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PubMed1983

The capacity of some nitro- and amino-heterocyclic sulfur compounds to induce base-pair substitutions.

The capacity of 27 heterocyclic sulfur compounds to induce base-pair substitutions was investigated with Klebsiella pneumoniae ur- pro- and Salmonella typhimurium TA100 as test organisms. Among the compounds tested, all sulfur compounds with nitro groups and some thiazoles with an amino group were mutagenic. Among the nitrothiazoles, the most potent mutagen was niridazole, followed by 2-acetamido-5-nitrothiazole, 2-bromo-5-nitrothiazole, N-(5-nitrothiazol-2-yl)benzamide, and 2-amino-5-nitrothiazole. Of the nitrothiophenes, 2-nitrothiophene was more mutagenic than 3-nitrothiophene and 2,4-dinitrothiophene. 4-Nitroisothiazole was also mutagenic. Of the aminothiazoles, 2-amino-5-bromothiazole and 2-amino-5-chlorothiazole were mutagenic to both test organisms. With 2-amino-5-(p-nitrophenylsulfonyl)thiazole, a mutagenic action was only found with Salmonella typhimurium TA100, whereas 2-aminothiazole and 2-amino-4-methylthiazole were only mutagenic with Klebsiella pneumoniae. With the other 13 compounds, no mutagenic activity was observed. Of the coccidiostatics, 2-acetamido-5-nitrothiazole was also mutagenic on Escherichia coli K12 and Saccharomyces cerevisiae D4 but non-mutagenic on Salmonella typhimurium TA1530, TA1535, TA1537 and TA98, while 2-amino-5-nitrothiazole was mutagenic on Escherichia coli K12, Salmonella typhimurium TA1530, TA1535 and TA98, and non-mutagenic on strain TA1537 and on Saccharomyces cerevisiae D4.

Escherichia coli↗
PubMed1991

Involvement of calcium ions in the modulation of electrically-induced rat vas deferens contractions by histaminergic drugs.

1. The modulatory action of histaminergic drugs: histamine; 2-(2-aminoethyl)thiazole (H1-agonist); dimaprit (H2-agonist); diphenhydramine (H1-receptor antagonist); and cimetidine (H2-receptor antagonist) on rat vas deferens contractions induced by electrical field stimulation (0.1 Hz, 1 pulse, 1 msec duration, supramaximal voltage) was studied either at different calcium concentrations in the nutrient fluid or after verapamil. 2. Histamine and 2-(2-aminoethyl)thiazole inhibited the electrically-evoked contractions (EEC). This effect was unchanged after verapamil. 3. Diphenhydramine potentiated the EEC. Verapamil added before the H1-receptor antagonist inhibited this action. 4. The effects of agonists and antagonists of H-receptors decreased with the increasing of calcium concentration. 5. The results obtained suggested the existence of heterogeneity of prejunctional H-receptors. The function of histaminergic drugs on adrenergic neurotransmission in field stimulated rat vas deferens is Ca(2+)-dependent.

Animals↗
PubMed2004

Design, synthesis, and biological activity of non-amidine factor Xa inhibitors containing pyridine N-oxide and 2-carbamoylthiazole units.

Based on the both of results for X-ray studies of tetrahydrothiazolopyridine derivative 1c and FXV673, we synthesized a series of thiazol-5-ylpyridine derivatives containing pyridine N-oxide and 2-carbamoylthiazole units to optimize the S4 binding element. N-Oxidation of thiazol-5-ylpyridine increased the anti-fXa activity more than 10-fold independent on the position of N-oxide. The 4-pyridine N-oxide derivatives 3a and 3d excelled over the tetrahydrothiazolopyridine 1b in potency. 2-Methylpyridine N-oxide 3d exhibited 49-fold selectivity over thrombin. Our modeling study proposed a binding mode that the pyridine N-oxide ring of 3a stuck into the "cation hole" , and the oxide anion of 3a occupied in the almost same space to that of FXV673. From observations of the SAR and modeling studies, we suggested the possibilities that the formation of hydrogen bond with the oxide anion in the "cation hole" and the affinity of cationic pyridine ring to S4 subsite were responsible for increase in anti-fXa activity.

