Synthesis of new 4-isopropylthiazole hydrazide analogs and some derived clubbed triazole, oxadiazole ring systems - A novel class of potential antibacterial, antifungal and antitubercular agents

In the present study a series of 4-isopropylthiazole-2-carbohydrazide analogs, derived clubbed oxadiazole-thiazole and triazole-thiazole derivatives have been synthesized and characterized by IR, H-1 NMR, C-13 NMR, elemental and mass spectral analyses. The synthesized compounds were evaluated for their preliminary in vitro antibacterial, antifungal and antitubercular activity against Mycobacterium tuberculosis H(37)Rv strain by broth dilution assay method. The synthesized compounds 7a, 7b, 7d and 4 showed an antitubercular efficacy considerably greater than that of the parent 4-isopropyl-1,3-thiazole-2-carbohydrazide 1, suggesting that the substituted 4-isopropylthiazole-2-carbohydrazide moiety plays an important role in enhancing the antitubercular properties of this class of compounds. Compounds 2c, 3, 4, 6d, 7a and 7b exhibited good or moderate antibacterial and antifungal activity. Compounds 4 and 7b showed appreciable cytotoxicity at a concentration of 250 mu M.

5-(4-Chlorophenyl)-3-(2,4-dimethylthiazol-5-yl)-1,2,4-triazolo[3,4-a]isoquinoline

In the title molecule, C21H15ClN4S, the triazoloisoquinoline ring system is approximately planar, with an r.m.s. deviation of 0.054 (2) angstrom and a maximum deviation of 0.098 (2) angstrom from the mean plane for the triazole ring C atom that is bonded to the thiazole ring. The thiazole and benzene rings are twisted by 66.36 (7) and 56.32 (7)degrees respectively, with respect to the mean plane of the triazoloisoquinoline ring system. In the crystal structure, molecules are linked by intermolecular C-H center dot center dot center dot N interactions along the a axis. The molecular conformation is stabilized by a weak intramolecular pi-pi interaction involving the thiazole and benzene rings, with a centroid-centroid distance of 3.6546 (11) angstrom . In addition, two other intermolecular pi-pi stacking interactions are observed, between the triazole and benzene rings and between the dihydropyridine and benzene rings [centroid-centroid distances = 3.6489 (11) and 3.5967 (10) angstrom, respectively].

Synthesis and biological evaluation of novel 2-aralkyl-5-substituted-6-(4 `-fluorophenyl)-imidazo2,1-b]1,3,4]thiadiazole derivatives as potent anticancer agents

Levamisole, the imidazo2,1-b]thiazole derivative has been reported as a potential antitumor agent. In the present study, we synthesized, characterized and evaluated biological activity of its novel analogues with substitution in the aralkyl group and on imidazothiadiazole molecules with same chemical backbone but different side chains namely 2-aralkyl-6-(4'-fluorophenyl)-imidazo2,1-b]1,3,4]thiadiazoles (SCR1), 2-aralkyl-5-bromo-6-(4'-fluorophenyl)-imidazo2,1-b]1,3,4]-thiadiaz oles (SCR2), 2-aralkyl-5-formyl-6-(4'-fluorophenyl)-imidazo2,1-b]1,3,4]-thiadia zoles (SCR3) and 2-aralkyl-5-thiocyanato-6-(4'-fluorophenyl)-imidazo2,1-b]1,3,4]-th iadiazoles (SCR4) on leukemia cells. The cytotoxic studies showed that 3a, 4a, and 4c exhibited strong cytotoxicity while others had moderate cytotoxicity. Among these we chose 4a (IC50, 8 mu M) for understanding its mechanism of cytotoxicity. FACS analysis in conjunction with mitochondrial membrane potential and DNA fragmentation studies indicated that 4a induced apoptosis without cell cycle arrest suggesting that it could be used as a potential chemotherapeutic agent. (C) 2011 Elsevier Masson SAS. All rights reserved.

