Anti-inflammatory, Analgesic and Anti-ulcerogenic Activities of Novel bis-thiadiazoles, bis-thiazoles and bis-formazanes.

BACKGROUND: Indane-1,3-dione, thiazole, bis-thiazole and thiadiazoles rings are very interested moieties in anti-inflammatory and analgesic drugs. OBJECTIVE: The goal of this work is to synthesize new derivatives of bis-thiazoles and bis-1,3,4- thiadiazoles for the investigation of their anti-inflammatory, anti-ulcerogenic and analgesic activities. METHODS: 1,1'-(1,2-phenylene)bis(3-phenylthiourea) (1) reacts with a number of N-aryl arenecarbohydrazonoyl chlorides 2 to give a series of new bis-1,3,4-thiadiazoles 4. Also, reaction of bisthiosemicarbazone of 1,3-indanedione 6 with another type of hydrazonoyl halides namely, N-aryl-2- oxapropanehydrazonoyl chlorides 7 and ethyl-(N-arylhydrazono)chloroacetate 8 in dioxane under reflux in the presence of triethylamine give the respective bis-thiazole derivatives 9 and 10, respectively. The products 9 and 10 can exist in five and seven tautomeric forms for each one. Their actual tautomeric forms were deduced based on electronic absorption data (UV / Vis spectra). Moreover, a series of novel bis-formazans 12 and 13 have been synthesized by reaction of 1,3-dihydrazono-2,3- dihydro-1H-indene (11) with both hydrazonoyl chlorides 7 and 8. RESULTS: The structure of all the novel products was deduced by elemental analysis and spectral data. In addition, the biological activity of the newly synthesized compounds was evaluated and the results obtained indicate their potency as anti-inflammatory, anti-ulcerogenic and analgesic agents. CONCLUSION: In this context, we synthesize new derivatives of bis-thiazoles and bis-1,3,4-thiadiazoles as anti-inflammatory, anti-ulcerogenic and analgesic agents.

On the photocatalytic reduction of MTT tetrazolium salt on the surface of TiO2 nanoparticles: Formazan production kinetics and mechanism.

HYPOTHESIS: The MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide] cell cytotoxicity indicator is photocatalytically reduced on the surface of TiO2 nanoparticles in phosphate-buffered-saline (PBS) environment. We hypothesize that specific phosphate adsorption may be used to modulate the efficiency of the TiO2-MTT reaction through colloidal and semiconductor-liquid interface processes. EXPERIMENTS: The TiO2-MTT reaction kinetics was studied in PBS, with respect to photocatalyst and MTT concentrations and irradiation wavelength. The effects of PBS and electron scavengers (Fe(3+) ions) on reaction efficiency and the role of colloidal surface charge in the photocatalytic process were investigated. The structural and spectroscopic characteristics of relevant TiO2-formazan systems were studied by X-ray diffraction, transmission electron microscopy and IR-spectroscopy. FINDINGS: The reaction was pseudo-first order with respect to photocatalyst and showed a negative and fractional partial order with respect to MTT. Formazan production rates were directly proportional to radiation wavelength and TiO2 concentration and inversely proportional to the MTT initial concentration. The addition of Fe(3+) ions, as well as the absence of PBS, induced strong reaction inhibition. Reaction efficiency and catalyst Zeta potential were enhanced by Na2HPO4 (PBS component) and showed a maximum around the phosphate concentration 0.005 M. Structural/spectroscopic characterization confirmed the formation of amorphous MTT-formazan on the surface of TiO2 and the TiO2-phosphate binding.

Formazanate ligands as structurally versatile, redox-active analogues of ß-diketiminates in zinc chemistry.

