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PubMed2002

4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1, 3-thiazol-2-amine hydrochloride (SSR125543A), a potent and selective corticotrophin-releasing factor(1) receptor antagonist. II. Characterization in rodent models of stress-related disorders.

The present study investigated the effects of the novel corticotrophin-releasing factor (CRF)(1) receptor antagonist 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A) in a variety of rodent models of anxiety, including conflict procedures (punished drinking and four-plate), exploration models (elevated plus-maze and light/dark), a fear/anxiety defense test battery, and several procedures based on stress-induced changes in physiological (isolation-induced hyperthermia and tail pinch-induced cortical norepinephrine release) or behavioral (social defeat-induced anxiety, maternal separation-induced vocalization) parameters. Moreover, the effects of SSR125543A were investigated in acute (forced swimming) and chronic (chronic mild stress; CMS) models of depression. SSR125543A and the CRF(1) receptor antagonist antalarmin displayed limited efficacy in exploration-based anxiety models. In contrast, both compounds produced clear-cut anxiolytic-like activity in models involving inescapable stress, including the conflict procedures, the social defeat-induced anxiety paradigm and the defense test battery (3-30 mg/kg i.p. or p.o.). These effects paralleled those of the anxiolytic diazepam. In addition, SSR125543A and antalarmin antagonized stress-induced hyperthermia, distress vocalization, and cortical norepinephrine release. In the forced swimming test, 30 mg/kg p.o. SSR125543A and 3 to 30 mg/kg p.o. antalarmin produced clear antidepressant-like effects. These latter results were strengthened by the findings from the CMS, which showed that repeated administration of 10 mg/kg i.p. SSR125543A for 30 days improved the degradation of the physical state, the reduction of body weight gain, and anxiety produced by stress. Together, these data indicate that SSR125543A shows good activity in acute and chronic tests of unavoidable stress exposure, suggesting that it may have a potential in the treatment of depression and some forms of anxiety disorders.

Animals↗
PubMed1996

From peptide precursors to oxazole and thiazole-containing peptide antibiotics: microcin B17 synthase.

Esherichia coli microcin B17 is a posttranslationally modified peptide that inhibits bacterial DNA gyrase. It contains four oxazole and four thiazole rings and is representative of a broad class of pharmaceutically important natural products with five-membered heterocycles derived from peptide precursors. An in vitro assay was developed to detect heterocycle formation, and an enzyme complex, microcin B17 synthase, was purified and found to contain three proteins, McbB, McbC, and McbD, that convert 14 residues into the eight mono- and bisheterocyclic moieties in vitro that confer antibiotic activity on mature microcin B17. These enzymatic reactions alter the peptide backbone connectivity. The propeptide region of premicrocin is the major recognition determinant for binding and downstream heterocycle formation by microcin B17 synthase. A general pathway for the enzymatic biosynthesis of these heterocycles is formulated.

Adenosine Triphosphate↗
PubMed1972

Genetic evidence for the action of oxathiin and thiazole derivatives on the succinic dehydrogenase system of Ustilago maydis mitochondria.

The inhibitory effect of fungitoxic derivatives of 1,4-oxathiin on substrate oxidation by the basidiomycete Ustilago maydis is diminished by a single-gene mutation (oxr). The difference between mutant and wild type is approximately the same on the basis of inhibition of either growth and operation of the tricarboxylic acid cycle in intact cells or succinate-driven reduction of ferricyanide by mitochondrial preparations. The mutation affects the behavior of the succinic dehydrogenase system of mitochondria not only in the presence but also in the absence of the toxicant, from which it is concluded that some component of the system itself has been modified. The malonate and the antimycin A sensitivity of the oxr mutant is similar to that of the wild type but cross-resistance to thiazole derivatives is easily demonstrated.

Antifungal Agents↗
PubMed1997

Characterization of thiI, a new gene involved in thiazole biosynthesis in Salmonella typhimurium.

Thiamine pyrophosphate (TPP) is a required cofactor in Salmonella typhimurium that is generated de novo by the condensation of 4-amino-5-hydroxymethyl pyrimidine (HMP) pyrophosphate and 4-methyl-5-(beta-hydroxyethyl)-thiazole (THZ) monophosphate. The THZ and HMP moieties are independently synthesized, and labeling studies have demonstrated probable metabolic precursors to both. We present herein the initial characterization of thiI, a gene required for THZ synthesis. We show that thiI is a 1,449-bp open reading frame located at minute 9.65 on the S. typhimurium chromosome and that it encodes a 483-amino-acid protein with a predicted molecular mass of 55 kDa. Unlike genes in the thiamine biosynthetic operon at minute 90, thiI is not transcriptionally regulated by TPP.