Amidines↗
PubMed2006

Structure-activity relationships from in vitro efficacies of the thiazolide series against the intracellular apicomplexan protozoan Neospora caninum.

Nitazoxanide (2-acetolyloxy-N-(5-nitro 2-thiazolyl) benzamide; NTZ) represents the parent compound of a novel class of broad-spectrum anti-parasitic compounds named thiazolides. NTZ is active against a wide variety of intestinal and tissue-dwelling helminths, protozoa, enteric bacteria and a number of viruses infecting animals and humans. While potent, this poses a problem in practice, since this obvious non-selectivity can lead to undesired side effects in both humans and animals. In this study, we used real time PCR to determine the in vitro activities of 29 different thiazolides (NTZ-derivatives), which carry distinct modifications on both the thiazole- and the benzene moieties, against the tachyzoite stage of the intracellular protozoan Neospora caninum. The goal was to identify a highly active compound lacking the undesirable nitro group, which would have a more specific applicability, such as in food animals. By applying self-organizing molecular field analysis (SOMFA), these data were used to develop a predictive model for future drug design. SOMFA performs self-alignment of the molecules, and takes into account the steric and electrostatic properties, in order to determine 3D-quantitative structure activity relationship models. The best model was obtained by overlay of the thiazole moieties. Plotting of predicted versus experimentally determined activity produced an r2 value of 0.8052 and cross-validation using the "leave one out" methodology resulted in a q2 value of 0.7987. A master grid map showed that large steric groups at the R2 position, the nitrogen of the amide bond and position Y could greatly reduce activity, and the presence of large steric groups placed at positions X, R4 and surrounding the oxygen atom of the amide bond, may increase the activity of thiazolides against Neospora caninum tachyzoites. The model obtained here will be an important predictive tool for future development of this important class of drugs.

Animals↗
PubMed2000

The agonist SR 146131 and the antagonist SR 27897 occupy different sites on the human CCK(1) receptor.

1-[2-(4-(2-Chlorophenyl)thiazol-2-yl) aminocarbonyl indoyl] acetic acid (SR 27897) is an effective CCK(1) receptor antagonist, while the structurally related molecule 2-[4-(4-chloro-2, 5-dimethoxyphenyl)-5-(2-cyclohexyl-ethyl)-thiazol-2-ylcarbamoyl ]-5, 7-dimethyl-indol-1-yl-1-acetic acid (SR 146131) is a highly potent and specific agonist for the same receptor. To discover how the two molecules interact with the human cholecystokinin (CCK) CCK(1) receptor, we have carried out binding and activity studies with 33-point mutated receptors. Only six mutants showed altered [3H]SR 27897 binding properties, Lys(115), Lys(187), Phe(198), Trp(209), Leu(214) and Asn(333). In contrast, numerous mutations throughout the receptor either reduced SR 146131 agonist potency, Phe(97), Gly(122), Phe(198), Trp(209), Ile(229), Asn(333), Arg(336) and Leu(356) or increased it, Tyr(48), Cys(94), Asn(98), Leu(217) and Ser(359). Only mutations of Phe(198), Trp(209) and Asn(333) affected both SR 27897 and SR 146131 binding or activity. The collated information was used to construct molecular models of SR 27897 and SR 146131 bound to the human CCK(1) receptor. The clear difference in the binding sites of SR 27897 and SR 146131 offers a molecular explanation for their contrasting pharmacological characteristics.

Amino Acid Sequence↗
PubMed1999

Contrasting roles of leu(356) in the human CCK(1) receptor for antagonist SR 27897 and agonist SR 146131 binding.