A range of tetrahedral bis(formazanate)zinc complexes with different steric and electronic properties of the formazanate ligands were synthesized. The solid-state structures for several of these were determined by X-ray crystallography, which showed that complexes with symmetrical, unhindered ligands prefer coordination to the zinc center via the terminal N atoms of the NNCNN ligand backbone. Steric or electronic modifications can override this preference and give rise to solid-state structures in which the formazanate ligand forms a 5-membered chelate by binding to the metal center via an internal N atom. In solution, these compounds show dynamic equilibria that involve both 5- and 6-membered chelates. All compounds are intensely colored, and the effect of the ligand substitution pattern on the UV-vis absorption spectra was evaluated. In addition, their cyclic voltammetry is reported, which shows that all compounds may be electrochemically reduced to radical anionic (L2Zn(-)) and dianionic (L2Zn(2-)) forms. While unhindered NAr substituents lie in the plane of the ligand backbone (Ar = Ph), the introduction of sterically demanding substituents (Ar = Mes) favors a perpendicular orientation in which the NMes group is no longer in conjugation with the backbone, resulting in hypsochromic shifts in the absorption spectra. The redox potentials in the series of L2Zn compounds may be altered in a straightforward manner over a relatively wide range (∼700 mV) via the introduction of electron-donating or -withdrawing substituents on the formazanate framework.

Synthesis and ligand-based reduction chemistry of boron difluoride complexes with redox-active formazanate ligands.

Mono(formazanate) boron difluoride complexes (LBF2), which show remarkably facile and reversible ligand-based redox-chemistry, were synthesized by transmetallation of bis(formazanate) zinc complexes with boron trifluoride. The one-electron reduction product [LBF2](-)[Cp2Co](+) and a key intermediate for the transmetallation reaction, the six-coordinate zinc complex (L(BF3))2Zn were isolated and fully characterized.

The formazanate ligand as an electron reservoir: bis(formazanate) zinc complexes isolated in three redox states.

The synthesis of bis(formazanate) zinc complexes is described. These complexes have well-behaved redox-chemistry, with the ligands functioning as a reversible electron reservoir. This allows the synthesis of bis(formazanate) zinc compounds in three redox states in which the formazanate ligands are reduced to "metallaverdazyl" radicals. The stability of these ligand-based radicals is a result of the delocalization of the unpaired electron over four nitrogen atoms in the ligand backbone. The neutral, anionic, and dianionic compounds (L2 Zn(0/-1/-2)) were fully characterized by single-crystal X-ray crystallography, spectroscopic methods, and DFT calculations. In these complexes, the structural features of the formazanate ligands are very similar to well-known ß-diketiminates, but the nitrogen-rich (NNCNN) backbone of formazanates opens the door to redox-chemistry that is otherwise not easily accessible.

Synthesis and spectral properties of some bis-substituted formazans.

Novel, 1,4-bis-[3,3'-phenyl-5,5'-(o-carboxyphenyl)-formaz-1-yl]-benzene-o-sulphonic acid and its derivatives contained OH group at the o-, m-, p-positions of the 3-phenyl ring were synthesized. The structures of the formazans were confirmed by elemental analyses, GC-mass, IR, (1)H NMR, UV-vis spectra. Their absorption properties were investigated. It was seen that lambda(max) values shifted towards shorter wave lengths by 130nm in CSPF relative to 1,3,5-triphenylformazan (TPF) due to the fact that the structure of CSPF contained electron withdrawing COOH and SO(3)H groups (hypsochromic effect). With binding of OH group to 3-phenyl ring of CSPF, it was observed a small bathochromic effect in accordance to the electron donating effect of OH group.

Developing azo and formazan dyes based on environmental considerations: Salmonella mutagenicity.