Amino Acid Sequence↗
PubMed1998

Inhibition of herpes simplex virus replication by a 2-amino thiazole via interactions with the helicase component of the UL5-UL8-UL52 complex.

With the use of a high-throughput biochemical DNA helicase assay as a screen, T157602, a 2-amino thiazole compound, was identified as a specific inhibitor of herpes simplex virus (HSV) DNA replication. T157602 inhibited reversibly the helicase activity of the HSV UL5-UL8-UL52 (UL5/8/52) helicase-primase complex with an IC50 (concentration of compound that yields 50% inhibition) of 5 microM. T157602 inhibited specifically the UL5/8/52 helicase and not several other helicases. The primase activity of the UL5/8/52 complex was also inhibited by T157602 (IC50 = 20 microM). T157602 inhibited HSV growth in a one-step viral growth assay (IC90 = 3 microM), and plaque formation was completely prevented at concentrations of 25 to 50 microM T157602. Vero, human foreskin fibroblast (HFF), and Jurkat cells could be propagated in the presence of T157602 at concentrations exceeding 100 microM with no obvious cytotoxic effects, indicating that the window between antiviral activity and cellular toxicity is at least 33-fold. Seven independently derived T157602-resistant mutant viruses (four HSV type 2 and three HSV type 1) carried single base pair mutations in the UL5 that resulted in single amino acid changes in the UL5 protein. Marker rescue experiments demonstrated that the UL5 gene from T157602-resistant viruses conferred resistance to T157602-sensitive wild-type viruses. Recombinant UL5/8/52 helicase-primase complex purified from baculoviruses expressing mutant UL5 protein showed complete resistance to T157602 in the in vitro helicase assay. T157602 and its analogs represent a novel class of specific and reversible anti-HSV agents eliciting their inhibitory effects on HSV replication by interacting with the UL5 helicase.

Amino Acid Sequence↗
PubMed1975

Centrally induced hypotension by 2-(2,6-dichlorophenyl)-5,6-dihydroimidazo (2,1-b)-thiazole fumarate (compound 44-549).

The experimental compound 44-549 = 2-(2,6-dichlorophenyl)-5,6-dihydroimidazo (2,1-b)-thiazole fumarate was tested in chloralose-anaesthetized cats. Low doses of compound 44-549 showed a much more pronounced hypotensive effect when injected into the left vertebral artery than upon intravenous administration. The compound possesses central hypotensive activity, which could be blocked by yohimbine, administered via the vertebral artery. Central alpha-adrenoreceptors are probably involved. Compound 44-549 resembles clonidine both pharmacologically and chemically. It is somewhat less potent.

Animals↗
PubMed2000

Assessment of in vivo chromosomal aberrations--potency of zinc mercapto benzo thiazole.

Chromosomal aberrations are microscopically visible changes in the chromosome structure. The double-stranded breaks are the ultimate DNA lesions for chromosomal aberrations. The purpose of the present study was to evaluate the induction of chromosomal aberrations by the rubber accelerator zinc mercapto benzo thiazole (ZMBT). The experiment was designed with five groups, each composed of four Swiss albino mice. The first three groups received ZMBT at 1920, 960, and 480 microg/20 g animal. The remaining two groups were the vehicle (cotton seed oil) and positive (methyl methane sulphonate) controls. Animals were given a single dose of test and control samples by IP injection. Colchicine (20 microg/animal) was administered 90 minutes before sacrificing the animals. All the animals were sacrificed at the end of 36 h by cervical dislocation. Bone marrow preparations were made, stained with Giemsa stain, and examined for chromosomal abnormalities. The results indicated a lack of incidence of chromosomal abnormalities in the test and control groups. However, significant chromosomal abnormalities such as gaps, breaks, and translocations were observed in the positive control group. Hence, the study concluded that ZMBT at different concentrations fails to induce structural chromosomal aberrations in bone marrow cells.

Animals↗
PubMed2002

Selection of a thiazole urea-resistant variant of bovine viral diarrhoea virus that maps to the RNA-dependent RNA polymerase.