Polymorphism in Opto-Electronic Materials with a Benzothiazole-fluorene Core: A Consequence of High Conformational Flexibility of pi-Conjugated Backbone and Alkyl Side Chains

Fluorene and its derivatives are well-known organic semiconducting materials in the field of opto-electronic devices because of their charge transport properties. Three new organic semiconducting materials, namely, 2,2'-((9,9-butyl-9H-fluorene-2,7-diyl)bis(4,1 phenylene))bisbenzod]thiazole, C4; 2,2'-((octyl-9H-fluorene-2,7-diyl)bis(4,1 phenylene))bisbenzod]thiazole, C8; and 2,2'-((9,9-dodecayl-9H-fluorene-2,7-diyl)bis(4,1 phenylene))bisbenzod]thiazole, C12 with a benzothiazole-fluorene backbone, were synthesized and characterized for their photophysical properties. A phenomenon of concomitant polymorphism has been investigated in the first two derivatives (C4 and C8) and has been analyzed systematically in terms of the packing characteristics involving pi ... pi interactions. The conformational flexibility of the pi-conjugated 2,2'-(fluorene-2,7-diyl)bis(4,1 phenylene)bisbenzod]thiazole backbone coupled with orientational freedom of the terminal alkyl chains were found to be the key factors responsible for these polymorphic modifications. Attempts to grow suitable crystals for single crystal X-ray diffraction of compound C12 were unsuccessful.

4-(4-Chlorophenyl)-N-[(E)-4-(dimethylamino)benzylidene]-1,3-thiazol-2- amine

The title compound, C(18)H(16)ClN(3)S, adopts an extended molecular structure. The thiazole ring is inclined by 9.2 (1) and 15.3 (1)degrees with respect to the chlorophenyl and 4-(dimethylamino)phenyl rings, respectively, while the benzene ring planes make an angle of 19.0 (1)degrees. A weak intermolecular C-H center dot center dot center dot pi contact is observed in the crystal structure.

Novel Levamisole Derivative Induces Extrinsic Pathway of Apoptosis in Cancer Cells and Inhibits Tumor Progression in Mice

Background: Levamisole, an imidazo(2,1-b) thiazole derivative, has been reported to be a potential antitumor agent. In the present study, we have investigated the mechanism of action of one of the recently identified analogues, 4a (2-benzyl-6-(4'-fluorophenyl)-5-thiocyanato-imidazo2,1-b]1,3,4]thi adiazole). Materials and Methods: ROS production and expression of various apoptotic proteins were measured following 4a treatment in leukemia cell lines. Tumor animal models were used to evaluate the effect of 4a in comparison with Levamisole on progression of breast adenocarcinoma and survival. Immunohistochemistry and western blotting studies were performed to understand the mechanism of 4a action both ex vivo and in vivo. Results: We have determined the IC50 value of 4a in many leukemic and breast cancer cell lines and found CEM cells most sensitive (IC50 5 mu M). Results showed that 4a treatment leads to the accumulation of ROS. Western blot analysis showed upregulation of pro-apoptotic proteins t-BID and BAX, upon treatment with 4a. Besides, dose-dependent activation of p53 along with FAS, FAS-L, and cleavage of CASPASE-8 suggest that it induces death receptor mediated apoptotic pathway in CEM cells. More importantly, we observed a reduction in tumor growth and significant increase in survival upon oral administration of 4a (20 mg/kg, six doses) in mice. In comparison, 4a was found to be more potent than its parental analogue Levamisole based on both ex vivo and in vivo studies. Further, immunohistochemistry and western blotting studies indicate that 4a treatment led to abrogation of tumor cell proliferation and activation of apoptosis by the extrinsic pathway even in animal models. Conclusion: Thus, our results suggest that 4a could be used as a potent chemotherapeutic agent.

Chiral gold(I) vs chiral silver complexes as catalysts for the enantioselective synthesis of the second generation GSK-hepatitis C virus inhibitor

The synthesis of a GSK 2(nd) generation inhibitor of the hepatitis C virus, by enantioselective 1,3-dipolar cycloaddition between a leucine derived iminoester and tert-butyl acrylate, was studied. The comparison between silver(I) and gold(I) catalysts in this reaction was established by working with chiral phosphoramidites or with chiral BINAP. The best reaction conditions were used for the total synthesis of the hepatitis C virus inhibitor by a four step procedure affording this product in 99% ee and in 63% overall yield. The origin of the enantioselectivity of the chiral gold(I) catalyst was justified according to DFT calculations, the stabilizing coulombic interaction between the nitrogen atom of the thiazole moiety and one of the gold atoms being crucial.

