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Synthesis, characterization, DFT studies of piperazine derivatives and its Ni(II), Cu(II) complexes as antimicrobial agents and glutathione reductase inhibitors
Abstract
1,4-Piperazinediacetic acid and 1,4-diethyl ester (1) were prepared by treating 1,4-piperazine with ethylchloroacetate; and its structure was identified by single crystal X-ray diffraction analysis. Then, 1,4-piperazinediacetic acid, 1,4-dihydrazide (2) and its metal complexes (2-Ni(II) and 2-Cu(II)) were synthesized, respectively. Their structures were characterized by elemental analysis, ESI-MS, IR and NMR spectral data. The electrochemical behavior of compounds was investigated using cyclic voltammetry (CV). The density functional theory (DFT) was used for geometry optimization, HOMO and LUMO energies, HOMO–LUMO energy gap and dipole moment of the compounds. It has been observed that the calculated band gaps for complexes are much smaller than ligands. Furthermore,¹³C and¹H NMR analyses of (1) and (2) compounds were performed at B3LYP/6-311++G(d,p) level of theory and compared with the experimental findings. Observed ¹³C and¹H NMR chemical shifts were very good agreement with calculated chemical shifts. The antibacterial activities of synthesized compounds were studied against three Gram-positive and three Gram-negative bacteria by using the microdilution and disk diffusion methods. Baker's yeast glutathione reductase and human erythrocyte glutathione reductase were evaluated for all compounds. Copper (II) complex has the most inhibition activities against glutathione reductase enzyme in all compounds.
... [1,2]. Many biological molecules, such as antifungal, antitumor, antibacterial, antimalarial, antipsychotic, and antidepressant agents, as well as drugs for Parkinson's disease [3,4], contain piperazine derivatives as pharmacophores or components. PPZ can function as a flexible ligand [2] and can encapsulate cations [5,6], which facilitates the design and synthesis of various metal ion coordination compounds [7][8][9][10]. ...
... The chloride anion can exist either freely or as part of metal salts (MX n m-, where X = Cl). For instance, the compound (C 6 H 18 N 3 ) 4 CuCl 52 CuCl 43 .1.42H 2 O consists of two discrete CuCl 5 3anions and three CuCl 4 2anions in the crystal network. The piperazinium ring within this crystallization system carries an electric charge of + 2 [13]. ...
The ionic compound N-(2-hydroxyethyl)piperazinium chloride (HEPH)Cl, containing a piperazinium cation with a + 1 charge, was crystallized in the orthorhombic space group P212121. The unit cell parameters were determined to be a = 8.6083(3) Å, b = 8.8523(3) Å, and c = 10.7405(4) Å. The volume of the unit cell was found to be 818.46(5) ų, with a Z value of 4. Refinement yielded R[F² > 2σ(F²)] = 0.018, wR(F²) = 0.028, and a goodness-of-fit parameter of S = 1.77. The crystal structure reveals the presence of three hydrogen bonds: O1–H1o1···Cl1, N1–H1n1···N2, and N1–H2n1···Cl1, which contribute to the specific molecular arrangements within the crystal lattice.Electrochemical properties of (HEPH)Cl were examined by cyclic voltammetry (CV). Molecular docking experiments were conducted to assess the interactions of (HEPH)Cl with Mycobacterium tuberculosis DNA gyrase, coronavirus main protease, Plasmodium falciparum protein, and human serum albumin.
Graphical Abstract
N-(2-hydroxyethyl)piperazinium chloride cation uniquely adopts a chair conformation carrying a +1 charge, stabilized by crucial hydrogen bonding interactions that enhance molecular recognition and binding affinity observed in docking study.
The antibacterial activity of silver species is well-established; however, their mechanism of action has not been adequately explored. Furthermore, issues of low-molecular silver compounds with cytotoxicity, stability, and solubility hamper their progress to drug leads. We have investigated silver N-heterocyclic carbene (NHC) halido complexes [(NHC)AgX, X = Cl, Br, and I] as a promising new type of antibacterial silver organometallics. Spectroscopic studies and conductometry established a higher stability for the complexes with iodide ligands, and nephelometry indicated that the complexes could be administered in solutions with physiological chloride levels. The complexes showed a broad spectrum of strong activity against pathogenic Gram-negative bacteria. However, there was no significant activity against Gram-positive strains. Further studies clarified that tryptone and yeast extract, as components of the culture media, were responsible for this lack of activity. The reduction of biofilm formation and a strong inhibition of both glutathione and thioredoxin reductases with IC50 values in the nanomolar range were confirmed for selected compounds. In addition to their improved physicochemical properties, the compounds with iodide ligands did not display cytotoxic effects, unlike the other silver complexes. In summary, silver NHC complexes with iodide secondary ligands represent a useful scaffold for nontoxic silver organometallics with improved physicochemical properties and a distinct mechanism of action that is based on inhibition of thioredoxin and glutathione reductases.
Purpose:
The hydrazide backbone is a well-known structural core system found in a broad range of biologically activated compounds. Among which, the compounds with anticancer activity have been cited in a number of studies. With this object in mind, we focused on the in vitro and in vivo anticancer potential of two novel hydrazide derivatives bearing furan or thiophen substituents (compounds 1 and 2).
Methods:
The cytotoxic property was evaluated using MTT assay against MCF-7 human breast adenocarcinoma cell line, while the in vivo antitumor activity was investigated in BALB/c mice bearing 4T1 mammary carcinoma cells. Flow cytometry was used for cell cycle analysis, and detection of apoptosis was examined by Annexin-V-FLUOS/PI assay. Protein expression of Bax, Bcl-2 and procaspase-3 was estimated by Western blotting.
Results:
Compounds 1 and 2 were found to be cytotoxic towards breast cancer cells presenting IC50 values of 0.7 and 0.18 µM, respectively, and selectivity over normal fibroblast cells. Our findings further indicated that 2 × IC50 concentrations of both compounds induce early stage apoptosis and increase percentage of sub-G1 population in MCF-7 cells at 48 h. An elevation in Bax/Bcl-2 ratio and caspase-3 cleavage suggested that apoptosis induced by the two compounds is through a caspase- and mitochondrial-dependent pathway. In the in vivo study, compounds 1 and 2 at doses of 10 and 1 mg/Kg/day, respectively, significantly hindered the growth of tumor after 3 weeks of i.p. administration, when compared to vehicle-treated mice.
