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PubMed1987

Synthesis and evaluation of non-catechol D-1 and D-2 dopamine receptor agonists: benzimidazol-2-one, benzoxazol-2-one, and the highly potent benzothiazol-2-one 7-ethylamines.

Our interest in identifying D-1 and D-2 dopamine receptor agonists that are not catechols led us to extend previous studies with oxindoles by investigating analogues of dopamine, N,N-dipropyldopamine, m-tyramine, N,N-dipropyl-m-tyramine, and epinine in which the m-hydroxyl is replaced by the NH portion of a thiazol-2-one, oxazol-2-one, or imidazol-2-one group fused to the 2,3-position. These compounds were evaluated for their affinity and agonist activity at D-1 and D-2 receptors by using in vitro assays. Replacement of the m-hydroxy in N,N-dipropyldopamine with the thiazol-2-one group resulted in a dramatic increase in D-2 receptor affinity and activity compared to that of N,N-dipropyldopamine itself or that of the corresponding oxindole, 1. The resulting compound, 7-hydroxy-4-[2-(di-n-propylamino)ethyl]benzothiazol-2(3H)-one (4), is the most potent D-2 receptor agonist reported to date in the field-stimulated rabbit ear artery (ED50 = 0.028 nM). The benzoxazol-2-one (6), benzimidazol-2-one (5), and isatin (51) analogues showed D-2 receptor agonist potency similar to that of 1. The des-7-hydroxyl analogue of 4 (21) also has enhanced D-2 receptor activity compared to that of the corresponding oxindole, 8. 7-Hydroxy-4-(2-aminoethyl)benzothiazol-2(3H)-one, 27, a non-catechol, has enhanced D-1 and D-2 receptor activity in vitro compared to that of the corresponding oxindole, 7. In vivo, 27 increased renal blood flow and decreased blood pressure in the dog. However, these effects were mediated primarily by D-2 receptor agonist activity. This may be a result of the D-1 partial agonist activity of 27 coupled with its potent D-2 receptor activity.

Animals↗
PubMed1987

Studies on histamine H2 receptor antagonists. 2. Synthesis and pharmacological activities of N-sulfamoyl and N-sulfonyl amidine derivatives.

A series of N-sulfamoyl and N-sulfonyl amidines have been prepared and tested in vitro for H2 antihistamine activity on guinea pig atrium. In addition, several selected compounds were assessed as inhibitors of gastric acid secretion induced by histamine in anesthetized dogs. Structure-activity relationship studies showed that those compounds containing 2-[(diaminomethylene)amino]thiazole exhibited potent H2-receptor antagonist activity. Introduction of alkyl or aralkyl groups to the terminal nitrogen of the sulfamoyl moiety reduced biological activities. Sulfamoyl amidines were more potent in both tests than sulfonyl amidines. Of these compounds, 3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]- N2-sulfamoylpropionamidine (2e, famotidine) showed extremely high potency in both assays and was selected for clinical trials as an antiulcer agent. Acid-catalyzed hydrolysis of famotidine gave the sulfamoyl amide 6 at room temperature and the carboxylic acid 7 at elevated temperatures. 15N NMR spectrum showed that famotidine in solution existed in only one of several possible tautomers derived from the amidine and the guanidine moieties. Nitrosation of famotidine was performed under mild condition and proved to occur on the 5-position of the thiazole ring.

Amidines↗
PubMed2006

Discovery of novel and potent thiazoloquinazolines as selective Aurora A and B kinase inhibitors.

The synthesis of a novel series of quinazolines substituted at C4 by five-membered ring aminoheterocycles is reported. Their in vitro structure-activity relationships versus Aurora A and B serine-threonine kinases is discussed. Our results demonstrate that quinazolines with a substituted aminothiazole at C4 possess potent Aurora A and B inhibitory activity and excellent selectivity against a panel of various serine-threonine and tyrosine kinases, as exemplified by compound 46. We found also that the position and nature of the substituent on the thiazole play key roles in cellular potency. Compounds with an acetanilide substituent at C5' have the greatest cellular activity. The importance of the C5' position for substitution has been rationalized by ab initio molecular orbital calculations. Results show that the planar conformation with the sulfur of the thiazole next to the quinazoline N-3 is strongly favored over the other possible planar conformation. Compound 46 is a potent suppressor of the expression of phospho-histone H3 in tumor cells in vitro as well as in vivo, where 46, administered as its phosphate prodrug 54, suppresses the expression of phospho-histone H3 in subcutaneously implanted tumors in nude mice.