A new highly specific, potent non-peptide agonist for the cholecystokinin subtype 1 receptor (CCK(1)), SR 146131 (2-[4-(4-chloro-2, 5-dimethoxyphenyl)-5-(2-cyclohexyl-ethyl)-thiazol-2-ylcarbamoyl ]-5, 7-dimethyl-indol-1-yl-1-acetic acid) was recently described [Bignon, E., Bachy, A., Boigegrain, R., Brodin, R., Cottineau, M., Gully, D., Herbert, J.-M., Keane, P., Labie, C., Molimard, J.-C., Olliero, D., Oury-Donat, F., Petereau, C., Prabonneaud, V., Rockstroh, M.-P., Schaeffer, P., Servant, O.Thurneyssen, O., Soubrié, P., Pascal, M., Maffrand, J.-P., Le Fur, G., 1999. SR 146131: a new, potent, orally active and selective non-peptide cholecystokinin subtype I receptor agonist: I. In vitro studies. J. Pharmacol. Exp. Ther. 289, 742-751]. From binding and activity assays with chimeric constructs of human CCK(1) and the cholecystokinin subtype 2 receptor (CCK(2)) and receptors carrying point mutations, we show that Leu(356), situated in transmembrane domain seven in the CCK(1) receptor, is a putative contact point for SR 146131. In contrast, Leu(356) is probably not in contact with the CCK(1) receptor specific antagonist SR 27897 (1-[2-(4-(2-chlorophenyl)thiazol-2-yl)aminocarbonyl indoyl]acetic acid), a compound structurally related to SR 146131, since its replacement by alanine, histidine or asparagine gave receptors having wild-type CCK(1) receptor SR 27897 binding affinity. Previous mutational analysis of His(381), the cognate position in the rat CCK(2) receptor, had implicated it as being involved in subtype specificity for SR 27897, results which we confirm with corresponding mutations in the human CCK(2) receptor. Moreover, binding and activity assays with the natural CCK receptor agonist, CCK-8S, show that CCK-8S is more susceptible to the mutations in that position in the CCK(1) receptor than in the CCK(2) receptor. The results suggest different binding modes for SR 27897, SR 146131 and CCK-8S in each CCK receptor subtype.

Animals↗
PubMed2000

Essential role of extracellular charged residues of the human CCK(1) receptor for interactions with SR 146131, SR 27897 and CCK-8S.

We hypothesized that charge-charge interactions may be important for the binding of the human cholecystokinin type 1 (CCK(1)) receptor-specific non-peptide full agonist SR 146131, (2-[4-(4-chloro-2, 5-dimethoxyphenyl)-5-(2-cyclohexyl-ethyl)-thiazol-2-ylcarbamoyl ]-5, 7-dimethyl-indol-1-yl-1-acetic acid), the competitive antagonist SR 27897, (1-[2-(4-(2-chlorophenyl)thiazol-2-yl) aminocarbonyl indoyl] acetic acid) and the natural octapeptide CCK-8S to the CCK(1) receptor. Alanine replacement studies of positively charged residues in the extracellular domains of the receptor showed that only the R336A mutation affected SR 146131 potency of mutated receptors transiently expressed in monkey kidney epithelial COS-7 cells. Two residues, Lys(115) and Lys(187), were implicated in SR 27897 binding. Only the replacement of Lys(115), Arg(197) and Arg(336) significantly affected CCK-8S binding or activity. These results clearly indicated the importance of certain charged residues, but not others, in SR 146131, SR 27897 and CCK-8S binding. Furthermore, although these molecules probably occupy different binding sites on the CCK(1) receptor, we show that a small non-peptide agonist, SR 146131, can stimulate the dual signaling pathways mediated by the CCK(1) receptor.

Amino Acid Sequence↗
PubMed1997

A single mutation in the M-subunit of Rhodospirillum rubrum confers herbicide resistance.

Cells of the photosynthetic bacterium Rhodospirillum rubrum were rendered resistant against the inhibitor 2-(1-phenyl)ethylamino-3-propionylamino-4-cyano-thiazole (PPCTH). Electron transport in reaction centers prepared from one of the mutants (M6) was neither inhibited by PPCTH and other NH-thiazoles nor terbutryn. These inhibitors are known to bind at the Q(B) site of the L-subunit. Compared to the wild type, chromatophores from M6 exhibited strongly altered Q(B)- Fe2+ and Q(A)- Fe2+ EPR signals. Inhibitor resistance is due to a mutation in the bacterial reaction center M-subunit, where Glu234 is exchanged against Lys. This is the first example of an inhibitor resistance in the Q(B) site caused by a mutation in the M-subunit.