Conclusion:
Collectively, the great potential exhibited by compound 2 could make it a promising chemotherapeutic candidate for human cancers, especially for breast cancer.
Mitochondria imparts crucial role in the regulation of programmed cell death, reactive oxygen species (ROS) generation besides serving as a primary energy source. Mitochondria appeared as an important target for therapy of cancer due to its significant contribution in cell survival and death. Here, we report the design and synthesis of a novel series of triazole-piperazine hybrids as potent anticancer agents. MCS-5 emerged as an excellent anticancer agent which showed better anticancer activity than standard drug Doxorubicin in-vitro and in-vivo studies. MCS5 displayed an IC50 value of 1.92 μM and induced apoptosis in Cal72 (human osteosarcoma cell line) cells by targeting mitochondrial pathway. This compound arrested G2/M phase of cell cycle, induced ROS production and mitochondrial potential collapse in Cal72 cells. MCS-5 displayed excellent anticancer activity in Cal72 Xenograft nude mice model where, it significantly reduced tumor progression leading to enhanced life span in treated animals compared to control and Doxorubicin treated animals without exerting noticeable toxicity. In addition, 2DG optical probe guided study clearly evokes that MCS-5 remarkably reduced tumor metastasis in Cal72 Xenograft nude mice model. These results indicate that MCS-5 appeared as a novel chemical entity which is endowed with excellent in-vitro as well as in-vivo anticancer activity and may contribute significantly for the management of cancer in the future.
Hydrazide–hydrazone derivatives are present in many bioactive molecules and display a wide variety of biological activities, such as antibacterial, antitubercular, antifungal, anticancer, anti-inflammatory, anticonvulsant, antiviral, and antiprotozoal action. Therefore, many medicinal chemists synthesize various hydrazide–hydrazones and evaluate them for biological activities. Among biological properties of this class of compounds, antimicrobial activity is the most frequently encountered in scientific literature. This paper is focused on the overview of the literature findings of the last six years (2010–2016) covering the research on antimicrobial activity of hydrazide–hydrazone derivatives. This review may also serve as a useful guide for the development of new hydrazide–hydrazones as potential antimicrobial agents.
The methane sulfonic acide hydrazide (1) was used to obtain furan sulfonylhydrazones; 2-acetylfuranmethanesulfonylhydrazone (2), 2-furaldehydemethanesulfonylhydrazone (3), 5-nitro-2-furaldehydemethanesulfonylhydrazone (4). The structures of furan sulfonylhydrazones were determined by using elemental analysis, FT-IR, 1H NMR, 13C NMR and UV-vis methods. The structure of 5-nitro-2-furaldehydemethanesulfonylhydrazone (4) was also supported with X-ray difraction method and found that compound 4 was crystallized in triclinic, space group P1¯. In order to gain insight into the structure of the compounds, we performed computational studies by using 6-311G(d,p) basic set in which B3LYP correlation function was implemented. The geometry of the sulfonylhydrazones were optimized at DFT method with Gaussian 09 program package and the global reactivity descriptors were also calculated by this basic set. The enzyme inhibition activities of the sulfonylhydrazones were investigated on carbonic anhydrase I (hCA I) isoenzyme and their activity parameters (Km, IC50 and Ki) were calculated by spectrophotometric method. And also, their inhibitor effects were also investigated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) methods. Inhibition results show that compound 4 containing electron withdrawing group (NO2) has higher inhibition effect on hCA I isoenzyme than other's.
In this study, the diazotized p-nitroaniline and p-methylaniline were coupled with malononitrile. The ring closure reaction of the obtained products with hydrazine monohydrate yielded 4-(4-methylphenylazo)-1H-pyrazole-3,5-diamine (L1) and 4-(4-nitrophenylazo)-1H-pyrazole- 3,5-diamine (L2). The structure of the ligands has been elucidated by spectroscopic analyses. Then, novel Ni(II) and Cd(II) complexes of the ligands have been synthesized and the structures of these complexes determined by elemental analysis, spectrometric and TGA/DTA methods, molar conductance and magnetic susceptibility measurements. All the complexes were monomeric and diamagnetic. From the elemental analyses and mass spectra data, the complexes were proposed to the formulae [Ni2(L1)2(OH)2]·2Cl·8.5H2O, [Cd2(L1)2(OH)2]·2Cl·DMF·3H2O, [Ni(L2)2]·2Cl·2DMF·7H2O and [Cd2(L2)2(OH)2(H2O)4]·2Cl·1.5H2O. For the Cd(L2) complex octahedral geometry was proposed, but the Ni(L1), Ni(L2) and Cd(L1) complexes show four coordinated structure. The Ni(L1), Cd(L1) and Cd(L2) complexes were found to be dinuclear. On the other hand the Ni(L2) complex was found to be mononuclear. All the complexes were found to be (1:2) electrolytes.
Key Words: 4-(4-Nitrophenylazo)-1
H -pyrazole-3,5-diamine and Metal complexes, 4-(4-Methylphenylazo)-1
H -pyrazole-3,5-di-
amine and Metal complexes, Azodyes complexes.
