexes with similar hydroxy-rich Schiff bases

Four new nickel(II), zinc(II), and cobalt(II) complexes, [Zn(L¹)₂]?·?H₂O (1), [Ni(L¹)₂]?·?H₂O (2), [Ni(L²)₂] (3), and [Co(L³)₂]?·?H₂O (4), derived from hydroxy-rich Schiff bases 2-{[1-(5-chloro-2-hydroxyphenyl)methylidene]amino}-2-methylpropane-1,3-diol (HL¹), 2-{[1-(2-hydroxy-3-methoxyphenyl)methylidene]amino}-2-ethylpropane-1,3-diol (HL²), and 2-{[1-(5-bromo-2-hydroxyphenyl)methylidene]amino}-2-methylpropane-1,3-diol (HL³) have been synthesized and characterized by elemental analyses, infrared spectroscopy, and single-crystal X-ray determination. Each metal in the complexes is six-coordinate in a distorted octahedral coordination. The Schiff bases coordinate to the metal atoms through the imino N, phenolate O, and one hydroxyl O. In the crystal structures of HL¹ and the complexes, molecules are linked through intermolecular O–H···O hydrogen bonds, forming 1-D chains. The urease inhibitory activities of the compounds were evaluated and molecular docking study of the compounds with the Helicobacter pylori urease was performed.     

Synthesis,structure, and urease inhibitory activities of Co(III), Mn(II) and Zn(II) complexes with hydrazone derived from protocatechuic acid

[Co^III(L₁)₂·H₂O]NO₃ (1), [Mn^II(L₁)₂·H₂O] (2), and [Zn^II(L₁)₂·H₂O] (3) with a hydrazone derived from protocatechuic acid (HL₁ = C₁₅H₁₃N₃O₃) were designed, synthesized, and characterized by C, H, N elemental analyses, single-crystal X-ray diffraction, and IR spectra, which revealed that the three complexes are similar structures. Docking study has been done. The urease inhibitory activities of the three complexes were tested. Complexes 1 and 3 showed strong inhibitory activity against jack bean urease with IC₅₀ values of 45.9 and 11.64 μM. Complex 2 had no obvious inhibitory activity to urease; the IC₅₀ was > 50 μM.     

Synthesis, structure, and activity evaluation of two silver(I) complexes as Helicobacter pylori urease inhibitors

Two silver(I) compounds, [Ag(R,R-hxn)](C₇H₄BrO₂) · 2H₂O (I) (Chxn = 1,2-diaminocyclohexane) and [Ag(C₅H₆N₂)₂]₂(C₈H₄O₄) · 10H₂O (II), were synthesized and complex I was structurally characterized by X-ray crystallography. Compound I contains a catena-(trans-1,2-diaminocyclohexane) silver polycation ([Ag(Chxn)]_∞) in a roughly linear fashion, while II possesses a linear-type silver monocation. Compounds I and II were evaluated for their inhibitory activities against Helicobacter pylori urease in vitro. Both were found to have strong inhibitory activities against H. pylori urease comparable to that of acetohydroxamic acid.     

Synthesis,structure and bioactivity of Ni2+ and Cu2+ acylhydrazone complexes

Two acylhydrazone complexes, bis{6‐methyl‐N′‐[1‐(pyrazin‐2‐yl‐κN¹)ethylidene]nicotinohydrazidato‐κ²N′,O}nickel(II), [Ni(C₁₃H₁₂N₅O)₂], (I), and di‐μ‐azido‐κ⁴N¹:N¹‐bis({6‐methyl‐N′‐[1‐(pyrazin‐2‐yl‐κN¹)ethylidene]nicotinohydrazidato‐κ²N′,O}nickel(II)), [Cu₂(C₁₃H₁₂N₅O)₂(N₃)₂], (II), derived from 6‐methyl‐N′‐[1‐(pyrazin‐2‐yl)ethylidene]nicotinohydrazide (HL) and azide salts, have been synthesized. HL acts as an N,N′,O‐tridentate ligand in both complexes. Complex (I) crystallizes in the orthorhombic space group Pbcn and has a mononuclear structure, the azide co‐ligand is not involved in crystallization and the Ni²⁺ centre lies in a distorted {N₄O₂} octahedral coordination environment. Complex (II) crystallizes in the triclinic space group P and is a centrosymmetric binuclear complex with a crystallographically independent Cu²⁺ centre coordinating to three donor atoms from the deprotonated L^? ligand and to two N atoms belonging to two bridging azide anions. The two‐ and one‐dimensional supramolecular structures are constructed by hydrogen‐bonding interactions in (I) and (II), respectively. The in vitro urease inhibitory evaluation revealed that complex (II) showed a better inhibitory activity, with the IC₅₀ value being 1.32±0.4 µM. Both complexes can effectively bind to bovine serum albumin (BSA) by 1:1 binding, which was assessed via tryptophan emission–quenching measurements. The bioactivities of the two complexes towards jack bean urease were also studied by molecular docking. The effects of the metal ions and the coordination environments in the two complexes on in vitro urease inhibitory activity are preliminarily discussed.     