Group 6 carbene complexes derived from lithiated azoles and the crystal structure of a molybdenum thiazolinylidene complex

Fischer-type (alkoxy)azolyl carbene complexes and Ofele-Lappert-type azolylinylidene complexes were synthesised by reaction of 1-phenylpyrazol-3 -yllithium, 4-methylthiazol-2-yllithium, benzothiazol-2-yllithium, 1-methylimidazol-2-yllithium with M(CO)(5)L (L = CO, THF or Cl-; M = Cr, Mo or W) and subsequent alkylation with CF3SO3CH3. The alkylation of Fischer-type carbene complexes containing an azolyl as the organic substituent proceeded via ring opening of tetrahydrofuran. When the alkylation is carried out in THF, the carbocation CH3O(CH2)(4)(+) acts as an electrophile. Protonation rather than alkylation of coordinated imidazolyl furnished cyclic imine complexes. Changing the donor atom of a coordinated thiazole from N to C by deprotonation and alkylation afforded a carbene complex. (C) 1999 Elsevier Science S.A. All rights reserved.

Studies on Thermoplastic Elastomers Based on Polyethylene/Elastomer Blends

Department of Polymer Science and Rubber Technology, Cochin University of Science and Technology.

Thiamine is synthesized by a salvage pathway in Rhizobium leguminosarum bv. viciae strain 3841

In the absence of added thiamine, Rhizobium leguminosarum bv. viciae strain 3841 does not grow in liquid medium and forms only "pin" colonies on agar plates, which contrasts with the good growth of Sinorhizobium meliloti 1021, Mesorhizobium loti 303099, and Rhizobium etli CFN42. These last three organisms have thiCOGE genes, which are essential for de novo thiamine synthesis. While R. leguminosarum bv. viciae 3841 lacks thiCOGE, it does have thiMED. Mutation of thiM prevented formation of pin colonies on agar plates lacking added thiamine, suggesting thiamine intermediates are normally present. The putative functions of ThiM, ThiE, and ThiD are 4-methyl-5-(beta-hydroxyethyl) thiazole (THZ) kinase, thiamine phosphate pyrophosphorylase, and 4-amino-5-hydroxymethyl-2-methyl pyrimidine (HMP) kinase, respectively. This suggests that a salvage pathway operates in R. leguminosarum, and addition of HMP and THZ enabled growth at the same rate as that enabled by thiamine in strain 3841 but elicited no growth in the thiM mutant (RU2459). There is a putative thi box sequence immediately upstream of the thiM, and a gfp-mut3.1 fusion to it revealed the presence of a promoter that is strongly repressed by thiamine. Using fluorescent microscopy and quantitative reverse transcription-PCR, it was shown that thiM is expressed in the rhizosphere of vetch and pea plants, indicating limitation for thiamine. Pea plants infected by RU2459 were not impaired in nodulation or nitrogen fixation. However, colonization of the pea rhizosphere by the thiM mutant was impaired relative to that of the wild type. Overall, the results show that a thiamine salvage pathway operates to enable growth of Rhizobium leguminosarum in the rhizosphere, allowing its survival when thiamine is limiting.