By passing wild type bovine viral diarrhoea virus (BVDV) in increasing concentrations of DPC-A69280-29, a thiazole urea class compound that inhibits BVDV replication, we were able to select several variants of BVDV that exhibited decreased susceptibility to this compound. When the non-structural genes of these variants were sequenced and compared with wild type, only one change was common to all the variants that also exhibited resistance to DPC-A69280-29 (>10-fold increase in IC50). This change was a T-to-A transversion at position 11198 of the BVDV genome, which would cause a predicted substitution of isoleucine for phenylalanine at amino acid 78 of the RNA-dependent RNA polymerase (RdRp). This substitution would occur in a region of the BVDV RdRp which has been proposed to be important for the formation of the RdRp homodimer that is essential for the activity of the enzyme. However, since DPC-69280-29 inhibits BVDV replication by interfering with the initiation of viral RNA synthesis, we discuss the possibility that this region of the BVDV RdRp also may play a role in the initiation process. Furthermore, since this region is located fairly close to the template RNA, we also propose that the role it plays may involve either template selection, stabilization or processivity.

Animals↗
PubMed2001

Synthesis of N-substituted 4,6-dioxo-imidazo[3,4-c] thiazoles and their analgesic activity in mice.

A new series of N-substituted dioxo-imidazo[3,4-c]thiazoles have been prepared and evaluated for their analgesic activity. The structures of these new derivatives were confirmed by lR, 1H NMR and 13C NMR spectra, and by elemental analysis. When administered intraperitoneally to mice all derivatives were devoid of any toxic effect, even at the high dose of 800 mg kg(-1). In the phenylbenzoquinone-induced abdominal constriction test in mice, eight of the nine synthesized compounds exhibited significant antinociceptive properties with ED50 values (50% effective dose) ranging from 46.7 to 104.7 mg kg(-1) intraperitoneally. Further investigation demonstrated that analgesic activity of the most effective derivatives 5e and 5f partly involved opioidergic and/or noradrenergic pathways.

Analgesics↗
PubMed1993

Diagnosis of drug allergy by the lymphocyte stimulation test with the MTT [3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay.

The lymphocyte stimulation test (LST) is one of the most useful laboratory tests for the identification of allergy to a specific drug. The present study was conducted to examine utility of the LST using the [3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) assay as a method for diagnosing drug allergy. The basic experimental conditions for the MTT assay were determined by using CTLL cells from human T-lymphoma, dependent on IL-2, and human peripheral blood lymphocytes. The amount of MTT needed was 0.5 mg per well and the peak maximum of MTT formazan was close to 565 nm. The blastogenesis of the lymphocytes was expressed as a Stimulation Index (SI). The value of the SI was almost constant at cell numbers ranging from 5 x 10(5) to 1 x 10(6) cells/ml. The SI of some drugs using normal peripheral blood lymphocytes was less than 1.3. We used the MTT assay in the LST to examine the allergenicity of 83 drugs which were used in 43 cases of suspected drug-induced hepatitis. The range of SI was 0.92-2.02. An SI of 1.2 or more was seen in 62.8% of cases, 1.3 or more in 51.2% of cases, and 1.4 or more in 41.9% of cases. There were 26 drugs with SI greater than 1.3. Seven of these were antibiotics, while the rest included antihypertensives, analgesics, psychotropics, antiallergics and antiepileptics. This method is extremely well suited for the diagnosis of drug allergy in a clinical situation. The greatest benefit of the MTT assay is that the complete test procedures can be carried out in a general laboratory.

Adult↗
PubMed1991

Synthesis and platelet aggregation inhibitory activity of diphenylazole derivatives. I. Thiazole and imidazole derivatives.

Diphenylimidazole and diphenylthiazole derivatives were synthesized and tested as inhibitors of platelet aggregation in in vitro experiments with the rabbit. Diphenylthiazole derivatives (10) were more potent than diphenylimidazole derivatives (4) in inhibiting arachidonic acid-induced platelet aggregation of rabbit platelet-rich plasma. Two diphenylimidazole and eight diphenylthiazole derivatives were evaluated for ex vivo arachidonic acid and collagen-induced platelet aggregation inhibitory activity using guinea pigs. In these compounds, 4,5-bis(4-methoxyphenyl)-2-(1,5-dimethyl-2-pyrrolyl)thiazole (10n) showed strong activity in vitro and ex vivo. The ex vivo activity of 10n was 200 times stronger than that of aspirin. The mechanism of the activity of 10n was the inhibition of cyclo-oxygenase.

Animals↗
PubMed1993

Synthesis and antithyroid activity of pyridine, pyrimidine and pyrazine derivatives of thiazole-2-thiol and 2-thiazoline-2-thiol.