Synthesis,characterization and antimicrobial activity of a Zn(II) complex with 1-(1H-benzoimidazol-2-yl)-ethanone thiosemicarbazone

A new Zn(II) complex with 1-(1H-benzoimidazol-2-yl)-ethanone thiosemicarbazone [Zn(NO₃)(H₂O)(C₁₀H₁₁N₅S)]NO₃ was prepared and characterized by elemental analyses, FT-IR, ¹H NMR spectroscopy, thermogravimetric analysis (TGA), X-ray diffraction (XRD), and single-crystal X-ray diffraction analysis. The coordination geometry of the pentacoordinated zinc is a distorted square pyramid. The antimicrobial activity of the complex was evaluated using a broth micro-dilution method against a panel of human pathogenic Gram positive, Gram negative bacteria and the yeast Candida albicans. The best inhibitory effect was observed against Enterobacter aerogenes (MIC = 0.031 mg mL^?1).     

Syntheses,urease inhibition activities,and fluorescent properties of transition metal complexes

Four transition metal complexes with Schiff base and 1,10-phenanthroline, [Cu(L)(phen)]₂·C₂H₅OH (1), [Zn(L)(phen)]₂·C₂H₅OH (2), [Ni(L)(phen)]₂·C₂H₅OH (3), and [Co(L)(phen)]₂·C₂H₅OH (4) (H₂L?=?1-((2-hydroxynaphthalen-1-yl)methylene)thiosemicarbazide; phen?=?1,10-phenanthroline) were synthesized and characterized by physico-chemical methods. The crystal structure of 1 was determined by X-ray single-crystal diffraction analysis. 1 crystallizes in the orthorhombic space group Pbca with a?=?15.008(9), b?=?16.100(10), c?=?37.54(2)?Å, V?=?9070(10)?ų, Z?=?8, GOOF?=?1.002, R ₁?=?0.0626, and wR ₂?=?0.0912. The fluorescence and urease inhibitory activities of the compounds were tested. The enzymatic activity study indicated that 3 possessed potent inhibition against jack bean urease, with IC₅₀?=?1.2?±?0.1?μM, and about 35 times more than 42.1?±?0.4 acetohydroxamic acid as positive reference. This suggests that inhibitory efficiency of these complexes can be strongly influenced by different transition metal ions.     

Synthesis,characterization, density functional theory calculations,and in vitro antibacterial activity of novel transition metal complexes containing an O3-tridentate amoxicillin-based Schiff base: A silver(II) complex as alternative against Pseudomonas aeruginosa resistant to amoxicillin

Transition metal complexes containing an amoxicillin-based Schiff base (H₂L, 3 ) obtained from the condensation of amoxicillin 1 with salicylaldehyde 2 were prepared. Spectroscopic and physicochemical techniques, namely, UV–visible, Fourier-transform infrared spectroscopy, ¹H NMR, electron paramagnetic resonance, transmission electron microscopy, mass spectrometry, magnetic susceptibility, molar conductance, density functional theory (DFT) calculations, together with elemental and thermal analyses were used to characterize the synthesized complexes. Based on these studies, the general formulae [ML(H₂O)₃], where M = Mn 4 , Ni 5 , Zn 6 , and [ML(H₂O)], where M = Cu 7 , Ag 8 , were proposed for the complexes. The amoxicillin-based Schiff base ligand behaved as a dianionic O₃-tridentate chelating agent. DFT studies and magnetic and spectral data revealed octahedral geometries for Mn, Ni, and Zn atoms and distorted tetrahedral geometries for Cu(II) and Ag(II) complexes. Synthesized compounds were tested for antibacterial activity by both agar disk diffusion method and the minimum inhibitory concentration. in vitro bacterial viability revealed that complex 5 had similar antibacterial activity as 1 against Staphylococcus aureus and Staphylococcus epidermidis, whereas Pseudomonas aeruginosa, resistant to amoxicillin, was sensitive to complex 8 . The antibacterial activity of complex 8 could be attributed to its greater catalytic activity as shown by DFT calculations. Toxicity bioassay of the tested compounds showed LC₅₀ values > 1000 ppm, indicating their nontoxicity against brine shrimp nauplii (Artemia salina).     