A new N’-Acetyl propane sulfonic acid hydrazide, C3H7SO2NHNHCOCH3 (Apsh, an sulfon amide compound) has been synthesized for the first time. The structure of Apsh was investigated using elemental analysis, spectral (IR, 1H/13C NMR) measurements. In addition, molecular structure of the Apsh was determined by single crystal X-ray diffraction technique and found that the compound crystallizes in monoclinic, space group P 21/c. 1H and 13C shielding tensors for crystal structure were calculated with GIAO/DFT/B3LYP/6-311++G(d,p) methods in CDCl3. The structure of Apsh is optimized using Density Functional Theory (DFT) method. The vibrational band assignments were performed at B3LYP/6-311++G(d,p) theory level combined with scaled quantum mechanics force field (SQMFF) methodology. The theoretical IR frequencies are found to be in good agreement with the experimental IR frequencies. Nonlinear optical (NLO) behaviour of Apsh is also examined by the theoretically predicted values of dipole moment (μ), polarizability (α0) and first hyperpolarizability (βtot). The antibacterial activities of synthesized compound were studied against Gram positive bacteria: Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 23212, Staphylococcus epidermidis ATCC 34384, Gram negative bacteria: Eschericha coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Klebsiella pneumoniae ATCC 70063 by using microdilution method (as MICs) and disc diffusion method.
In this study, the diazotized o-nitroaniline was coupled with malononitrile. The ring closure reaction of the obtained product with hydrazine monohydrate yielded 4-(2-nitrophenylazo)-1H-pyrazole-3,5-diamine (L). The structure of L has been elucidated by spectroscopic analyses. Then, novel Mn(II), Co(II), Ni(II) and Cd(II) complexes of L have been synthesized, and the structures of these complexes determined by elemental analysis, spectrometric and TGA/DTA methods, molar conductance and magnetic susceptibility measurements. All complexes were monomeric. Except Mn(II) complex, other complexes were diamagnetic. From the elemental analyses and mass spectra data, the complexes were proposed to the formulas [MnL2(CH3O)H2O]center dot Cl center dot CH3OH, [CoL2(CH3O)(2)]center dot Cl center dot 2.5CH(3)OH, [NiL2(CH3OH)(2)]center dot 6.5CH(3)OH and [Cd2L2(Cl)(2)(CH3O)(2)]center dot CH3OH center dot 1.5H(2)O. For Mn(II) and Co(III) complexes octahedral and for the Ni(II) complex square planar geometry were proposed, but the Cd(II) complex includes five coordinated structure. The Mn(II), Co(II) and Ni(II) complexes were found to be mononuclear and electrolytes. On the other hand Cd(II) complex was found to be dinuclear and non-electrolyte.
Abuse of synthetic drugs is widespread among young people worldwide. In this context, piperazine derived drugs recently appeared in the recreational drug market. Clinical studies and case-reports describe sympathomimetic effects including hypertension, tachycardia, and increased heart rate. Our aim was to investigate the cytotoxicity of N-benzylpiperazine (BZP), 1-(3-trifluoromethylphenyl) piperazine (TFMPP), 1-(4-methoxyphenyl) piperazine (MeOPP), and 1-(3,4-methylenedioxybenzyl) piperazine (MDBP) in the H9c2 rat cardiac cell line. Complete cytotoxicity curves were obtained at a 0-20mM concentration range after 24h incubations with each drug. The EC50 values (μM) were 343.9, 59.6, 570.1, and 702.5 for BZP, TFMPP, MeOPP, and MDBP, respectively. There was no change in oxidative stress markers. However, a decrease in total GSH content was noted for MDBP, probably due to metabolic conjugation reactions. All drugs caused significant decreases in intracellular ATP, accompanied by increased intracellular calcium levels and a decrease in mitochondrial membrane potential that seems to involve the mitochondrial permeability transition pore. The cell death mode revealed early apoptotic cells and high number of cells undergoing secondary necrosis. Among the tested drugs, TFMPP seems to be the most potent cytotoxic compound. Overall, piperazine designer drugs are potentially cardiotoxic and support concerns on risks associated with the intake of these drugs.
The aromatic/heteroaromatic sulfonylhydrazone derivatives as indole-3-carboxaldehyde methanesulfonylhydrazone (1), indole-3-carboxaldehydeethanesulfonyl hydrazone (2), thiophene-2-carboxaldehydeethanesulfonylhydrazone (3), 2-hydroxybenzaldehydeethanesulfonyl hydrazone (4), 2-hydroxyacetophenoneethanesulfonylhydrazone (5) and 2-hydroxy-1-naphth aldehydeethane sulfonylhydrazone (6) were synthesized by the reaction of sulfonic acids with aromatic/heteroaromatic aldehydes and characterized by using elemental analysis, 1H–13C NMR, LC–MS and IR spectra. The electrochemical behavior of the sulfonylhydrazones in DMSO at glassy carbon electrode was investigated using cyclic voltammetry, controlled potential electrolysis and chronoamperometry techniques. The number of electrons transferred, diffusion coefficient and standard heterogeneous rate constants were determined using electrochemical methods. Antimicrobial activities of the compounds 1–6 were tested against some microorganisms. The biological activity screening showed that compound 6 exhibited better activity than the others. Structure–activity relationship analysis of the sulfonylhydrazone derivatives was performed to explain the trend of activity with molecular descriptors. The indicator descriptors for compound 6 having naphtyl ring are the most important descriptos that are sensitive both to the size and electrophility of the molecules.
In the title compound, C20H27N5O3, the central piperazine ring adopts a chair conformation, with the N-bound carboxylate and methylene substituents occupying bisectional and equatorial orientations, respectively. A twist is evident between the aromatic rings [dihedral angle = 25.61 (9)°] but an intramolecular O—H⋯N hydrogen bond persists between these. Supramolecular tapes along [1-10] are formed in the crystal packing through N(amino)—H⋯O(hydroxyl) and N(amino)—H⋯N(pyrimidinyl) hydrogen bonds, and these are linked into layers in the ab plane by π–π interactions [inter-centroid distance between pyrimidinyl rings = 3.5919 (9) Å].
In the title salt, C11H17N2O2S(+)·CF3COO(-), the cation is protonated at the secondary piperazine N atom. The dihedral angle between the benzene ring and the piperazine mean plane is 85.54 (10)°. In the crystal, cations and anions are connected by two types of strong N-H⋯O hydrogen bonds into chains extending along [101]. The chains are further assembled into (10-1) layers via stacking inter-actions between benzene rings of the cations [centroid-centroid distance = 3.7319 (13) Å] and a C-H⋯O inter-action involving a piperazine C-H group and a sulfonyl O atom. Another C-H⋯O inter-action between the piperazine ring and the sulfonyl group connects the ions into a three-dimensional network.