Animals↗
PubMed1997

Synthesis and biochemical evaluation of N-(4-phenylthiazol-2-yl)benzenesulfonamides as high-affinity inhibitors of kynurenine 3-hydroxylase.

In this paper we describe the synthesis, structure-activity relationship (SAR), and biochemical characterization of N-(4-phenylthiazol-2-yl)benzenesulfonamides as inhibitors of kynurenine 3-hydroxylase. The compounds 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide 16 (IC50 = 37 nM, Ro-61-8048) and 4-amino-N-[4-[2-fluoro-5-(trifluoromethyl)phenyl]-thiazol-2-yl] benzenesulfonamide 20 (IC50 = 19 nM) were found to be high-affinity inhibitors of this enzyme in vitro. In addition, both compounds blocked rat and gerbil kynurenine 3-hydroxylase after oral administration, with ED50's in the 3-5 mumol/kg range in gerbil brain. In a microdialysis experiment in rats, 16 dose dependently increased kynurenic acid concentration in the extracellular hippocampal fluid. A dose of 100 mumol/kg po led to a 7.5-fold increase in kynurenic acid outflow. These new compounds should allow detailed investigation of the pathophysiological role of the kynurenine pathway after neuronal injury.

Animals↗
PubMed1999

Thiazolothiazepine inhibitors of HIV-1 integrase.

A series of thiazolothiazepines were prepared and tested against purified human immunodeficiency virus type-1 integrase (HIV-1 IN) and viral replication. Structure-activity studies reveal that the compounds possessing the pentatomic moiety SC(O)CNC(O) with two carbonyl groups are in general more potent against purified IN than those containing only one carbonyl group. Substitution with electron-donating or -withdrawing groups did not enhance nor abolish potency against purified IN. By contrast, compounds with a naphthalene ring system showed enhanced potency, suggesting that a hydrophobic pocket in the IN active site might accommodate an aromatic system rather than a halogen. The position of sulfur in the thiazole ring appears important for potency against IN, as its replacement with an oxygen or carbon abolished activity. Further extension of the thiazole ring diminished potency. Compounds 1, 19, and 20 showed antiviral activity and inhibited IN within similar concentrations. These compounds inhibited IN when Mn(2+) or Mg(2+) was used as cofactor. None of these compounds showed detectable activities against HIV-1 reverse transcriptase, protease, virus attachment, or nucleocapsid protein zinc fingers. Therefore, thiazolothiazepines are potentially important lead compounds for development as inhibitors of IN and HIV replication.

Cell Adhesion↗
PubMed2003

Scope and mechanism of palladium-catalyzed amination of five-membered heterocyclic halides.

Detailed studies have been conducted to determine the activity of palladium catalysts for the amination of five-membered heterocyclic halides and to determine the factors that control the scope of this reaction. Palladium-catalyzed aminations of the electron-rich furanyl, thiophenyl, and indolyl halides and of the related 2-halogenated thiazoles, benzimidazole, and benzoxazole have been shown to occur with a subset of amines. Various combinations of palladium precursors and P(t)Bu(3) were tested as catalysts for reaction of 3-bromothiophene with N-methylaniline, and the fastest reactions occurred with the Pd(I) dimer, [PdBr(P(t)Bu(3))](2). The fastest aminations of thiazoles, benzimidazoles, and benzoxazoles occurred with the combination of palladium trifluoroacetate and P(t)Bu(3) as catalyst.

Amination↗
PubMed2005

Facile synthesis of highly substituted 3-aminofurans from thiazolium salts, aldehydes, and dimethyl acetylenedicarboxylate.

[reaction: see text] A facile preparation of 3-aminofuran derivatives via multicomponent reactions of thiazole carbenes, aldehydes, and dimethyl acetylenedicarboxylate (DMAD) is reported. In this process, the thiazole carbenes, generated in situ from thiazolium salts, reacted with aldehydes and DMAD at -78 to 0 degree C in CH(2)Cl(2) to afford the substituted furans in moderate to good yields. Eight substituted thiazolium salts were employed as carbene precursors in the reaction. Besides aryl aldehydes, alpha,beta-unsaturated aldehydes, aliphatic aldehydes, and arenedial were also investigated and found to be applicable to this reaction.