Bioactive Heteroleptic Bismuth(V) Complexes: Synthesis,Structural Analysis and Binding Pattern Validation

Heteroleptic triorganobismuth (V) complexes of general formula, R₃Bi(OOCR')₂ ( 1 – 7 ), where R = C₆H₅ ( 1 – 3 ), p‐CH₃C₆H₄ ( 4 – 7 ) and R' = 3,5‐Cl₂C₆H₃ ( 1 , 5 ); 3,4,5‐(OCH₃)₃C₆H₂ ( 2 , 6 ); 3‐CH₃C₆H₄ ( 3 , 7 ); 2‐OH‐3‐OCH₃C₆H₃ ( 4 ) have been synthesized and fully characterized by FT‐IR, ¹H &¹³C NMR spectroscopy, single crystal X‐ray crystallography and elemental analysis. The molecular geometry observed for the compounds is predominantly distorted trigonal bipyramidal, the fact which was subsequently authenticated through X‐ray analyses for ( 1 – 4 ). All the synthesized compounds have been bio‐assayed for antileishmanial (Leishmania tropica KWH23) and Jack beans urease inhibitory activity, and human Lymphocytes were used to measure the general toxicity. Of these, ( 4 ) proved to be highly effective against the target species (Leishmania tropica KWH23), while being non‐toxic towards the mammalian cells at levels below 0.74 μgmL^?1, making it highly promising drug candidate. The high activities for ( 2 , 4 , and 6 ) against Jack beans Urease as compared to the reference standard demonstrate their significance in searching of therapeutic agents in future programs. The significant binding score of ( 2 & 4 ) against H. pylori in molecular docking studies further revealed their importance in future drug discovery processes.     

Synthesis,crystal structure,and Helicobacter pylori urease inhibition of a dicyanoamide bridged Cu(I/II) complex

A dicyanoamide-bridged polymeric copper(I/II) complex, [Cu^II(sal)(bipy)Cu^I(dca)₂]_n, was prepared by reaction of 5-methylchlorosalicylaldehyde (Hsal), 2,2′-bipyridine (bipy), sodium dicyanoamide (Nadca), and copper perchlorate in methanol. The complex was characterized by elemental analyses, infrared and electronic spectroscopy, and single-crystal X-ray determination. Cu^II has a square pyramidal coordination, and Cu^I has triangular coordination. The complex showed high urease inhibitory activity with IC₅₀ value of 0.16 ± 0.23 μM.     

Syntheses,characterizations, crystal structures,and biological activities of two new mixed ligand Ni(II) and Cu(II) Schiff base complexes

Two mixed-ligand complexes, [Cu(L)(2imi)] (1) and [Ni(L)(2imi)]·MeOH (2) [L = 2-(((5-chloro-2-oxyphenyl)imino)methyl)phenolato) and 2imi = 2-methyl imidazole], have been prepared by the reaction of appropriate metal salts with H₂L and 2-methyl imidazole. Their structures were characterized by microanalysis, FT-IR, UV–vis, molar conductivity, and ¹H NMR for [Ni(L)(2imi)]·MeOH. The structures were determined using single crystal X-ray diffraction. Each four-coordinate metal center, Cu(II) in 1 and Ni(II) in 2, is surrounded by donors of Schiff base (L^2?) and N of 2-methyl imidazole in square planar geometries. α-Amylase activities of these compounds have also been investigated. The experimental data showed that α-amylase was inhibited by Ni(II) complex while the Cu(II) complex causes a 1.3-fold decrease in K_m value. Antimicrobial results show that these compounds, especially the Cu(II) complex, have potential for antibacterial activity against Gram negative and Gram positive bacteria and antifungal activity against Aspergillus fumigatus.     

Synthesis,characterization, antimicrobial,and nuclease activity studies of some metal Schiff-base complexes

A Schiff base (L) is prepared by condensation of cuminaldehyde and L-histidine, and characterized by elemental analysis, IR, UV-Vis, ¹H-NMR, ¹³C-NMR, and mass spectra. Co(II), Ni(II), Cu(II), and Zn(II) complexes of this Schiff-base ligand are synthesized and characterized by elemental analysis, molar conductance, mass, IR, electronic spectra, magnetic moment, electron spin resonance (ESR), CV, TG/DTA, powder XRD, and SEM. The conductance data indicate that all the complexes are 1 : 1 electrolytes. IR data reveal that the Schiff base is a tridentate monobasic donor, coordinating through azomethine nitrogen, imidazole nitrogen, and carboxylato oxygen. The electronic spectral data and magnetic measurements suggest that Co(II) and Ni(II) complexes are tetrahedral, while Cu(II) complex has distorted square planar geometry. XRD and SEM show that Co(II), Cu(II), and Zn(II) complexes have crystalline nature, while the Ni(II) complex is amorphous and the particles are in nanocrystalline phase. The in vitro biological activities of the synthesized compounds were tested against the bacterial species, Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa, and Staphylococcus aureus; and fungal species, Aspergillus niger, Aspergillus flavus, and Candida albicans by the disc diffusion method. The biological study indicates that complexes exhibit more activity than the ligand. The nuclease activity of the ligand and its complexes are assayed on CT DNA using gel electrophoresis in the presence and the absence of H₂O₂. The Cu(II) complex shows increased nuclease activity in the presence of an oxidant when compared to the ligand, Co(II) and Ni(II) complexes.