In previous papers, the synthesis and chemical properties of iron-complexed azo and formazan dyes were reported. It was shown that in certain cases iron could be substituted for the traditionally used metals such as chromium and cobalt, without having an adverse effect on dye stability. While these results suggested that the iron analogs were potential replacements for the commercially used chromium and cobalt prototypes, characterization of potentially adverse environmental effects of the new dyes was deemed an essential step in their further development. The present paper provides results from using the Salmonella/mammalian microsome assay to determine the mutagenicity of some important commercial metal complexed dyes, their unmetallized forms, and the corresponding iron-complexed analogs. The study compared the mutagenic properties of six unmetallized azo dyes, six commercial cobalt- or chromium-complexed azo dyes, six iron-complexed azo dyes, six unmetallized formazan dyes, and six iron-complexed formazan dyes. The results of this study suggest that the mutagenicity of the unmetallized dye precursors plays a role in determining the mutagenicity of the iron-complexes. For the monoazo dye containing a nitro group, metal complex formation using iron or chromium decreased or removed mutagenicity in TA100; however, little reduction in mutagenicity was noted in TA98. For the formazan dye containing a nitro group, metal-complex formation using iron increased mutagenicity. Results varied for metal-complexes of azo and formazan dyes without nitro groups, but in general, the metal-complexed dyes based on mutagenic ligands were also mutagenic, while those dyes based on nonmutagenic ligands were nonmutagenic.

Design, synthesis and biological activity of novel non-peptidyl endothelin converting enzyme inhibitors, 1-phenyl-tetrazole-formazan analogues.

A novel non-peptidyl endothelin converting enzyme inhibitor was obtained through a pharmacophore analysis of known inhibitors and three-dimensional structure database search. Analogues of the new inhibitor were designed using the structure-activity relationship of known inhibitors and synthesized. In anesthetized rats, intraperitoneal administration of the analogues suppressed the pressor responses induced by big endothelin-1.

Tetrazolium salts and metal complexes of some formazans.

This paper presents the synthesis of some tetrazolium salts and metal complexes combinations, which are derived from aromatic and heterocyclic formazans. Elemental quantitative analyses and spectral data confirmed the structure of the new synthesized compounds. The new synthesized compounds were submitted to microbiological tests.

Hydrazones and formazans with possible biological activity.

This paper presents a synthesis about some hydrazones, formazans and copper's complexes combinations. The structure of the new compounds was confirmed by the results of the quantitative elementary and IR spectral analysis. The antimicrobial and antiinflammatory activities were investigated.

Anti-inflammatory activity of quinazolinoformazans.

Eight substituted quinazolonoformazans were synthesized and evaluated for anti-inflammatory activity. The degree of protection provided by seven of these compounds, at a dose of 100 mg/kg, po, against carrageenin-induced edema in rat paw ranged from 26 to 57%. The four active substituted quinazolonoformazans (1, 2, 6, 8), on further evaluation for antiwrithmogenic activity, provided 10-80% protection against the aconitine-induced writhing response in mice. The ulcerogenic liabilities of two of the most active compounds were also determined. The doses producing ulcers in 50% of the treated rats (UD50) were 155 and 260 mg/kg, ip, for 2 and 8, respectively. The low toxicities possessed by these substituted quinazolonoformazans were indicated by their LD50 values which ranged from 600 to 1300 mg/kg, ip, in mice.

Novel formazans as potent anti-inflammatory and analgesic agents.

Various new substituted formazans were synthesized and characterized by elemental analyses, IR and mass spectral data. The compounds were evaluated for their ability to protect against inflammation by carrageenin-induced paw edema in albino rats of either sex. The active derivatives of the present series were also tested for their analgesic activity against aconitine-induced writhing in albino mice and ulcerogenic activity in albino rats. The toxicity of the compounds was assessed by determination of their approximate LD50 on albino mice. An attempt has also been made to establish a structure-activity relationship.

Fluorescent redox dyes. 1. Production of fluorescent formazan by unstimulated and phorbol ester- or digitonin-stimulated Ehrlich ascites tumor cells.

