Thiazole Compounds Research Articles

ChemInform Abstract: Nitrogen Heterocycles as Potential Monoamine Oxidase Inhibitors: Synthetic Aspects

AbstractReview: 73 refs.

Anti-biofilm activity and synergism of novel thiazole compounds with glycopeptide antibiotics against multidrug-resistant staphylococci.

Methicillin-resistant Staphylococcus aureus (MRSA) infections are a leading cause of death among all fatalities caused by antibiotic-resistant bacteria. With the rise of increasing resistance to current antibiotics, new antimicrobials and treatment strategies are urgently needed. Thiazole compounds have been shown to possess potent antimicrobial activity. A lead thiazole 1 and a potent derivative 2 were synthesized and their activity in combination with glycopeptide antibiotics was determined against an array of MRSA and vancomycin-resistant S. aureus (VRSA) clinical isolates. In addition, the anti-biofilm activity of the novel thiazoles was investigated against S. epidermidis. Compound 2 behaved synergistically with vancomycin against MRSA and was able to resensitize VRSA to vancomycin, reducing its MIC by 512-fold in two strains. In addition, both thiazole compounds were superior to vancomycin in significantly reducing S. epidermidis biofilm mass. Collectively, the results obtained demonstrate that compounds 1 and 2 possess potent antimicrobial activity alone or in combination with vancomycin against multidrug-resistant staphylococci and show potential for use in disrupting staphylococcal biofilm.

Synthesis and antifilarial activity of chalcone–thiazole derivatives against a human lymphatic filarial parasite, Brugia malayi

Here we report the synthesis of novel chalcone–thiazole compounds and their antifilarial activity. The antifilarial properties of these hybrids were assessed against microfilariae as well as adult worms of Brugia malayi. Among all the synthesized compounds, only two compounds, namely 4g and 4n were identified to be promising in vitro. These active compounds were tested in B. malayi-jird (Meriones unguiculatus) and B. malayi–Mastomys coucha models. Compound 4n showed 100% embryostatic effect and 49% macrofilaricidal in jirds and M. coucha models, respectively. This study provides a new structural clue for the development of novel antifilarial lead molecules.

Bifunctional ethyl 2-amino-4-methylthiazole-5-carboxylate derivatives: Synthesis and in vitro biological evaluation as antimicrobial and anticancer agents

Thirty thiazole compounds bearing chemotherapeutically-active pharmacophores were synthesized and evaluated for their preliminary in vitro antimicrobial and anticancer activities. Nineteen compounds displayed obvious antibacterial potential, with special bactericidal activity against Gram positive bacteria, whereas, nine analogs showed moderate to weak antifungal activity against Candida albicans. The analog 12f proved to be the most active antimicrobial member identified in this study being comparable to ampicillin and gentamicin sulfate against Staphylococcus aureus and Bacillus subtilis, together with a moderate antifungal activity. Additionally, nine derivatives were tested for their preliminary in vitro anticancer activity according to the current one-dose protocol of the NCI. Compound 9b revealed a broad spectrum of anticancer activity against 29 out of the tested 60 subpanel tumor cell lines. Collectively, compounds 4, 9b, 10b and 12f could be considered as promising dual anticancer antibiotics.

Abstract B265: Targeting Wnt signaling: Discovery and characterization of novel thiazole-based Traf2- and NCK-interacting kinase (TNIK) inhibitors.