Drug Resistance, Microbial↗
PubMed2000

Induction of class alpha glutathione S-transferases by 4-methylthiazole in the rat liver: role of oxidative stress.

The expression of glutathione S-transferase (GST) is a crucial factor in determining the sensitivity of cells and organs in response to a variety of toxicants. Expression of class alpha GST genes by methyl-substituted thiazoles was assessed in the rat liver. Northern blot analysis revealed that 4-methylthiazole (4-MT) elevated rGSTA2, A3, A5 and M1 mRNAs in the liver by 19-, 4-, 6- and 9-fold at 24 h after treatment, respectively, as compared to control. Consecutive 3-day treatment with 4-MT resulted in 4- to 7-fold increases in rGSTA and M1 mRNAs. Multiple treatments with 5-methylthiazole (5-MT) caused marginal increases in GST mRNAs in spite of the large increases in certain GST mRNAs at 24 h. Either 4, 5-dimethylthiazole (DT) or 2,4,5-trimethylthiazole (TT) minimally affected the rGSTA and rGSTM mRNA expression at 1-3 day(s). Western blot analysis showed that 4-MT induced rGSTA1/2, rGSTA3/5 and rGSTM1 proteins by 2.6-, 2.1- and 2.1-fold at 3 days, respectively, while other methylthiazoles failed to induce the GST subunits. Starving rats were treated with a lower dose of methylthiazoles to study the role of oxidative stress in the mRNA expression. The levels in rGSTA2/3/5 mRNAs were significantly enhanced by 4-MT in starving rats, whereas rGSTM1/2 mRNAs were not further increased. Other methylthiazoles were inactive in enhancing the mRNAs in starving animals. Pretreatment of starving rats with either cysteine or methionine completely prevented the increases in class alpha GST mRNAs by 4-MT. Data showed that 4-MT induces class alpha GSTs with the increases in the mRNAs, whereas 5-methyl-, dimethyl- and trimethyl-substituted thiazoles were minimally active. Increases in the class alpha GST mRNAs by 4-MT may be associated with the oxidative stress in hepatocytes, as supported by starvation and sulfur amino acid experiments.

Animals↗
PubMed2000

Synthesis and evaluation of oligo-1,3-thiazolecarboxamide derivatives as HIV-1 reverse transcriptase inhibitors.

A set of oligo-1,3-thiazolecarboxamide derivatives able to interact with the minor groove of nucleic acids was synthesized. These oligopeptides contained different numbers of thiazole units presenting dimethylaminopropyl or EDTA moieties on the C-terminus, and aminohexanoyl or EDTA moieties on the N-terminus. The inhibition of such compounds on HIV-1 reverse transcriptase activity was evaluated using different model template primer duplexes: DNA x DNA, RNA x DNA, DNA x RNA and RNA x RNA. The biological properties of the thiazolecarboxamide derivatives were compared to those of distamycin, another minor groove binder which contains three pyrrole rings. Similar to distamycin, the thiazole containing oligopeptides were good inhibitors of the reverse transcription reaction in the presence of DNA x DNA. But in contrast to distamycin, the oligothiazolide derivatives were able to inhibit reverse transcription in the presence of RNA x DNA or DNA x RNA template primers. Both distamycin and oligothiazolecarboxamides had low affinity for RNA x RNA duplexes. The inhibition obtained with the newly synthesized thiazolecarboxamides showed that these compounds were more powerful and versatile inhibitors of the RT-dependent polymerization than the natural minor groove binder distamycin.

Anti-HIV Agents↗
PubMed2001

Design, synthesis, and evaluation of alpha-ketoheterocycles as class C beta-lactamase inhibitors.