Abstract Carboxamide complexes having general formula
as [ML]Cl2�nH2O (where M = Cu(II), Zn(II); n = 0,
1/2) were synthesized using heterocyclic carboxamide
ligands: 1,4-bis[3-(2-thiophenecarboxamido)propyl]piperazine
(L1) and 1,4-bis[3-(2-furancarboxamido) propyl]
piperazine (L2). Their structures were characterized with
elemental analysis, molar conductivity, magnetic susceptibility,
and spectral methods (1H-NMR, 13C-NMR, FT-IR,
LC-MS). TGA and DTA curves were also performed. The
structure–activity relationship for the ligands was investigated
using PM3 semi-empirical method. The antibacterial
activities of the carboxamides and their complexes were
investigated against bacteria; Staphylococcus aureus ATCC
25923, Escherichia coli ATCC 11230, Bacillus magaterium
RSKK 5117, B. cereus RSKK 863, Salmonella enteritidis
ATCC 13076, B. subtilis RSKK 244 using microdilution
method.
Methanesulfonicacid hydrazide (a sulfonamide compound, msh: CH3SO2NHNH2)
14 derivatives: salicylaldehydemethanesulfonylhydrazone (salmsh), 2-
15 hydroxyacetophenonemethanesulfonyl hydrazone (afmsh), 2-hydroxy-3-
16 metoxybenzaldehydemethanesulfonylhydrazone (o-vanmsh) and their Ni(II), Pd(II) and Pt
17 (II) complexes have been synthesized. The structure of these compounds has been investigated
18 by using elemental analyses; FT-IR, 1H-NMR, LC-MS, UV-Visible spectrometric methods;
19 magnetic susceptibility; conductivity measurements; thermal studies. The antibacterial
20 activities of synthesized compounds have been determined in vitro against gram positive
21 bacteria; Staphylococcus aureus ATCC 25923, Bacillus cereus RSKK 709, and gram negative
22 bacteria; Pseudomonos aeruginosa ATCC 27853, Escherichia coli ATCC 35268 by paper
23 disc diffusion and microdilution broth methods. The biological activity screening showed that
24 metal complexes have more activity than their ligands against the tested bacteria.
New software,
OLEX2
, has been developed for the determination, visualization and analysis of molecular crystal structures. The software has a portable mouse-driven workflow-oriented and fully comprehensive graphical user interface for structure solution, refinement and report generation, as well as novel tools for structure analysis.
OLEX2
seamlessly links all aspects of the structure solution, refinement and publication process and presents them in a single workflow-driven package, with the ultimate goal of producing an application which will be useful to both chemists and crystallographers.
An account is given of the development of the SHELX system of computer programs from SHELX-76 to the present day. In addition to identifying useful innovations that have come into general use through their implementation in SHELX, a critical analysis is presented of the less-successful features, missed opportunities and desirable improvements for future releases of the software. An attempt is made to understand how a program originally designed for photographic intensity data, punched cards and computers over 10000 times slower than an average modern personal computer has managed to survive for so long. SHELXL is the most widely used program for small-molecule refinement and SHELXS and SHELXD are often employed for structure solution despite the availability of objectively superior programs. SHELXL also finds a niche for the refinement of macromolecules against high-resolution or twinned data; SHELXPRO acts as an interface for macromolecular applications. SHELXC, SHELXD and SHELXE are proving useful for the experimental phasing of macromolecules, especially because they are fast and robust and so are often employed in pipelines for high-throughput phasing. This paper could serve as a general literature citation when one or more of the open-source SHELX programs (and the Bruker AXS version SHELXTL) are employed in the course of a crystal-structure determination.
A convenient and facile synthesis of 4-(3-chlorophenyl)-1-(3-chloropropyl)piperazin-1-ium chloride is accomplished by stirring 1-(3-Chlorophenyl)piperazine hydrochloride with 3-chloropropanal by reductive amination in ethanol. The resulting compound was characterized using spectral data analysis augmented by X-ray. Single crystal analysis depicted that the synthesized compound crystallizes in monoclinic crystal system with P 21/c point group. The structural and electronic properties of the title compound have been calculated at DFT/B3LYP/6-311G (d,p) level of theory. Theoretically obtained parameters were well compared to the experimentally obtained results, showing excellent agreement. Molecular electrostatic potential surface, frontier orbital analysis and vibrational analysis were also carried out. HOMO-LUMO energy gap was calculated which allowed the calculation of relative properties like chemical hardness, chemical inertness, chemical potential, nucleophilicity and electrophilicity index of the synthesized products. Pass prediction was carried out which revealed that the target compound can be active against Prostate specific membrane protein, bearing Pa value of 0.411. Based on Pass, molecular docking studies of compound was carried out against Prostate specific membrane protein. The title compound depicted a binding free energy of −6.3 kcal/mol and is seen to be involved in key bonding interactions which include both alkyl and mixed pi-alkyl hydrophobic interactions: Alkyl hydrophobic interactions: (LEU 259; 4.64 Å, LEU 261; 3.79 Å), mixed Pi/alkyl hydrophobic interactions: (HIS 552; 4.96 Å, HIS 553; 4.64, 5.31 Å LEU; 3.45 Å) respectively with Prostate specific membrane protein. Target compound was screened for their cytotoxic potential with various cancer cell lines being most effective against prostate. In short, this study reveals the synthesis of a 4-(3-Chlorophenyl)-1-(3-chloropropyl)piperazin-1-ium chloride and exposes its structural, electronic and biological properties, paving way for further research in the field of drug development.
A series of arylalkanol and aralkyl piperazine derivatives have been synthesized and evaluated for 5-HT reuptake inhibitory abilities and binding affinities at the 5-HT1A/5-HT7 receptors. Antidepressant activities of the compounds in vivo were screened using the forced swimming test (FST). The results indicated that the compound 8j exhibited high affinities for the 5-HT1A/5-HT7 receptors (5-HT1A, ki = 0.84 nM; 5-HT7, ki = 12 nM) coupling with moderate 5-HT reuptake inhibitory activity (RUI, IC50 = 100 nM) and showed a marked antidepressant-like activity in the FST model.