Abstract Introduction: Aberrant activation of Wnt pathway is a major force driving colorectal carcinogenesis, and therefore the Wnt pathway has been thought of as an attractive anticancer drug target. However, its complexity has made it difficult to find druggable targets in the Wnt pathway. Recently, we reported Traf2- and NCK-interacting kinase (TNIK) plays important roles in the Wnt signaling pathway by making a complex with beta-catenin and T-cell factor-4 (TCF4) in a nucleus. We also found that TNIK is activated in human colorectal cancer cell lines, and proliferations of those cells are highly dependent upon the expression and catalytic activity of TNIK. Therefore inhibitors of TNIK may represent a promising therapeutic approach for treating colorectal cancer. Here we describe a discovery and characterization of a novel TNIK inhibitor. Methods: To identify compounds that inhibit TNIK acitivity, we have produced a recombinant catalytic domain of human TNIK, and developed a high throughput screening (HTS) assay system using a peptide substrate. TCF/LEF reporter gene assay using HEK293 was established to validate hit compounds. To study the effects of TNIK inhbitors on the Wnt signal pathway, Wnt target genes were analyzed by RT-PCR and Western blotting. The selected compounds were subjected to a kinase selectivity panel assay. Results: By performing a high throughput screening campaigns of our 10K kinase-focused compound library against a recombinant human TNIK, we identified a series of novel thiazole compounds as a potent inhibitor of TNIK. Hit compound, NCB-0001 exhibited potent inhibitory activity for TNIK with an IC50 value of 8.6 nM. After subsequent optimization, N1662 was identified as a lead compound having a strong anti-proliferative activity in colorectal cancer cell lines. N1662 inhibited tumor growth in a mouse xenograft model of colorectal cancer. Further optimization led to compound N5355 that showed good TNIK enzyme inhibition and potent Wnt signal inhibition in the TCF reporter gene assay, as well as down-regulation of Wnt target genes. N5355 showed excellent kinase selectivity against a panel of 311 kinases. Detailed results will be presented in the conference. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B265. Citation Format: Yuko Uno, Hideki Moriyama, Shigeki Kashimoto, Yusuke Kawase, Miki Shitashige, Masaaki Sawa, Tesshi Yamada. Targeting Wnt signaling: Discovery and characterization of novel thiazole-based Traf2- and NCK-interacting kinase (TNIK) inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B265.

Evaluation of the Anti-Schistosoma mansoni Activity of Thiosemicarbazones and Thiazoles

Schistosomiasis is a chronic and debilitating disease caused by a trematode of the genus Schistosoma and affects over 207 million people. Chemotherapy is the only immediate recourse for minimizing the prevalence of this disease and involves predominately the administration of a single drug, praziquantel (PZQ). Although PZQ has proven efficacy, there is a recognized need to develop new drugs as schistosomicides since studies have shown that repeated use of this drug in areas of endemicity may cause a temporary reduction in susceptibility in isolates of Schistosoma mansoni. Hydrazones, thiosemicarbazones, phthalimides, and thiazoles are thus regarded as privileged structures used for a broad spectrum of activities and are potential candidates for sources of new drug prototypes. The present study determined the in vitro schistosomicidal activity of 10 molecules containing these structures. During the assays, parameters such motility and mortality, oviposition, morphological changes in the tegument, cytotoxicity, and immunomodulatory activity caused by these compounds were evaluated. The results showed that compounds formed of thiazole and phthalimide led to higher mortality of worms, with a significant decline in motility, inhibition of pairing and oviposition, and a mortality rate of 100% starting from 144 h of exposure. These compounds also stimulated the production of nitric oxide and tumor necrosis factor alpha (TNF-α), thereby demonstrating the presence of immunomodulatory activity. The phthalyl thiazole LpQM-45 caused significant ultrastructural alterations, with destruction of the tegument in both male and female worms. According to the present study, phthalyl thiazole compounds possess antischistosomal activities and should form the basis for future experimental and clinical trials.

Hit-to-lead optimization of 2-(1H-pyrazol-1-yl)-thiazole derivatives as a novel class of EP1 receptor antagonists

We describe a medicinal chemistry approach to generate a series of 2-(1H-pyrazol-1-yl)thiazole compounds that act as selective EP1 receptor antagonists. The obtained results suggest that compound 12 provides the best EP1 receptor antagonist activity and demonstrates good oral pharmacokinetics.