A series of specific alpha-ketoheterocycles (benzoxazole, thiazole, imidazole, tetrazole, and thiazole-4-carboxylate) has been synthesized in order to assess their potential as beta-lactamase inhibitors. The syntheses were achieved either by construction of the heterocycle (benzoxazole) from an appropriate alpha-hydroxyimidate, followed by oxidation of the alcohol, or by direct reaction of methyl phenaceturate with a lithiated heterocycle. The properties of these compounds in aqueous solution are described and their inhibitory activity against beta-lactamases assessed. They did inhibit the class C beta-lactamase of Enterobacter cloacae P99 but not the TEM beta-lactamase. The most effective inhibitor of the former enzyme (K(i)=0.11 mM) was 5-(phenylacetylglycyl) tetrazole, probably because it is an anion at neutral pH. Interpretation of the results was aided by computational models of the tetrahedral adducts. Most of the compounds also inhibited alpha-chymotrypsin but not porcine pancreatic elastase.

Drug Design↗
PubMed2001

Mechanistic studies on thiamin phosphate synthase: evidence for a dissociative mechanism.

Thiamin phosphate synthase catalyzes the coupling of 4-methyl-5-(beta-hydroxyethyl)thiazole phosphate (Thz-P) and 4-amino-5-(hydroxymethyl)-2-methylpyrimidine pyrophosphate (HMP-PP) to give thiamin phosphate. In this paper, we demonstrate that 4-amino-5-(hydroxymethyl)-2-(trifluoromethyl)pyrimidine pyrophosphate (CF(3)-HMP-PP) is a very poor substrate [k(cat)(CH(3)) > 7800k(cat)(CF(3))] and that 4-amino-5-(hydroxymethyl)-2-methoxypyrimidine pyrophosphate (CH(3)O-HMP-PP) is a good substrate [k(cat)(OCH(3)) > 2.8k(cat)(CH(3))] for the enzyme. We also demonstrate that the enzyme catalyzes positional isotope exchange. These observations are consistent with a dissociative mechanism (S(N)1 like) for thiamin phosphate synthase in which the pyrimidine pyrophosphate dissociates to give a reactive pyrimidine intermediate which is then trapped by the thiazole moiety.

Alkyl and Aryl Transferases↗
PubMed2003

Structural and mechanistic studies on ThiO, a glycine oxidase essential for thiamin biosynthesis in Bacillus subtilis.

The thiO gene of Bacillus subtilis encodes an FAD-dependent glycine oxidase. This enzyme is a homotetramer with a monomer molecular mass of 42 kDa. In this paper, we demonstrate that ThiO is required for the biosynthesis of the thiazole moiety of thiamin pyrophosphate and describe the structure of the enzyme with N-acetylglycine bound at the active site. The closest structural relatives of ThiO are sarcosine oxidase and d-amino acid oxidase. The ThiO structure, as well as the observation that N-cyclopropylglycine is a good substrate, supports a hydride transfer mechanism for the enzyme. A mechanistic proposal for the role of ThiO in thiazole biosynthesis is also described.

Amino Acid Oxidoreductases↗
PubMedDate not supplied

A facile solid-phase synthesis of 1,2,4,5-tetrasubstituted imidazoles using sodium benzenesulfinate as a traceless linker.

The preparation of substituted imidazoles, thiazoles, and oxazoles using traceless solid-phase sulfone linker strategy is described. Key steps involved are (i) sulfinate acidification, (ii) sulfinic acid condensation with aldehyde and amine, and (iii) traceless product release by a one-pot elimination-cyclization reaction. The elimination reaction was carried out in the presence of a thiazolium catalyst that facilitated the in situ formation of the alpha-ketoamide, which was subsequently converted to the corresponding imidazoles, oxazoles, and thiazoles by treatment with amines, PPh(3)/I(2) or Lawesson's reagent. A library of 18 compounds was synthesized.

Combinatorial Chemistry Techniques↗
PubMed2000

Anti-Helicobacter pylori agents. 4. 2-(Substituted guanidino)-4-phenylthiazoles and some structurally rigid derivatives.