Two azo group-containing Schiff base ligands, namely 4-(2,4-dichlorophenyl)diazenyl)-2-(3-hydroxypropylimino)methyl)phenol (L¹) and 2-((3-hydroxypropylimino)methyl)-4-(thiazol-2 yldiazenyl)phenol (L²) were prepared. The synthesis and characterization of Co(II), Ni(II), Cu(II), and Zn(II) complexes of the ligands (L¹) and (L²) have been described. Elemental analyses, magnetic moment, mass spectrometry, ¹H-NMR, ¹³C-NMR, electronic and infrared data suggest a mono-nuclear structure for all compounds. All these complexes have a general formula of type [M(L)2] (M= Co, Ni, Cu and Zn). The complexes are powders, insoluble in regular organic solvents but soluble in DMSO. Their probable structures have been estimated as per the basis of their spectroscopic data. The lagans show bidentate behavior in the complexes. The coordination occurs through azomethine nitrogen atom and an oxygen atom of the OH group. The infrared spectra of all complexes within the region of 540-500 cm⁻¹ and 470-420 cm⁻¹ can be assigned to M-O and M-N modes, respectively. The ligands (L¹ and L²) and the synthesized complexes were tested for their antimicrobial activity against clinical isolates of Escherichia coli (the Gram-negative bacteria), Staphylococcus aureus (the Gram-positive bacteria) and Candida albicans (the fungus) using Kirby–Bauer and Micro plate dilution methods.
The new Schiff base 1-[(2-{1-[(dicyclohexylamino)-methyl]-1H-indol-3-yl}-ethylimino)-methyl]naphthalen-2-ol (HL) was prepared from 1-{[2-(1H-Indol-3-yl)-ethylimino] methyl}-naphthalen-2-ol and dicyclohexyl amine. From this Schiff base, monomeric complexes [M (L)n (H2O)2 Cl2] with M = Cr, Fe, Mn, Cd, and Hg were synthesized and characterized based on elemental analysis (EA), FT-IR, mass(MS), UV-visible, thermal analysis, magnetic moment, and molar conductance. The results showed that the geometrical structural were octahedral geometries for the Cr(III) and Fe(III) complexes, square planer for Pd(II) complex, and tetrahedral for Mn(II), Cd(II), and Hg(II) complexes. Kinetic parameters such as ΔE*,ΔH*, ΔG*, and K of the thermal decomposition stages were calculated from the TGA curves using Coats-Redfern method. Additionally, density functional theory (DFT) was applied for calculations of both electronic structure and spectroscopic properties of synthesized Schiff base and its complexes. The analysis of electrostatic potential (EPS) maps correlates well with the computed energies providing on the dominant electrostatic nature of N-H---O interactions. The biological activities had been tested in vitro against Staphylococcus aureus, Pseudomonas aeruginosa, as well fungi like Penicillium expansum, Fusarium graminearum, Macrophomina phasealina, and Candida albicans bacteria in order to assess their antimicrobial potential.
A novel series of hybrid molecules (5a-5m) was designed, synthesized and evaluated as multifunctional cholinesterase (ChE) inhibitors against cognitive dysfunction. Heterocyclic moieties acridine and piperazine were conjugated with suitable linkers in a single scaffold and the structures of the target compounds were confirmed by IR, (1) H NMR, (13) C NMR and LC-MS analysis. The pharmacological activity of synthesized compounds was evaluated using behavioral models of amnesia viz. step down passive avoidance and elevated plus maze at a dose 0.5mg/kg as compared to standard rivastigmine. In vitro acetylcholinesterase (AChE) inhibition studies using brain homogenate of mice as the enzyme source revealed that most of the compounds exhibited a significant ability to inhibit the enzyme cholinesterase with compound 5c being the most potent (IC50 0.33 μM). Biochemical estimation of oxidative stress markers viz. plasma nitrite, thiobarbituric acid reactive substances, catalase, superoxide dismutase and glutathione has been carried out using the respective assays to see the effect of the synthesized compounds on the scopolamine induced oxidative damage. The molecular docking studies indicated the binding mode of the compounds to the catalytic site, peripheral site and mid-gorge of AChE simultaneously. The calculated ADME properties ensured the drug-likeness of the target compounds. The synthesized compounds were found to be potential cognitive enhancers, which were able to interfere with the scopolamine-induced oxidative stress also. This article is protected by copyright. All rights reserved.
Two new Schiff base ligands, H2L¹ and H2L², have been prepared from the condensation of 2-hydroxybenzaldehyde or 2-hydroxy-3-methoxybenzaldehyde with 2,2'-(piperazine-1,4-diylbis (methylene))dianiline (A¹), respectively. In the presence of appropriate metal ions and in methanolic/ethanolic solution four Cobalt (III) and Copper (II) macroacyclic Schiff-base complexes were prepared. All resultant products were characterized by elemental analysis, mass spectrometry and spectroscopic methods such as: FT-IR, ¹H and ¹³C NMR. In addition the crystal structures of [CoL¹](ClO4) and [CoL²](ClO4)(CH3CN) complexes have been revealed by single-crystal X-ray crystallography. The cytotoxic and antibacterial properties of some of complexes were studied. The geometries of the [CoL¹]⁺ and [CoL²]⁺ complexes have been optimized at the BP86/def2-SVP level of theory. Also the nature of the metal-ligand bond in the complexes is analyzed with NBO and EDA analysis. Results confirm that the nature of metal-ligand bond in the complexes is slightly more covalent with a contribution of about 53% in total interaction energies.
Asymmetric synthesis is one of the important topics in organic synthesis. Hydrazide compounds are valuable substrates in the fields of both chemical reactions and medicinal chemistry due to their chemical reactivity and biological activities, respectively. In this review, the role of hydrazides as substrates and/or chiral catalysts are investigated in the asymmetric organic reactions to gain chiral products.