Synthesis and biological evaluation of some novel thiazole compounds as potential anti-inflammatory agents

In the present investigation, furo[2,3-d]thiazol-5(2H)-one 5 was obtained from reaction of thiosemicarbazone derivative 2 with diethyl acetylene dicarboxylate. A series of newly synthesized 2-(hydrazinyl)thiazol-4(5H)-one 6, 7 &8 and 2-(4-(substituted)-thiazol-2-yl)hydrazono derivatives 9a, b &10 were synthesized from treatment of thiosemicarbazone derivative 2 with appropriate α-halogenated compounds. Also, a one pot synthesis of thiazole derivatives 13 &15 was achieved from three components reaction of hydrazone derivative 11 with phenyl isothiocyanate and α-halogenated compounds catalyzed by DMF/KOH. 4-(4-Morpholino phenyl) thiazol-2-amino 17 was obtained via the reaction of acetophenone derivative 1 with thiourea in presence of iodine. The reactivity of 2-aminothiazole 17 toward some electrophilic reagents was investigated. The structure of the newly compounds was confirmed on the basis of elemental analysis and spectral data. The antibacterial activity towards two Gram negative (Proteus mirabilis &Serratia marcesens) and two Gram positive (Staphylococcus aureus &Bacillus cereus) bacteria was investigated. The anti-inflammatory activity was also investigated and the inhibition of the carrageenin-induced oedema by these compounds was established.

New anti-inflammatory thiazolyl-carbonyl-thiosemicarbazides and thiazolyl-azoles with antioxidant properties as potential iNOS inhibitors

The objective of this study was to investigate the anti-inflammatory and antioxidant activity of new thiazolyl-carbonyl-thiosemicarbazides and thiazolyl-azole derivatives as potential iNOS inhibitors. The in vivo anti-inflammatory effects of the new thiazole compounds were studied in a turpentine oil induced inflammation model. Their anti-inflammatory activity was assessed by evaluating the acute phase bone marrow response, phagocytes' activity, NO synthesis and antioxidant capacity. The new thiazole compounds have anti-inflammatory effects by lowering bone marrow acute phase response and oxidative stress. The best anti-inflammatory and antioxidant effect was found for thiazolyl-carbonyl-thiosemicarbazides Th-1-8, thiazolyl-1,3,4-oxadiazole Th-20 and thiazolyl-1,3,4-thiadiazole Th-21. Virtual screening of thiazole derivatives against the oxygenase domain of chain A from 2Y37 revealed that all twenty-two compounds bind the active site of inducible nitric oxide synthase (iNOS). Based on the virtual screening and on the results obtained above, the activity may be due to their capacity to reduce the NO synthesis by blocking the bind of L-Arg in the active site of iNOS, the compounds binding the synthase by hydrogen bonds between the NH (2 and/or 4) of thiosemicarbazide fragment (Th-2-8) or N2/N3 from azole cycles and by the thiol function (Th-9-22).

Novel Conformationally Constrained Analogues of Agomelatine as New Melatoninergic Ligands

Novel conformationally restricted analogues of agomelatine were synthesized and pharmacologically evaluated at MT1 and MT2 melatoninergic receptors. Replacement of the N-acetyl side chain of agomelatine by oxathiadiazole-2-oxide (compound 3), oxadiazole-5(4H)-one (compound 4), tetrazole (compound 5), oxazolidinone (compound 7a), pyrrolidinone (compound 7b), imidazolidinedione (compound 12), thiazole (compounds 13 and 14) and isoxazole moieties (compound 15) led to a decrease of the melatoninergic binding affinities, particularly at MT1. Compounds 7a and 7b exhibiting nanomolar affinity towards the MT2 receptors subtypes have shown the most interesting pharmacological results of this series with the appearance of a weak MT2-selectivity.

噻唑类化合物应用研究新进展

Thiazole ring is an important five-member aromatic heterocycle with nitrogen and sulfur atoms. This special structure of thiazole ring endows its derivatives to exhibit wide potential application in chemical, pharmaceutical, biological and material scicences and so on, which show great development value and attract increasingly special attention. A large number of researches have been focusing on thiazole compounds, the progress have been rapidly developing, and become one of highly active topics in recent years. Combining with authors’ researches and referring to other works from literatures in recent five years, this work systematically reviewed the recent advances of the whole range of thiazole compounds in medicinal agents, agrochemicals, materials, biological stains and supramolecular chemistry.