Acetylene↗
PubMed2006

Synthesis and configurational assignment of the amino alcohol in the eastern fragment of the GE2270 antibiotics by regio- and stereoselective addition of 2-metalated 4-bromothiazoles to alpha-chiral electrophiles.

A synthesis of the eastern fragment of the thiazole peptide GE2270 A (1) has been developed. The synthetic approach relies on the regioselective functionalization of 2,4-dibromothiazole (5) via metalation and nucleophilic addition (at C2) or palladium-mediated cross-coupling (at C2 or C4). The stereochemistry at the N-bearing stereocenter was established by coupling of 2-metalated 4-bromothiazoles (4) to enantiomerically pure mandelic acid derivatives. Both the erythro (2) and threo (3) configurated amino alcohols were prepared with high diastereoselectivities depending on the electrophile employed. More specifically, the threo-configurated (S,R)-4-bromothiazolyl beta-amino alcohol 6 was synthesized from O-TBS protected (R)-mandelonitrile in 62% yield. Its N-PMB protected (R,S)-enantiomer 20 was obtained from O-TBS protected (S)-mandelic aldehyde in 67% yield. The erythro-configurated (S,S)-4-bromothiazolyl beta-amino alcohol 29 was prepared from O-TBS protected (S)-ethyl mandelate in four steps and 33% overall yield. The bithiazole moiety in the desired products 2 and 3 was finally established by the regioselective Negishi coupling of 2,4-dibromothiazole (5) and the 4-zincated, N-Boc protected thiazole derivatives of the diastereomeric 4-bromothiazolyl beta-amino alcohols 6 and 29.

Amino Alcohols↗
PubMed1997

Isolation and structure elucidation of the major degradation products of cefaclor formed under aqueous acidic conditions.

The aqueous acidic degradation of the oral cephalosporin cefaclor was investigated. A number of degradation products were isolated and characterized. The degradation products can be loosely classified into three categories: thiazole derivatives, pyrazine derivatives, and simple hydrolysis or rearrangement products. Degradation pathways are proposed that involve (1) hydrolysis of the beta-lactam carbonyl with subsequent rearrangement, (2) ring contraction of the six-membered cephem nucleus to five-membered thiazole derivatives through an episulfonium ion intermediate, and (3) attack of the primary amine of the phenylglycyl side chain on the "masked aldehyde" at carbon-6 to form fluorescent substituted pyrazines.

Cefaclor↗
PubMed2001

New natural epothilones from Sorangium cellulosum, strains So ce90/B2 and So ce90/D13: isolation, structure elucidation, and SAR studies.

In addition to epothilones A (1) and B (2), 37 natural epothilone variants and epothilone-related compounds were isolated from the culture broth of a 700 L fermentation of Sorangium cellulosum, strain So ce90/B2. Of these, only the 12,13-desoxyepothilones, epothilone C (14) and D (15), were produced in significant amounts (3-6 mg/L); the 21-hydroxy derivatives and epothilones E (3) and F (4), in low and variable amounts due to further degradation by the producing organism. Most of the other epothilone variants were produced only in 1-100 microg/L amounts. The new compounds are very similar in structure to the parent compounds 1, 2 and 14, 15 and are presumably the result of the imperfect selectivity of the biosynthetic enzymes for acetate and propionate. Further, epothilones containing an oxazole moiety (10-13) in the side chain instead of a thiazole as well as ring-expanded 18-membered macrolides, epothilones I (30-35), and a ring contracted 14-membered macrolide, epothilone K (36), were found as very minor metabolites. The mutant strain, So ce90/D13, instead of macrolactones, produced short-chain carboxylic acids 40, 41, and 42 bearing the characteristic thiazole side chain. The structures of the new epothilones were elucidated on the basis of comprehensive NMR and MS data. The new epothilone variants were tested in a cytotoxicity assay with mouse fibroblasts (cell line L929), and structure-activity relationships were established. Several new natural epothilones showed activity comparable to 1 and 2, but in no case exceeded that of 2.

Animals↗
PubMed2000

Asymmetric total synthesis of (-)-mycothiazole.

