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Water-soluble copper(II) complexes with 4,5-dichloro-isothiazole-3-carboxylic acid and heterocyclic N-donor ligands: Synthesis, crystal structures, cytotoxicity, and DNA binding study

Mixed-ligand copper(II) complexes based on 1,10-phenanthroline and related compounds are of interest to scientists due to their promising anticancer properties. In this study, four new water-soluble copper(II) complexes [Cu(dmbipy)L2], [Cu(phen)(H2O)L2], [Cu(dmphen)L2] and [Cu2(bipy)2L4], where HL ? 4,5-dichloro-isothiazole-3-carboxylic acid, bipy ? 2,2?-bipyridine, dmbipy ? 2,2?-bi-4-picoline, phen ? 1,10-phenanthroline, dmphen ? 4,7-dimethyl-1,10-phenanthroline are reported. All complexes have been characterized by elemental and powder X-ray diffraction analysis, EPR and IR-spectroscopy. Molecular structures of the reported complexes have been determined by single crystal X?ray diffraction. Copper(II) ion, HL and heterocyclic N-donor ligands have been found to form 1:2:1 complexes that possess square bipyramid or square pyramidal geometry. The UV?vis spectroscopy and mass spectrometry have been applied to show the behavior of the compounds in solution. All complexes have been screened in vitro for their cytotoxic activity against Hep-2 and MCF-7 cell lines. They exhibit significant dose-dependent cytotoxic effect and [Cu(dmphen)L2] is found to be the most cytotoxic (IC50 = 0.97 ¡À 0.03 muM when compared to IC50 = 9.2 ¡À 0.5 muM for control, cisplatin ? Hep-2 cell line). The investigation of DNA binding ability by UV?vis titration technique indicates that complexes obtained exhibit moderate binding affinity toward calf thymus DNA. Effect of [Cu(dmbipy)L2] and [Cu(dmphen)L2] on activity of drug-metabolizing enzymes cytochromes P450 has also been investigated. The addition of complexes to the hepatic microsomes of 3-MC or PB-treated rat, lead to a dose-dependent decrease of CYP’s activities. The data obtained indicate that [Cu(dmphen)L2] and [Cu(phen)(H2O)L2] can be potential anticancer agents.

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Reference£º
Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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Carbene complexes derived from lithiated heterocycles, mainly azoles, by transmetallation

Heterocyclic carbene complex formation can be achieved by lithiation of CH-acidic azoles, transmetallation involving a variety of transition metal complexes and, finally, protonation or alkylation. This article describes the synthetic methodology involved with a special emphasis on unexpected or (presently) unusual features of the reactions or products. The procedure can be extended to allow carbene complex formation by reaction at remote heteroatoms and also for diorgano(carbene) complex formation. Certain azolyls do not substitute but add to coordinated carbonyls and the resulting anionic Fischer-type carbene complexes can function as bidentate ligands. With gold(I) as central metal, many azolyls as well as carbene complexes participate in homoleptic rearrangement.

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Reference£º
Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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Recent advances in computing heteroatom-rich five- and six-membered ring systems

Recent developments in computer technology and the increasing efficiency and accuracy of current ab initio and density functional programs allow the investigation of increasingly complex systems. Molecules that could be treated only at the semiempirical level ten years ago can now be computed at the density functional or the MP2 level with basis sets of double-zeta quality. Very often, these calculations are accurate enough to explain experimental findings, and consequently many experimental studies are augmented by quantum chemical calculations. However, in many cases just a few kilocalories per mole may decide between different reaction mechanisms, different explanations of physical effects, or even a preferred tautomer or conformer. Since the inherent errors of MP2 and DFT calculations are still significantly larger than chemical accuracy, high-level calculations are mandatory for many problems. This holds particularly true for the investigation of reaction {A figure is presented}{A figure is presented} barriers involving bond-breaking processes. Although these problems have been recognized by many investigators, a substantial number of papers lack sufficient accuracy. This accuracy problem appears to be more severe for heteroatom-rich species than for other systems, in particular for systems with adjacent heteroatoms. However, DFT calculations were found to cope surprisingly well with the geometric parameters of most of these systems. As is common in heterocyclic chemistry, many studies concern tautomeric equilibria. While quantum chemical calculations are straightforward for the question of the most stable isomer, experiments are sometimes very demanding. Therefore, quantum chemistry can easily provide answers that may require substantial experimental effort. Comparatively few studies concern the investigation of entire reaction paths. This is much more demanding than computing a limited number of tautomers, of course, but usually provides a very detailed picture of the reaction mechanism. In certain cases, it was only possible to judge the nature of a chemical reaction on the basis of quantum chemical calculations. Most studies concerning pyrimidines originate from biochemical questions. Since these systems are dominated by hydrogen-bonding and/or dispersion contributions, methods beyond the Hartree-Fock level are mandatory. The success of quantum chemical studies in this field is impressive and many effects could be explained on the basis of these theoretical investigations.