Biological and Anti-inflammatory Evaluation of Two Thiazole Compounds in RAW Cell Line: Potential Cyclooxygenase-2 Specific Inhibitors

The anti-inflammatory effect of two new thiazoles derivatives CX-32 (N-[4-(4-hydroxy-3-methoxyphenyl)-1,3-thiazol-2-yl]acetamide) and CX-35 (4-(2-amino-1,3-thiazol-4-yl)-2-methoxyphenol), was investigated in LPS-stimulated RAW 264.7 cell line. Synthesis, structure analysis and purity of these compounds were evaluated by high performance liquid chromatography, H1 NMR, and C13 NMR. Assessment of CX-32 and CX-35 inhibitory effect on cyclooxygenase-2 (COX-2) activity was achieved by incubating LPS-activated RAW cells with 25 μM, 50 μM or 100 μM of CX-32 or CX-35 respectively. Levels of secreted PGE2 were evaluated by enzyme immunoassay (EIA) and levels of COX-2 protein were measured by western blot. Finally, cell viability experiments were undertaken to assess the toxicity of each compound. Treatment of LPS-activated RAW cells with 25 μM, 50 μM, or 100 μM of CX-35 or CX-32 respectively, prevented the production of prostaglandins, but was without effect on COX-2 protein levels. Moreover, CX-35 and CX-32 reduced PGE2 production to levels comparable to those obtained in LPS-activated RAW cells incubated with the selective COX-2 inhibitor NS 398. Furthermore, both CX-32 and CX-35 showed no toxic effects, since viability of non-treated Hela cells was similar to Hela cells incubated with either CX-35 or CX-32. Our data demonstrated that CX-32 and CX-35 significantly blocked prostaglandin production induced during inflammatory cellular stress, possibly acting through specific COX-2 inhibition; confirmation of this hypothesis requires further investigation.

Synthesis and Biological Evaluation of N‐aryl‐4‐aryl‐1,3‐Thiazole‐2‐Amine Derivatives as Direct 5‐Lipoxygenase Inhibitors

Biological evaluation of N-aryl-4-aryl-1,3-thiazole-2-amine derivatives was examined for anti-inflammatory activity in in vitro and in vivo assays. The thiazole compounds showed direct inhibition of 5-lipoxygenase (LOX) that is a key enzyme of leukotrienes synthesis and involved in the inflammation-related diseases, including asthma and rheumatoid arthritis. To optimize biological activity, we synthesized 1,3-thiazole-2-amine derivatives and investigated for structure and activity relationship. Especially, N-(3,5-dimethylphenyl)-4-(4-chlorophenyl)-1,3-thiazole-2-amine was shown to have a potent anti-inflammatory activity as a 5-LOX inhibitor.

Classification of novel thiazole compounds for sensitizing Ru–polypyridine complexes for artificial light harvesting

A systematic study of the Förster resonance energy transfer (FRET) efficiency between thiazole dyes and a ruthenium–polypyridine complex is presented. While ruthenium–polypyridines are conventionally used in artificial light harvesting systems as primary electron donors, their application suffers from rather low extinction coefficients in the visible spectral range and an absorption gap between the ππ ⁎ transitions of the ligands and the MLCT transitions. In this paper it is shown how thiazoles might help to circumvent theses issues. The absorption and emission spectra of the thiazole can be synthetically adjusted to fall into the absorption gap of the Ru dye and to efficiently overlap with the 1MLCT absorption of the complex, respectively. Thereby, the thiazoles might serve as antenna structures to funnel energy to the Ru-polypyridine unit, which finally can act as a photoactivated primary electron donor. Systematic investigations of the Förster radii of representative thiazole Ru-polypyridine dye pairs corroborate this potential quantitatively.

ChemInform Abstract: Chemistry and Heterocyclization of Dithiobiurea and Thioureidoalkylthiourea

AbstractReview: 104 refs.