[structure: see text] In this Letter we describe the first total synthesis of mycothiazole, a polyketide thiazole from a marine sponge. Key steps include our CMD oxidation for the conversion of thiazolidine 11 to thiazole 12 and the Nagao acetate aldol reaction of 5 with aldehyde 4 to construct the chiral secondary alcohol. The skipped diene was constructed by the standard Stille coupling, and the conjugated diene was synthesized by lithium(I)- and copper(I)-mediated Stille coupling.

Animals↗
PubMed1989

Tubular basement membrane change occurs pari passu with the development of cyst formation.

Our previous studies have shown that 2-amino-4,5-diphenyl thiazole hydrochloride (DPT) administered orally to rats induces a urine concentrating defect (within 1 to 2 days) and progressive, but reversible, cystic change of all collecting tubules (prominent between 4 and 8 weeks). Cystic change was characterized by tubular cell and basement membrane changes consisting of alterations in cellular biosynthetic/secretory organelles, followed by thickening of the basement membrane with marked reduction (approximately 50%) of the de novo synthesis of sulfated proteoglycans, suggesting that altered synthesis of tubular basement membrane plays a role in the development of cystic disease. In this study, following the administration of [14C]-DPT in vivo, a major urinary metabolite (greater than 70%) was isolated by HPLC and characterized by gas chromatographic-mass spectral and NMR analyses as 2-amino-4-hydroxyphenyl-5 phenyl thiazole, designated phenol II. Phenol II was synthesized and administered orally to rats for four days to compare its biological effects with DPT. Phenol II induced a significantly greater impairment of concentrating ability and tubular cystic transformation than DPT. At day 5, in phenol II treated animals, basement membranes lining cysts were thickened several-fold and exhibited extensive loss and disorder of ruthenium red binding sites, indicative of loss of sulfated proteoglycans (heparin sulfate proteoglycan). The basement membrane changes occurred in tandem with the development of cystic transformation and strongly suggests that the basement membrane has a key role in the pathogenesis of PKD. The findings support the hypothesis that PKD may be due to a defect in the synthesis/degradation of one or more basement membrane components (sulfated proteoglycans) resulting in faulty tubular morphogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Interference of blood leucocytes in the measurements of immature red cells (reticulocytes) by two different (semi-) automated flow-cytometry technologies.

Flow cytometrical methods have been introduced recently as an alternative to the enumeration of reticulocytes by microscopy. Two of these methods have gained widespread use in haematological practice; the multiparametric flow cytometer using thiazole orange staining (Retic-Count, FACScan) and the single-application reticulocyte counter using auramine-O staining (R-series, Sysmex). Several studies have emphasized the excellent correlations between microscopy and these techniques. The purpose of our study has been to examine the specificity of these automated devices with regard to cells classified as 'reticulocytes' and the effect that this may have on measures of reticulocyte maturity. Our results indicate that the specificity of reticulocyte measurements by both the Sysmex R-1000/-3000 and the Retic-Count system is relatively low. This is due to the presence of leucocytes amongst cells classified as reticulocytes. These leucocytes display intense staining with either dye, leading to an erroneous estimation of RMI (thiazole orange) and high fluorescence count (R-1000/-3000). This error is directly correlated with the leucocyte count. The basis for reticulocyte identification should be improved before automated estimation of reticulocyte maturation can be used in clinical practice.

Automation↗
PubMed2003

The structure of neuromelanin as studied by chemical degradative methods.

The biosynthesis, structure and function of neuromelanin (NM), the dark brown melanin-like pigment present in the substantia nigra (SN), are not well characterized, in spite of the possible involvement of NM in the etiology and pathogenesis of Parkinson's disease. NM was isolated from the SN of five non-Parkinsonian human brains. NM and synthetic melanins, employed as models, were characterized by chemical analysis. Alkaline hydrogen peroxide (H2O2) oxidation of NM generated four degradation products, pyrrole-2,3-dicarboxylic acid (PDCA), pyrrole-2,3,5-tricarboxylic acid (PTCA), thiazole-4,5-dicarboxylic acid (TDCA) and thiazole-2,3,5-tricarboxylic acid (TTCA), whose ratios, especially the TTCA to PDCA ratio, indicate that NM is derived mostly from dopamine (DA) with 25% incorporation of cysteine (Cys) in the form of a benzothiazine structure. Hydriodic acid (HI) reductive hydrolysis of NM yielded 4-amino-3-hydroxyphenylethylamine (4-AHPEA) as a marker of cysteinyldopamine (CysDA)-derived units. The 4-AHPEA to PDCA ratio indicates a 21% incorporation of CysDA-derived units into NM. These degradative experiments also suggest that DOPA is not incorporated into NM to a significant extent (approximately 6% the level of DA). It is concluded that the TTCA to PDCA ratio is a useful indicator of CysDA-derived units in NM, and NM consists mainly of DA-melanin with some contribution from CysDA-melanin. The involvement of DA and CysDA as building blocks of NM demonstrates the detoxifying role of NM synthesis, since it prevents the intraneuronal accumulation of DA and CysDA, which would cause toxic effects.