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Reference£º
Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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Critical overview on the structure and metabolism of human aldehyde oxidase and its role in pharmacokinetics

Aldehyde oxidases are molybdenum and flavin dependent enzymes characterized by a very wide substrate specificity and performing diverse reactions that include oxidations (e.g., aldehydes and aza-heterocycles), hydrolysis of amide bonds, and reductions (e.g., nitro, S-oxides and N-oxides). Oxidation reactions and amide hydrolysis occur at the molybdenum site while the reductions are proposed to occur at the flavin site. AOX activity affects the metabolism of different drugs and xenobiotics, some of which designed to resist other liver metabolizing enzymes (e.g., cytochrome P450 monooxygenase isoenzymes), raising its importance in drug development. This work consists of a comprehensive overview on aldehyde oxidases, concerning the genetic evolution of AOX, its diversity among the human population, the crystal structures available, the known catalytic reactions and the consequences in pre-clinical pharmacokinetic and pharmacodynamic studies. Analysis of the different animal models generally used for pre-clinical trials and comparison between the human (hAOX1), mouse homologs as well as the related xanthine oxidase (XOR) are extensively considered. The data reviewed also include a systematic analysis of representative classes of molecules that are hAOX1 substrates as well as of typical and well characterized hAOX1 inhibitors. The considerations made on the basis of a structural and functional analysis are correlated with reported kinetic and metabolic data for typical classes of drugs, searching for potential structural determinants that may dictate substrate and/or inhibitor specificities.

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Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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Hetarylazo disperse dyes derived from substituted N,N-bis-beta-hydroxy- and N,N-bis-beta-acetoxy-ethylaniline

The heterocyclic amines 2-amino-6-methoxy- and 2-amino-6-nitro-benzothiazole, 3-amino-5-nitro[2,1]benzisothiazole and 2-amino-3,5-dinitro-thiophene were diazotised and coupled to substituted N,N-di-beta-hydroxyethylaniline and N,N-di-beta-acetoxyethylaniline to give dyes which coloured cellulose acetate in red to greenish-blue hues. The colour of the dyes is discussed with respect to the nature of the heterocyclic ring and to the substituents in the diazo and coupling component and compared to the corresponding dye using aniline as diazo component. Dyeing and fastness properties of the dyes are also reported.

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Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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Synthesis, characterization and antibacterial activity of 3-(2-(Heterocyclo-2-ylthio)-ethoxy)benzo[d]isothiazoles(1)

Seven novel 3-(2-(heterocyclo-2-ylthio)ethoxy)benzo[d]isothiazoles (3a?3g) have been synthesized and characterized by ESI-MS and 1H and 13C NMR spectra. The crystal structures of 3a and 3g have been determined. Compound 3a (C11H11N5O1S2) belongs to the monoclinic system and 3g (C12H11N3OS3) to the triclinic system. The title compounds show excellent in vitroantibacterial activities, with the minimum inhibitory concentrations varying from 4 to 32 ug/mL.

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Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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Pollutants released from the pulp paper industry: Aquatic toxicity and their health hazards

The pulp paper industries release wastewater containing very complex organic and inorganic pollutants. These pollutants are discharged mainly pulping and bleaching process during paper manufacturing. The main gaseous pollutants hydrogen sulfides, sodium sulfide, methyl mercaptan, sulfur, and chlorine dioxide is reported for chronic, respiratory disorder and irritation to skin, eyes and cardiac problem along with nausea and headache. The major inorganic pollutants include ferrous, copper, zinc, nickel, and magnesium, which is reported for neurotoxicity, toxic to juvenile channel catfish (Ictalurus punctatus) and Accumulation to gill > liver > ovary > muscle. The detected major organic and inorganic pollutants are hexadecanoic acids, octacosane, beta-sitosterol trimethylsilyl ether, 1-tetradecane, 2-methoxy phenol, trichlorocatechol, tetrachlorocatechol, chlorophenols, chloroguaiacols, chlorosyringols, chlorocatechols, terpenes, methanol, phenol, alkylated phenols, decalone, benzoic acid, abietic acid, and dehydroabietic acid. Several of these compounds are reported as endocrine-disrupting chemicals (EDCs). Therefore, direct toxicity of effluent to the reproductive system in aquatic flora and fauna are reported. Several reports have highlighted reduced gonad size, change in secondary sexual character, delayed maturity and suppression of sex hormone in fish rainbow trout (Oncorhynchus mykiss) and mosquitofish (Gambusia holbrooki) further the in-vitro studies of organic compounds on fish, Salmonella typhimurium, Vibrio fischeri, and Saccharomyces have shown inhibition in growth and luminescence properties. The presence of organic and inorganic pollutants in pulp paper industry wastewater causes phytotoxicity chromosomal aberration in Allium cepa. Thus the manuscript has concluded that detected pollutants produced foul odors and cause hermaphroditism in fish, hepatotoxicity and mutagenic effect. In addition, the growth of coliform bacteria in River and other aquatic resources has been reported due to contamination of PPI effluent. The studies also highlighted the presence of tannins, chlorophenols, dioxins, furans, biocide, fatty acids, and resin acids along with chlorolignine compounds as persistent organic pollutants (POP), which needs special attention for pollution prevention of rivers, lakes and other aquatic resources.