In order to find a new class of anti-Helicobacter pylori (H. pylori) agents, a series of 4-[(3-acetamido)phenyl]-2-(substituted guanidino)thiazoles and some structurally rigid analoges were synthesized and evaluated for antimicrobial activity against H. pylori. Among the compounds obtained, high anti-H. pyrori activities were observed in benzyl derivative 34 (MIC = 0.025 microg/mL) and phenethyl derivatives 35 and 36 (MIC = 0.037 microg/mL and 0.017 microg/mL). Though alkyl derivatives generally showed lower activity, the 2-methoxyethyl derivative 28 preserved significant activity (MIC = 0.32 microg/mL) and also exhibited more potent gastric antisecretory activity than ranitidine. Structural restriction by bridging between the thiazole and the phenyl rings with an alkyl chain did not improve the activity in this series.

Animals↗
PubMed1992

Methoxytetrahydropyrans. A new series of selective and orally potent 5-lipoxygenase inhibitors.

Investigation of the SAR of the lead (methoxyalkyl)thiazole 1-[3-(naphth-2-ylmethoxy)phenyl]-1-thiazol-2-ylprop yl methyl ether (1, ICI 211965) led to the methoxytetrahydropyrans, a new series of 5-lipoxygenase (5-LPO) inhibitors exemplified by the parent compound 4-[3-(naphth-2-ylmethoxy)phenyl]-4- methoxy-3,4,5,6-tetrahydro-2H-pyran (4f). In vitro 4f inhibited leukotriene C4 (LTC4) synthesis in zymosan-stimulated plasma-free mouse macrophages and LTB4 synthesis in A-23187-stimulated human whole blood (IC50s 0.5 nM and 0.07 microM, respectively). In the rat 4f inhibited LTB4 synthesis in blood ex vivo and in zymosan-inflamed air pouch exudate with an ED50 3 h after oral dosing of 10 mg/kg in each system. In seeking more potent orally active compounds, strategies were explored in congeners of 4f for reducing lipophilicity without sacrificing potency. For example, replacement of 2-naphthyl of 4f by various aza- and oxoheterocycles afforded compounds in which log P is reduced by 1.7-2.3 units while potency in human whole blood in vitro was maintained or enhanced relative to 4f. In addition, the oxoheterocyclic replacements provided compounds with improved oral potency and the preferred compound from this group is 6-[[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4- yl)phenoxy]methyl]-1-methylquinol-2-one (4y). In the in vitro systems, 4y inhibited LT formation with IC50s in mouse macrophages and human whole blood of 3 nM and 0.02 microM, respectively. 4y did not inhibit the synthesis of cyclooxygenase (CO) products at concentrations up to 500 microM in human blood, a selectivity for 5-LPO over CO of greater than 20,000-fold. In the rat 4y inhibited the formation of LTB4 in blood ex vivo and in inflammatory exudate with ED50s 3 h after oral dosing of 0.9 and 0.3 mg/kg, respectively. 4y was more potent in vitro in human whole blood and in rat blood ex vivo at 3 h than either the 5-LPO inhibitor A-64077 or the FLAP antagonist MK-886. Based on these data 4y (ICI D2138) has been entered into development as an orally active, selective 5-LPO inhibitor for clinical evaluation in inflammatory conditions in which LTs are believed to play a role.

Administration, Oral↗
PubMed1989

Organic phosphorus compounds. 2. Synthesis and coronary vasodilator activity of (benzothiazolylbenzyl) phosphonate derivatives.

Structural modification and the coronary vasodilator activity of the calcium antagonist fostedil (KB-944) are described. Elimination of the bezothiazole ring or replacement of the benzothiazole ring of fostedil with other hetero rings leads to a decrease in vasodilator activity. Change of the distance from the aromatic ring to the phosphorus of fostedil causes a decrease in the activity. The present study indicates that the presence of an aromatic ring substituted thiazole ring and the presence of phosphonate at an appropriate distance from the thiazole ring are important for the coronary vasodilator action of fostedil.

Allosteric Site↗