Aged↗
PubMed2002

Synthesis and evaluation of anticancer activity of some imidazothiazolyl, imidazobenzothiazolyl and dihydroimidazothiazolyl coumarins.

A series of 6-(2H-1-benzopyran-2-one-3-yl)imidazo[2,1-b]thiazoles (1), 2-(2H-1-benzopyran-2-one-3-yl)imidazo[2,1-b]benzothiazoles (2) and 3-(2H-1-benzopyran-2-one-3-yl)-5,6-dihydroimidazo[2,1-b]thiazoles (3) have been synthesized and evaluated for anticancer activity in vitro. The compounds showed very good activity against different tumor cell lines.

Antineoplastic Agents↗
PubMed2002

A ligand for the aryl hydrocarbon receptor isolated from lung.

The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that is best known because it mediates the actions of polycyclic and halogenated aromatic hydrocarbon environmental toxicants such as 3-methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. We report here the successful identification of an endogenous ligand for this receptor; approximately 20 microg was isolated in pure form from 35 kg of porcine lung. Its structure was deduced as 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester from extensive physical measurements and quantum mechanical calculations. In a reporter gene assay, this ligand activates the AHR with a potency five times greater than that of beta-naphthoflavone, a prototypical synthetic AHR ligand. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester competes with 2,3,7,8-[(3)H]tetrachlorodibenzo-p-dioxin for binding to human, murine, and fish AHRs, thus showing that AHR activation is caused by direct receptor binding, and that recognition of this endogenous ligand is conserved from early vertebrates (fish) to humans.

Animals↗
PubMed2000

Computational analysis of the first biheterocyclization site of the antibiotic microcin B17.

Microcin B 17 (MccB17) undergoes an enzyme catalyzed posttranslational modification to form four oxazole and four thiazole rings. Four of these rings form 4,2 - connected biheterocyclic functionalities. In this study, the hexapeptide sequence surrounding the first biheterocyclization site of microcin B17 was examined using computational calculations and database analysis to see if it was preorganized for cyclization in a manner similar to that found in the autocatalytic posttranslational cyclization of Green Fluorescent Protein (GFP). Attention was focused on the intermolecular distances between the sulfur and oxygen atoms of the cysteine and serine residues and the carbonyl carbons which they attack in the ring formation. Conformational searches located some low energy conformations that contained relatively short oxygen to carbonyl carbon distances, which indicated that the oxazole forming fragment in microcin B17 is preorganized for cyclization. However, the lack of any clear patterns for the sulfur to carbon distances show that the side-chain of cysteine does not adopt any low energy conformations that are geometrically preorganized for cyclization. The MccB17 synthetase enzyme complex which catalyzes the cyclization process therefore has both steric and electronic functions. The data obtained in this investigation is in agreement with empirical data which shows that biheterocyclization will only occur if the thiazole forms before the oxazole.

Anti-Bacterial Agents↗
PubMed2001

A 3D QSAR study of monoamino oxidase-B inhibitors using the chemical function based pharmacophore generation approach.

A molecular modelling study was performed using the CATALYST software package on a dataset of 100 thiosemicarbazide and thiazole derivatives acting as MAO-B irreversible inhibitors in order to, (i) better elucidate the possible role of the ligand features which are significant for binding and (ii) generate chemical features based pharmacophore models which were subsequently used as 3D queries for database searching. Based on known MAO-B inhibitors, pharmacophore hypotheses were created in order to find similarities between the thiazoles and thiosemicarbazides and identify the key sub-structures most likely to be significant for high MAO-B inhibitory activity.

Animals↗