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Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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Synthesis and biological activity of novel comenic acid derivatives containing isoxazole and isothiazole moieties

Methyl 5-hydroxy-4-oxo-4H-pyran-2-carboxylate was synthesized by esterification of methanol with comenic acid under acidic catalysis. The obtained ester was alkylated with 3-(chloromethyl)-5-phenylisoxazole and 4,5-dichloro-3-(chloromethyl)isothiazole to afford corresponding conjugates containing isoxazole and isothiazole moieties which then were transformed into water-soluble Li-salts. During the bioassays of synthesized isoxazole and isothiazole derivatives of comenic acid in mixtures with first-line antitumor drug Temobel (Temozolomid) used in brain tumors chemotherapy, a synergetic effect was observed.

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Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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Thiazole and Isothiazole Ring?Containing Compounds in?Crop Protection

Organic compounds containing five-membered aromatic heterocyclic rings play an important role in life science. Among them thiazole and isothiazole heterocycles are present in many pharmaceutical drugs and crop protection compounds and have sparked over past years an enormous interest on these scaffolds. In agrochemicals these moieties are found in 11 commercial products as well as in two development compounds. A thiazole moiety is present in seven currently marketed agrochemicals, namely the insecticides thiamethoxam and clothianidin, the fungicides thiabendazole, thifluzamide, ethaboxam, and oxathiapiprolin, and the nematicide fluensulfone, as well as in the development compound dicloromezotiaz. One compound, the fungicide isotianil, contains an isothiazole ring and three compounds a benzothiazole ring, namely the fungicide benthiavalicarb and the herbicides methabenzthiazuron and mefenacet. A benzisothiazole ring is not yet present in any commercial product, however, is found in the former nematicide development compound benclothiaz. Interestingly thiazole and isothiazole heterocycles are much less frequently found in agrochemicals than pyridine and pyrazole despite their bioisosteric relationship, which may indicate that these heterocycles have still not been explored to their full scope in crop protection lead discovery and optimization. Detailed information on the discovery, synthesis, and the structure?activity relationships of thiazole- and isothiazole-containing agrochemicals is provided in this review.

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Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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Aldehyde oxidase and its role as a drug metabolizing enzyme

Aldehyde oxidase (AO) is a cytosolic enzyme that belongs to the family of structurally related molybdoflavoproteins like xanthine oxidase (XO). The enzyme is characterized by broad substrate specificity and marked species differences. It catalyzes the oxidation of aromatic and aliphatic aldehydes and various heteroaromatic rings as well as reduction of several functional groups. The references to AO and its role in metabolism date back to the 1950s, but the importance of this enzyme in the metabolism of drugs has emerged in the past fifteen years. Several reviews on the role of AO in drug metabolism have been published in the past decade indicative of the growing interest in the enzyme and its influence in drug metabolism. Here, we present a comprehensive monograph of AO as a drug metabolizing enzyme with emphasis on marketed drugs as well as other xenobiotics, as substrates and inhibitors. Although the number of drugs that are primarily metabolized by AO are few, the impact of AO on drug development has been extensive. We also discuss the effect of AO on the systemic exposure and clearance these clinical candidates. The review provides a comprehensive analysis of drug discovery compounds involving AO with the focus on developmental candidates that were reported in the past five years with regards to pharmacokinetics and toxicity. While there is only one known report of AO-mediated clinically relevant drug-drug interaction (DDI), a detailed description of inhibitors and inducers of AO known to date has been presented here and the potential risks associated with DDI. The increasing recognition of the importance of AO has led to significant progress in predicting the site of AO-mediated metabolism using computational methods. Additionally, marked species difference in expression of AO makes it is difficult to predict human clearance with high confidence. The progress made towards developing in vivo, in vitro and in silico approaches for predicting AO metabolism and estimating human clearance of compounds that are metabolized by AO have also been discussed.

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Reference£º
Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com