A series of novel non-covalent piperidine-containing dipeptidyl derivatives were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome chymotrypsin-like inhibitory activities, and selected derivatives were evaluated for the anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and MM-1S. Among all of these compounds, eight exhibited significant proteasome inhibitory activities with IC50 less than 20 nM, and four are more potent than the positive control Carfilzomib. Compound 28 displayed the most potent proteasome inhibitory activity (IC50: 1.4±0.1 nM) and cytotoxicities with IC50 values at 13.9±1.8 nM and 9.5±0.5 nM against RPMI 8226 and MM-1S, respectively. Additionally, the ex vivo blood cell proteasome inhibitory activities of compounds 24 and 27-29 demonstrated that the enzymatic metabolism in the whole blood could be well tolerated. All these experiments confirmed that the piperidine-containing non-covalent proteasome inhibitors are potential leads for exploring new anti-cancer drugs.
Schiff bases; 1,8-bis(thiophene-2-carboxaldimine)-p-menthane (L1) and 1,8-bis(furan-2-carboxaldimine)-p-menthane (L2) have been synthesized and characterized by elemental analysis, 1H13C NMR, UV–Vis, FT-IR and LC-MS methods. 1H and 13C shielding tensors for L1 and L2 were calculated with GIAO/DFT/B3LYP/6-311++G(d,p) methods in CDCl3. The vibrational band assignments, nonlinear optical (NLO) activities, frontier molecular orbitals (FMOs) and absorption spectrum have been investigated by the same basis set. Schiff base-copper(II) complexes have been synthesized and structurally characterized with spectroscopic methods, magnetic and conductivity measurements. The spectroscopic data suggest that Schiff base ligands coordinate through azomethine-N and thiophene-S/furan-O donors (as SNNS and ONNO chelating systems) to give a tetragonal geometry around the copper(II) ions. Schiff bases and Cu(II) complexes have been screened for their biological activities on different species of pathogenic bacteria, those are, Gram positive bacteria: Bacillus subtitilus, Yersinia enterotica, Bacillus cereus, Listeria monocytogenes, Micrococcus luteus and Gram negative bacteria: Escherichia coli, Pseudomonas aeroginosa, Shigella dysenteriae, Salmonella typhi, Klebsiella pseudomonas by using microdilution technique (MIC values in mM). Biological activity results show that Cu(II) complexes have higher activities than parent ligands and metal chelation may affect significantly the antibacterial behavior of the organic ligands.
New antimony(III) complexes, [Sb(2-aminopyridine)2Cl3] (1a), [Sb(2-aminopyridine)2Br3] (1b), [Sb(5-methyl-2-aminopyridine)2Cl3] (2a), [Sb(5-methyl-2-aminopyridine)2Br3] (2b), [Sb(2-aminopyrimidine)2Cl3] (3a), [Sb(2-aminopyrimidine)2Br3] (3b), [Sb(4,6-dimethoxy-2-aminopyrimidine)2Cl3] (4a), [Sb(4,6-dimethoxy-2-aminopyrimidine)2Br3] (4b), [Sb(2-amino-1,3,5-triazine)2Cl3] (5a), [Sb(2-amino-1,3,5-triazine)2Br3] (5b), [Sb(2-guanidinobenzimidazole) Cl3] (6a), [Sb(2-guanidinobenzimidazole)Br3] (6b) [Sb(2- benzyl-2-thiopseudeourea)2Cl3] (7a) and [Sb(2- benzyl-2-thiopseudeourea)2Br3] (7b) were synthesized. Their structures were characterized by elemental analysis, molecular conductivity, FT-IR, (1)H NMR, LC-MS techniques. Glutathione reductase inhibitor activity, antimicrobial activity and DNA cleavage studies of the complexes were determined. The geometrical structures of the complexes were optimized by DFT/B3LYP method with LANL2DZ as basis set. Calculation results indicated that the equilibrium geometries of all complexes have square pyramidal shape. About 350 molecular descriptors (constitutional, topological, geometrical, electrostatic and quantum chemical parameters) of the complexes were calculated by DFT/B3LYP/LANL2DZ method with CODESSA software. Calculated molecular parameters were correlated to glutathione reductase inhibitory activity values (pIC50) of all complexes by Best Multi-Linear Regression (BMLR) method. Obtained two-parameter QSAR equation shows that increase in "maximum partial charge for a H atom" and decrease in HOMO-LUMO gap would be favorable for the glutathione reductase inhibitory activity.
Copyright © 2014 Elsevier B.V. All rights reserved.
The phthalazine carbohydrazide 2 was prepared and incorporated into the corresponding 1,2,4-triazole and carbamate derivatives. Phthalazine carboxylic acid hydrazide 2 was treated with isatine and cyclohexanone to give the corresponding hydrazone derivatives 16, 19 in good yields. Furthermore, α-amino acid derivative conjugated with 1-oxophthalazine moiety 35 was synthesized by the reaction of the corresponding aizde 28, via the azide-coupling method, with glycine methyl ester. The peptide ester 35 was converted into their corresponding amide 36 by treating with methanolic ammonia. Moreover, 35 was boiled with hydrazine hydrate to afford the corresponding hydrazide 37. Finally, the dipeptide 38 was prepared by coupling of 35 with l-alanine methyl ester. Some of these compounds were screened in vitro for their antimicrobial activity. The energy gap between the highest occupied molecular orbital and lowest unoccupied molecular orbital has been calculated using the theoretical computations to reflect the chemical reactivity and kinetic stability of compounds.
We report synthesis, anti-tuberculosis activity and 3D-QSAR study of forty nine hydrazide, semicarbazide and thiosemicarbazide derivatives of 4-(adamantan-1-yl)quinoline. The most potent compounds upon evaluation for anti-tuberculosis activity exhibited MIC99 of 3.125 μg/mL against M. tuberculosis H37Rv strain. We applied the in silico technique of 3D-QSAR to study structure activity relationship of the synthesized compounds. The developed CoMFA model exhibited excellent r2ncv of 0.971, and r2cv of 0.543. The predicted r2pred of 0.883 showed that the predicted values were in good agreement with the experimental values. Further, the contour map analysis, suggested that the sterically bulky and electronegative substitutions at the para position of the phenyl ring are favorable for anti-tuberculosis activity.