The reduction of a new series of tetrazolium salts to red fluorescent formazans by Ehrlich ascites tumor cells is described. The qualitative effect on this reaction of two cell surface-active compounds and of six exogenous electron carriers was investigated by varying the incubation conditions. After incubation of Ehrlich ascites cells with the new colourless, water soluble 5-cyan-2.3-ditolyltetrazolium salts, bright red water-insoluble formazan crystals on the cell surface can be observed under fluorescence microscopy. The production of formazan is enhanced by 12-0-tetradecanoyl-phorbol-13-acetate (TPA) or digitonin (DIG), two potent stimulators of oxygen consumption or by the electron carriers phenazine methosulphate (PMS), 1-methoxy-phenazine methosulphate (MPMS), meldola blue (MB), methylene blue (MTB), and 2.6-dichlorindophenol (DCIP). These results provide further evidence for the existence of redox enzymes bound to the plasma membrane of intact ascites cells and for a free radical mechanism of tetrazolium salt reduction. The fluorescence property of the new redox dyes offers the advantage of high sensitivity. Moreover, their greater homogeneity relative to the commonly used di-tetrazolium salts lowers the chances of misinterpretations due to impurities. The possible application of these new mono-tetrazolium salts to cytochemical investigations of oxidative metabolic reactions is discussed.

Newer formazans and tetrazolium indoles as potential CNS-active agents.

Some new 2-aryl-5-(3'-indole)-3'-substituted phenyl tetrazolium bromide/iodide salts (IV) were synthesized by the oxidation of 1-aryl-3-(3'-indole)-5-substituted phenyl fromazans (III). These compounds III and IV were evaluated for their monoamine oxidase (MAO) inhibitory activity in vitro and various CNS activities in vivo. Several compounds exhibited promising CNS activities, III-b being the most active member of the present series showing marked antidepressant and MAO inhibitory activities and having low toxicity.

Synthesis of some newer formazans and tetrazolium salts and their effect on Ranikhet disease virus and the vaccinia virus.

Synthesis and biological evaluation of a series of formazans and their corresponding tetrazolium salts are described. Several 1,3,5-trisubstituted formazans were prepared by condensing 4-acetoxy-3-methoxybenzaldehydephenylhydrazone and 2,4-dinitrophenylhydrazone of 2-benzimidazolecarboxaldehyde, with an appropriate phenyldiazonium salt. The formazans derived from 4-acetoxy-3-methoxybenzaldehydephenylhydrazone were further oxidized to their corresponding cyclization products, 2,3,5-trisubstituted tetrazolium salts. Oxidation of 1-aryl-3-(2'-benzimidazolyl)-5-(5-(2',4'-dinitrophenyl) formazans to their corresponding tetrazolium salt did not meet with success. Both the highly coloured formazans and water-soluble tetrazolium salts were screened for their antiviral, activity against vaccinia virus and Ranikhet disease virus in a stationary culture of chorioallantoic membrane of chick embryo. Two of the compounds were found to exhibit significant activity (87% and 83%) against the Ranikhet disease virus. However no activity against vaccinia virus could be observed.

Synthesis of some newer formazans and tetrazolium salts as antiviral agents.

Thirteen new formazans were prepared by the condensation of the phenylhydrazone of 3.4-dimethoxy-6-nitro-veratraldehyde with the appropriate phenyl diazonium salts. Attempts were made to oxidize these highly coloured formazans with various oxidizing agents to their corresponding tetrazolium salts. The most suitable oxidizing agent was found to be H2O2/Fe2+. Both the formazans and tetrazolium salts were screened for their antiviral activity against the Ranikhet disease virus and vaccinia virus in a stationary culture of chorioallantoic membrane of chick embryo. Among the 15 compounds tested one of the compounds namely 1-o-carboxyphenyl-3[3'.4'-dimethoxy-6'-nitrophenyl]-5-phenylformazan evinced 100% protection against the Ranikhet disease virus. Rest of the compounds showed significant protection ranging from 83 to 20%. An attempt has also been made to arrive at some structure-activity relationship.

Tetrazolium salts and formazans.

The history of the tetrazolium salts and formazans goes back 100 years, to when Friese (1875) reacted benzene diazonium nitrate with nitromethane, to produce a cherry-red "Neue Verbindung". This was the first formazan. 19 years later, Von Pechmann and Runge (1894) oxidised a formazan to produce the first tetrazolium salt. Many hundreds of tetrazolium salts and formazans were prepared in the following years, but only a handful have found applications in biological research. This article has attempted to describe the properties of these compounds, and to illustrate how the tetrazolium salt-formazan reaction has been exploited to serve an extremely wide variety of functions.