Chemistry and heterocyclization of dithiobiurea and thioureidoalkylthiourea

Abstract magnified imageThis review summarizes published data on the behavior and reactions of dithiobiurea and thioureidoalkylthiourea derivatives, which lead to the formation of heterocyclic systems, including methods of preparation in addition to synthesis of imidazolidine, thiazole, thioazolidine, triazolidine, thiadiazine, and spiro compounds. J. Heterocyclic Chem., (2010).

Discovery of pyrazolthiazoles as novel and potent inhibitors of bacterial gyrase

Bacterial DNA gyrase is an attractive target for the investigation of new antibacterial agents. Inhibitors of the GyrB subunit, which contains the ATP-binding site, are described in this communication. Novel, substituted 5-(1 H-pyrazol-3-yl)thiazole compounds were identified as inhibitors of bacterial gyrase. Structure-guided optimization led to greater enzymatic potency and moderate antibacterial potency. Data are presented for the demonstration of selective enzyme inhibition of Escherichia coli GyrB over Staphlococcus aureus GyrB.

Rapid and efficient synthesis of stable isotope labeled [13C4, D4]‐5‐(hydroxymethyl)thiazole: versatile building block for biologically interesting compounds

Abstract5‐(Hydroxymethyl)thiazole is a versatile building block for many biologically active compounds. A rapid and efficient four‐step synthesis of its stable isotope labeled counterpart with four 13C and four deuterium atoms in 32% total yield is reported. Condensation of [13C2]‐chloro acetic acid with [13C]‐thiourea gave [13C3]‐2,4‐thiazolidinedione. Reaction of [13C3]‐2,4‐thiazolidinedione with phosphorus oxybromide and [13C, D]‐DMF (Me2N13CDO) produced [13C4, D]‐2,4‐dibromo‐thiazole‐5‐carboxaldehyde. The resultant aldehyde was then reduced by sodium borodeuteride to [13C4, D2]‐(2,4‐dibromo‐thiazol‐5‐yl)‐methanol. Catalytic deuteration of [13C4, D2]‐(2,4‐dibromo‐thiazol‐5‐yl)‐methanol by palladium black with deuterium gas at 1 atm pressure and room temperature produced completely de‐brominated [13C4, D4]‐5‐(hydroxymethyl)thiazole. De‐bromination of the 2,4‐dibromothiazole by the catalysis of palladium black provides a simple and convenient synthetic method for the stable isotope labeled and potentially radioactive isotope labeled thiazole compounds. Copyright © 2009 John Wiley & Sons, Ltd.

Design, Synthesis, and Biological Evaluation of Antiviral Agents Targeting Flavivirus Envelope Proteins

Flavivirus envelope proteins (E proteins) have been shown to play a pivotal role in virus assembly, morphogenesis, and infection of host cells. Inhibition of flavivirus infection of a host cell by means of a small molecule envelope protein antagonist is an attractive strategy for the development of antiviral agents. Virtual screening of the NCI chemical database using the dengue virus envelope protein structure revealed several hypothetical hit compounds. Bioassay results identified a class of thiazole compounds with antiviral potency in cell-based assays. Modification of these lead compounds led to a series of analogues with improved antiviral activity and decreased cytotoxicity. The most active compounds 11 and 36 were effective in the low micromolar concentration range in a cellular assay system.

Some new thiazolyl thiazolidinedione derivatives as aldose reductase inhibitors

In diabetes, increased flux through the polyol pathway has been implicated in the development of diabetic complications such as cataract, retinopathy, neuropathy, and nephropathy. Aldose reductase (AR) appears to be the key factor in the reduction of glucose to sorbitol. Aldose reductase inhibitors have been found to prevent sorbitol accumulation in tissues. A series of thiazolyl-2,4-thiazolidinediones was prepared by Knoevenagel reaction of substituted benzyl-2,4-thiazolidinediones with chlorothiazolecarbaldehydes and were evaluated for their ability to inhibit rat kidney AR by an in vitro spectrophotometric assay. Results showed that compounds containing piperidine at the C-2 position of thiazole ring showed better inhibitory activity than thiazole compounds having 4-chlorobenzylsulfanyl at the same position.