A simple level of ab initio molecular orbital theory with a split-valence shell basis with d-type polarization functions (6-31G*) is used to predict equilibrium geometries for the ground and some low-lying excited states of AHn molecules and cations where A is carbon, nitrogen, oxygen or fluorine. The results are shown to be close to the limit for single determinant wave functions in cases where corresponding computations with more extensive bases are available. Comparison with experimental results also shows good agreement although a systematic underestimation of bond lengths up to 3 per cent is evident. For systems where no experimental data are available, the results provide predictions of equilibrium geometry.
The asymmetric unit of the title compound, C8H14N2O4·2H2O, contains one water molecule and one half-molecule of piperazine-1,4-diacetic acid in salt form. Intramolecular N—H⋯O and O—H⋯O and intermolecular O—H⋯O hydrogen bonds are involved in the crystal packing. In the centrosymmetric title compound, the six-membered piperazine ring is in a standard chair form, and the two acetates are mutually trans. The 2,2′-(piperazine-1,4-diyl)diacetic acid and water molecules are connected through a complex pattern of hydrogen-bonding interactions, resulting in a three-dimensional network.
A multilayer model for the study of space distributed redox modified electrodes (redox polymer electrodes, or adsorption of an electroactive substance in several layers) is described and discussed in detail. It is shown in particular that it is equivalent to a system in which the electrons diffuse in the coating.
A tridentate ONN donor Schiff-base hydrazone ligand, H2L, was synthesized by the condensation of 2-amino-4-hydrazino-6-methyl pyrimidine with o-hydroxyacetophenone. The structure of the ligand was elucidated by IR and 1H NMR spectra which indicated the presence of three different coordinating groups, the oxygen atom of the phenolic OH group, the nitrogen atom of the azomethine, C=N, group and one of the nitrogen atoms of the heterocyclic ring. The ligand behaves either as a tridentate (N2O sites) neutral, mono- or di-basic ligand or as a bidentate (NO sites) monobasic ligand depending on the pH of the reaction medium and the metal ion. The mass spectrum of the ligand showed the presence of the molecular ion peak. Different types of metal complexes, mononuclear such as [(HL)M(OAc)]·xH2O (M = Cu or Zn), [(HL)M(OAc)H2O]·xH2O (M = Ni or UO2), [(HL)Co(OH2)Cl]·2H2O, [(H2L)FeCl3]·3½H2O, [(L)FeCl(H2O)2]· 2¼H2O, [(HL)LFeCl(H2O)]·H2O (L = 8-hydroxyquinoline, 8-HQ), [(HL)LFeCl]Cl·xH2O (L = 1,10-phenanthroline, phen, or 2,2-bipyridyl, bpy) and [(HL)LCu]·ClO4 (L = phen). Also, binuclear complexes with oxalic acid of the type [(HL)ClFe(ox)FeCl(HL)], [(HL)Cu(ox)Cu(HL)] were obtained. The IR spectra of the binuclear complexes indicated that the oxalate anion acts as a bridging tetradentate ligand. Elemental analyses, IR, electronic and ESR spectra as well as conductivity and magnetic susceptibility measurements were used to elucidate the structures of the newly prepared metal complexes. Square-planar geometry is suggested for the Cu(II) complex, octahedral geometry for the Fe(III), Ni(II) complexes, tetrahedral geometry for the Co(II) and Zn(II) complexes and pentagonal-bipyramidal geometry for the UO2(VI) complex.
The measurement of the heterogeneous rate constants for electron transfer from standard cyclic-voltammetric (CV) data is described. A variety of organometals are employed as the electroactive species in which the forward electron transfer is unidirectional, i.e., totally irreversible. The heterogeneous rate constants for the anodic process are quantitatively correlated with electron-transfer rate constants obtained in homogeneous solution with a variety of chemical oxidants. Since the CV method derives from a totally irreversible electrode process, a quantitative measure of electrochemical reversibility is developed. The reversibility factor fr is a continuous function of the electrode kinetics, varying smoothly from fr = 1 for Nernstian behavior to fr = 0 for total irreversibility. The theoretical and experimental limits of error encountered in the application of the CV method are quantitatively evaluated by the reversibility factor fr.
A method for determining the number of electrons involved in an electrode reaction on the basis of chronoamperometric measurements is described. The method involves comparing the parameters of current against time transients at a microelectrode and an electrode of more usual dimensions in the same solution under conditions that the current is limited by mass transfer and that nonlinear diffusion is predominant at the microelectrode whereas linear diffusion is predominant at the other electrode. The method is assessed by examining the reduction of several organic molecules and sulfur at carbon electrodes in dimethyl sulfoxide. In the case of the last reaction, it is confirmed that the number of electrons involved is two. It is stressed that the present technique is very useful in cases where catalytic or disproportionation reactions subsequent to electron transfer preclude the use of coulometry.
The reactivity of acetaldehyde and some aromatic aldehydes towards acid-catalysed oxygen-18 exchange reactions with H2O18 was studied using the density functional theory (DFT)-based reactivity descriptors local softness and local hardness. Local softness is used to predict the preferable reactive sites within a given molecule, whereas local hardness reproduces the experimental intermolecular reactivity trends. A new concept, intrinsic global hardness, obtained via filtering out the volume effect of the global softness, shows an excellent correlation with the degree of aromaticity of the compounds. Copyright © 1999 John Wiley & Sons, Ltd.
The concept of chemical hardness is reviewed from a personal point of view.