A series of compounds was synthesized by linking various derivatives of pyridine, pyrimidine or pyrazine to thiazole-2-thiol or to its partially hydrogenated derivative 2-thiazoline-2-thiol. The reactions of the compounds with molecular iodine and lactoperoxidase were examined in vitro. Their antithyroid activity was also examined in vivo in the rat. T4 and TSH levels were determined, and the thyroid gland was examined histologically. 2-(3-Hydroxy-2-pyridyl)-2-thiothiazoline had the highest antithyroid activity of the compounds tested (Kc = 14931.mol(-1),IC(50)0.65 x 10(-4) M, activity of thyroid gland).

Animals↗
PubMed1995

Synthesis and pharmacological activities of novel bicyclic thiazoline derivatives as hepatoprotective agents II. (7-Alkoxycarbonyl-2,3,5,6-tetrahydropyrrolo[2,1-b]thiazol-3-ylidend) acetamid derivatives.

A series of exomethylenic bicyclic thiazoline derivatives (3a--i) was synthesized and evaluated for hepatoprotective activity against galactosamine-induced and monoclonal antibody-induced acute liver injuries in rats. The structure-activity relationships were investigated. Among the compounds synthesized, N-methyl-(7-isopropoxy-carbonyl-6,6-dimethyl-2,3,5,6- tetrahydropyrrolo[2,1-b]thiazol-3-ylidene)acetamide (3i) exhibited the most potent hepatoprotective activity. This compound suppressed galactosamine-induced hepatic injury at 100 mg/kg by oral administration and further prevented monoclonal antibody-induced hepatic injury at 30 mg/kg by intraperitoneal injection, as judged from the changes in serum transaminase activities.

Animals↗
PubMed2005

Synthesis and biological activities of 4-phenyl-5-pyridyl-1,3-thiazole derivatives as p38 MAP kinase inhibitors.

A novel series of 4-phenyl-5-pyridyl-1,3-thiazole analogues possessing potent in vitro inhibitory activity against p38 mitogen-activated protein kinase and the release of tumor necrosis factor-alpha (TNF-alpha) from human monocytic THP-1 cells stimulated by lipopolysaccharide has been identified. Subsequent structure-activity relationship (SAR) studies and optimization for absorption, distribution, metabolism, and elimination (ADME) profiles led to the identification of compounds 7 g and 10b as orally active lead candidates that block the in vivo production of proinflammatory cytokine (TNF-alpha). In pharmacokinetic studies, compound 10b showed good oral administration in mice and demonstrated significant in vivo anti-inflammatory activity in an anti-collagen monoclonal antibody-induced arthritis mouse model (minimum effective dose (MED)=30 mg/kg). Further elucidation of this class of compounds may provide novel anti-inflammatory agents, such as anti-rheumatoid arthritis drugs.

Animals↗
PubMed1989

Immunomodulatory activity of the newly synthesized compound TOK-8801 (N-(2-phenylethyl)-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2- carboxamide).

The in vitro and in vivo effects of the newly synthesized compound TOK-8801 (N-(2-phenylethyl)-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b] thiazole-2-carboxamide) on immune responses were investigated in comparison with that of levamisole (LMS). TOK-8801 enhanced the anti-sheep red blood cells (SRBC) plaque forming cells (PFC) response and mitogen-induced proliferative responses in murine splenocytes and thymocytes in vitro at concentrations of 10(-7)-10(-5) M, while LMS augmented these responses at 10(-4) M. The stimulatory effect of TOK-8801 as well as LMS on the antibody production was eliminated by the removal of T cells. TOK-8801 (0.5 mg/kg, p.o.) suppressed the in vivo generation of anti-SRBC PFC in normal mice, but the compound restored the depressed antibody production in restraint-stress mice which was mainly caused by helper T cell defects. From these results, TOK-8801 was shown to have an immunomodulatory activity in the antibody production.

Adjuvants, Immunologic↗
PubMedDate not supplied

Mammalian pheromone studies, VII. Identification of thiazole derivatives in the preorbital gland secretions of the grey duiker, Sylvicapra grimmia, and the red duiker, Cephalophus natalensis.

2-Isobutyl-1,3-thiazole and its 4,5-dihydro derivative were identified in the preorbital gland secretions of the grey duiker, Sylvicapra grimmia, and the red duiker, Cephalophus natalensis, but are absent from the preorbital secretion of the blue duiker, C. monticola. These two compounds which are present in high, but varying concentrations in the secretions of male grey duikers, are present in low concentrations in the secretions of females. This seems to be the only consistent significant difference between the secretions of male and female grey duikers and together with the fact that only males mark out their territories, was construed as evidence in favour of these two compounds playing a significant role in the territorial behaviour of male grey duikers.

Animals↗