Synthesis of heterosulfamates. Search for structure-taste relationships

Thirty one new sodium heterosulfamates, RNHSO3Na, where the R portion contains mainly thiazole, benzothiazole, thiadiazole and pyridine ring structures, have been synthesized and their taste portfolios have been assessed. A database of 132 heterosulfamates ( both open-chain and cyclic) has been formed by combining these new compounds with an existing set of 101 heterosulfamates which were previously synthesized and for which taste data are available. Simple descriptors have been obtained using (i) measurements with Corey-Pauling-Koltun (CPK) space- filling models giving x, y and z dimensions and a volume VCPK, (ii) calculated first order molecular connectivities ((1)chi(v)) and (iii) the calculated Spartan program parameters to obtain HOMO, LUMO energies, the solvation energy E-solv and V-SPART AN. The techniques of linear (LDA) and quadratic (QDA) discriminant analysis and Tree analysis have then been employed to develop structure-taste relationships (SARs) that classify the sweet (S) and non-sweet (N) compounds into separate categories. In the LDA analysis 70% of the compounds were correctly classified ( this compares with 65% when the smaller data set of 101 compounds was used) and in the QDA analysis 68% were correctly classified ( compared to 80% previously). TheTree analysis correctly classified 81% ( compared to 86% previously). An alternative Tree analysis derived using the Cerius2 program and a set of physicochemical descriptors correctly classified only 54% of the compounds.

Ultrasound promoted greener synthesis of 2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)-4-phenylthiazoles

A rapid and cleaner procedure for the synthesis of a series of 2-(3,5-diaryl-45-dihydro-1H-pyrazol-1-yl)-4-phenylthiazoles under ultrasonic irradiation in ethanol is described. (C) 2010 Elsevier B.V. All rights reserved.

Cytotoxicity of hard chairside reline resins: Effect of microwave irradiation and water bath postpolymerization treatments

Purpose: To evaluate the influence of water bath and microwave postpolymerization treatments on the cytotoxicity of 6 hard reline acrylic resins. Materials and Methods: The materials tested were Tokuso Rebase Fast (TR), Ufi Gel Hard (UGH), Duraliner II (D), Kooliner (K), New Truliner (NT), and Light Liner (LL). LL resin was additionally tested with an air-barrier coating (LLABC). Nine disks of each material (10 × 1 mm) were made and divided into 3 groups: group 1 (no postpolymerization treatment); group 2 (postpolymerization in microwave oven); group 3 (postpolymerization in water bath at 55°C for 10 minutes). L929 cells were cultured in 96-well plates and incubated for 24 hours in Eagle's medium. Eluates prepared from the disks or medium without disks (control) replaced the medium. Cytotoxicity was assessed by both dehydrogenase succinic activity (MTT) assay and incorporation of radioactive 3H-thymidine assay. Tests were carried out in quadruplicate and repeated twice. Differences between groups were determined by analysis of variance with Tukey multiple-comparison intervals (α = .05). Results: For MTT assay, the postpolymerization treatments had no effect on the cytotoxicity of all materials (P > .05). For 3H-thymidine assay, the postpolymerization treatments significantly decreased the cytotoxicity of UGH (P < .05). The cytotoxicity of K, NT, LL, and LLABC increased after microwave irradiation (P < .05). TR, NT, and LLABC showed an increase in cytotoxicity after water bath (P < .05). Conclusion: When assessed by MTT assay, the cytotoxicity of the materials was not affected by postpolymerization treatments. 3H-Thymidine assay showed that the cytotoxicity of the resins was not improved by the postpolymerization treatments, with the exception of UGH.

Cytotoxic effects of different concentrations of chlorhexidine

Purpose: To evaluate the cytotoxic effects of different concentrations of Chlorhexidine (Chx) to the odontoblast cell line MDPC-23. Methods: The odontoblast-like cells were seeded (30,000 cells/cm 2) in 60 wells of 24-well dishes and then incubated in contact with the following experimental and control solutions: Group 1: 0.0024% Chx; Group 2: 0.004% Chx; Group 3: 0.02% Chx; Group 4: Phosphate buffer saline solution (PBS, negative control); and Group 5: 0.06% H 2O 2 (positive control). Cell metabolic activity was measured by MTT assay and the cell morphology was analyzed by SEM. Results: The cytotoxic effects of Chx are dose-dependent. The reduction in the cell metabolism for Groups 1, 2, and 3 was 24.8%, 29.9% and 70.8%, respectively. No statistical difference was observed between the Groups 1 and 2 in which no significant cell morphology changes occurred. Consequently, it was concluded that 0.02% Chx solution presents high cytotoxicity to the odontoblast-like cells MDPC-23. On theother hand, 0.0024% and 0.004% Chx causes slight cytopathic effects to the cultured cells.