Two new Schiff bases of 1,3-diphenyl-1H-pyrazole-4-carboxaldehyde and 4-amino-5-mercapto-3-methyl/H-1,2,4-triazole [HL(1-2)] and their Cobalt, Nickel, Copper and Zinc complexes have been synthesized and characterized by elemental analyses, spectral (UV-vis, IR, (1)H NMR, Fluorescence) studies, thermal techniques and magnetic measurements. A square planar geometry for Cu(II) and octahedral geometry for Co(II), Ni(II) and Zn(II) complexes have been proposed. In order to evaluate the biological activity of Schiff bases and to assess the role of metal ion on biological activity, the pyrazole Schiff bases and their metal complexes have been studied in vitro antibacterial against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and antifungal against Aspergillus niger, and Aspergillus flavus. In most of the cases higher activity was exhibited upon coordination with metal ions.
For neutral and charged species, atomic and molecular, a property called absolute hardness η is defined. Let E(N) be a ground-state electronic energy as a function of the number of electrons N. As is well-known, the derivative of E(N) with respect to N, keeping nuclear charges Z fixed, is the chemical potential μ or the negative of the absolute electronegativity χ: μ = (∂E/∂N)Z = -χ. The corresponding second derivative is hardness: 2η = (∂μ/∂N)Z = -(∂χ/∂N)Z = (∂2E/∂N2)Z. Operational definitions of χ and η are provided by the finite difference formulas (the first due to Mulliken) χ = 1/2(I + A), η = 1/2(I - A), where I and A are the ionization potential and electron affinity of the species in question. Softness is the opposite of hardness: a low value of η means high softness. The principle of hard and soft acids and bases is derived theoretically by making use of the hypothesis that extra stability attends bonding of A to B when the ionization potentials of A and B in the molecule (after charge transfer) are the same. For bases B, hardness is identified as the hardness of the species B+. Tables of absolute hardness are given for a number of free atoms, Lewis acids, and Lewis bases, and the values are found to agree well with chemical facts.
Three azines, two of them doubly labeled with (15)N, have been studied by multinuclear magnetic resonance in solution and in the solid state. The spectral parameters obtained by iterative analyses have been compared with DFT/B3LYP calculated values (absolute shieldings and coupling constants). The agreement is generally good. Some anomalies have been discussed in relation to the structure of these compounds.
A Tetraaza Macrocylic Ligand (H2L) and its complexes, [Cd(H2L)(OH2)2](NO3)(2)·1/2OH2 (I), [Co(H2L)(OH2)](NO3)(2)·1/2OH2 (II), [Cu(H2L)(NO3)2]·3/2OH2 (III) and [Ni(H2L)(NO3)(OH2)]NO3·OH2 (IV), have been synthesized and characterized on the basis of elemental analysis, molar conductivity, 1H NMR, UV-vis, FT-IR and mass spectroscopy. All results confirm that the prepared compounds have 1:1 metal-to-ligand stoichiometry, octahedral configuration and the ligand behaves as a neutral tetradendate towards the metal ions. [CdL(OH2)2] (V), [CoL(OH2)2] (VI), [CuL(OH2)2] (VII) and [Ni(H2L)(NO3)2] (VIII) were synthesized pyrolytically in solid state from corresponding compounds (I-IV). Analytical results of complexes (V-VIII) show that the ligand behaves either as a neutral tetradendate or dianionic tetradentate ligand towards the metal ions. The binding of H2L and its copper complex (III) to DNA has been investigated by ultraviolet absorption spectroscopy. The experiments indicate that H2L and its copper complex (III) can bind to DNA through an intercalative mode. The H2L and its copper complex (III) exhibited anti-tumor activity against Ehrlich Acites Carcinoma (E.A.C) at the concentration of 100 μg/ml.
In this study new 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(p-substituted benzal)hydrazone V derivatives were synthesized as analgesic and anti-inflammatory agents. The structures of compounds were elucidated by spectral and elemental analysis. Compounds Va, Vb and Vc were exhibited more potent analgesic activity than ASA. Also these derivatives demonstrated anti-inflammatory activity as well as standard compound indomethacin. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with reference nonsteroidal anti-inflammatory drugs (NSAIDs). On the basis of available data, the structure-activity relationship of V derivatives was also discussed.
In an attempt to design novel 5-HT(1A) agonists/partial agonists, based on an arylpiperazine nucleus, a series of N-{4-[4-(aryl)piperazine-1-yl]-phenyl}-amine derivatives were synthesized and biologically tested. The anxiolytic effect of the compounds was investigated employing the Elevated plus Maze (EPM) task. On the basis of in vivo functional test, compound 1c (3mg/kg) and 4c (3mg/kg) induced significant increments in open arm entries and time on EPM as compared to Buspirone. The anxiolytic effects of compounds 1c and 4c were effectively antagonized by WAY-100635, a 5-HT(1A) receptor antagonist (0.5mg/kg). Furthermore, we have also evaluated the concentration of 5-HT in the brain tissue using HPLC with fluorescent detection. Our result showed that serotonin levels were significantly decreased by approximately 38% (p<0.001) and approximately 32% (p<0.001) after acute administration of compounds 1c and 4c, respectively. These findings suggest that the anxiolytic like activity of these new arylpiperazines is mediated via 5-HT(1A) receptors in the brain.
A group of original symmetrical and asymmetrical piperazine compounds containing ester function have been synthesized and pharmacologically characterized. All compounds are pharmacologically active. Some relationships between their chemical structure and biological activity are discussed. Analgesic and coronary dilatory and especially spasmolytic effects are marked for all asymmetrical esters. A number of the compounds are interesting for further investigations relative to their possible application in medical practice.
The (13)C and (15)N absolute shieldings of 28 compounds have been calculated at the GIAO/B3LYP/6-311 + + G** level to complete a collection of data already published. This has allowed us to devise new equations relating delta and sigma for these nuclei based on 461 points ((13)C) and 70(72) points ((15)N).
Synthesis and biological activity of pyrrole and pyrrolidine compounds from 4-chloro 2-hydroxybenzoic acid hydrazide
- S Mehta
S. Mehta, Synthesis and biological activity of pyrrole and pyrrolidine compounds from 4-chloro 2-hydroxybenzoic acid hydrazide, Int. J. Pharm. Res.
Bio-Sci. 2 (2013) 382e394. http://www.ijprbs.com/issuedocs/2013/2/IJPRBS
311.pdf.