Thiazole Ring System Research Articles

Synthesis of various dihydro‐thiazole and selenazole heterocycles

We prepared numerous thiazole derivatives from push‐pull alkenes such as nitroenamines, enaminoester, and enaminonitrils in a two‐step reaction with thiocyanate ion. The first step was the formation of the thiocyanate‐substituted push‐pull alkene from an iodine‐containing intermediary. We demonstrated this sequence through the preparation and identification of the iodine‐substituted enamines. In the second step, thiazole ring closure took place in methanol, at room temperature. The imino group of the condensed thiazole ring systems was successfully acylated. The same reaction sequence with potassium selenocyanate resulted in two selenocyanate and a selenazole heterocyclic derivatives. The mechanism of the reaction with thiocyanate ion and the heterocycle formation was investigated by computational methods. We performed quantum chemical calculations, involving both the thermodynamic and the kinetic aspects of the ring closure reaction.

Synthesis of tetrazole hybridized with thiazole, thiophene or thiadiazole derivatives, molecular modelling and antimicrobial activity

BackgroundTetrazole-based derivatives and their electronic structures have displayed interesting antimicrobial activity. MethodsThe tetrazole-based hybrids linked with thiazole, thiophene and thiadiazole ring systems have been synthesized through various chemical reactions. The computational method DFT/B3LYP has been utilized to calculate their electronic properties. The antimicrobial effectiveness was investigated against representative bacterial and fungal strains. Additionally, the synthesized derivatives binding interaction was stimulated by docking program against PDB ID: 4URO as a model of the ATP binding domain of S. aureus DNA Gyrase subunit B. ResultsThe structures of the synthesized tetrazole-based derivatives were confirmed by IR, NMR, and Mass spectroscopic data. The DFT/B3LYP method showed that the thiadiazole derivatives 9a–c had lower ΔEH-L than the thiophenes 7a–c and thiazoles 5a–c. The hybrids 5b, 5c, and 7b exhibited proper antibacterial activity against Gram’s +ve bacterial strains (S. aureus and S. pneumonia), while 9a displayed potent activity towards Gram’s -ve bacterial strains (S. typhimurium and E. coli). Meanwhile, derivatives 5a-b, 7a, 7c, and 9c showed good effectiveness towards fungal strain (C. albicans). ConclusionThe study provides valuable tetrazole core-linked heterocyclic rings and opens the door to further research on their electrical characteristics and applications. Tetrazoles and thiazoles have antibacterial properties in pharmacological frameworks, making these hybrids potential lead molecules for drug development. The conclusion summarizes the data and suggests that the synthesized chemicals' interaction with a particular protein domain suggests focused biological activity.

Thiazolobenzamide-Naphthalene Hybrids as Potent Anticancer agents compared to Doxorubicin: Design, Synthesis, SAR, In-silico and Toxicity Analysis.

In order to determine whether thiazolobenzamide molecules connected to naphthalene could inhibit the growth of three different tumor cell lines, MCF7 (breast carcinoma), A549 (pulmonary carcinoma), and DU145 (prostatic adenocarcinoma) a novel series of ten molecules, designated TA 1-10, was designed, synthesized, and tested. Among these compounds, TA7 showed promising results against cell lines, especially showing exceptional efficacy against breast cancer. Antioxidant activity tests consistently showed the best performance from the TA7 molecule. Furthermore, when a dose of 50 to 500 mg/kg of the total mass of rats is given, the most effective chemical, TA7, did not exhibit any harmful effects during acute oral toxicity tests. The biochemical indicators (SGOT and SGPT) for hepatotoxicity associated with compound TA7 were found to be fairly similar to those of the control group. The findings from molecular docking, XP visualization, and MM-GBSA dG binding investigations are in agreement with the outcomes of in-vitro tests of antioxidant and anticancer capabilities. TA7 was the most effective compound among those that were docked; it bound free energy and had adequate properties for metabolism (biochemical processes), distribution (dispersion), absorption (assimilation), and excretion (elimination). This study found that the TA7 molecule, a thiazole ring system derivative connected to naphthalene, is to be a promising and possible anticancer agent and its efficacy may be further explored in clinical studies.

New thieno[2,3-b]pyridine-based compounds: Synthesis, molecular modelling, antibacterial and antifungal activities

New thieno[2,3-b]pyridine clubbed various thiazole ring systems were synthesized by the reaction of 2-(1-(3-amino-4,6-dimethylthieno[2,3-b]pyridin-2-yl)ethylidene)hydrazine-1-carbothioamide with chloroacetone, phenacyl chloride, and chloroacetic acid. The molecular modeling of the synthesized compounds using DFT/B3LYP methodology revealed that all have a low HOMO and LUMO energies, −4.85 - −5.52 and −2.79 - −3.62, respectively, where the compound 10 has the highest values. The targeting thienopyridine analogues with various thiazole moieties 3–10 was assessed in order to create new antimicrobial agents and compared with ampicillin, gentamicin and miconazole as reference antibacterial and antifungal drugs. Compounds 8–10 exhibited potent antimicrobial activity against Gram positive S. aureus, Gram Gram negative E. coli bacteria, and C. albicans (antifungal), with IC50 (18.9 ± 0.63––24.3 ± 0.74 µg/mL), (14.2 ± 0.41––19.5 ± 0.64 µg/mL), and (19.2 ± 0.58–––23.4 ± 0.65 µg/mL), respectively. Furthermore, Molecular docking stimulation on MOE program was applied to expect the effect and interactions of the newly thienopyridine analogues and E. coli DNA gyrase B as it expressed by PDB ID: 1AJ6.

Luminescent, highly halogenated 2-(2-hydroxyphenyl)benzothiazole derivatives and their zinc complexes

We have developed synthetic routes to new luminescent materials which are fully halogenated analogues of the zinc(II) complex of 2-(2-hydroxyphenyl)benzothiazole. 2,4-Difluoro-6-methoxybenzoyl chloride is a useful intermediate in this approach, which involves condensation with fluorinated arylamines to form the arylamide, cyclisation using P2S5, demethylation with BBr3 and halogenation to replace hydrogen atoms present on the phenolic ring. When 2-amino-1,3,4,5,6,7,8-heptafluoronaphthalene was used as the amine component the cyclisation step caused loss of F-1 in preference to F-3, and thus to the formation of the angular naphtho[2,1-d]thiazole ring system (confirmed by X-ray diffraction and NMR). The introduction of chlorine and bromine atoms at specific positions allows fine tuning of emission properties, compared with the analogous fully fluorinated materials.

Design, synthesis, in vitro and in silico studies of some novel thiazole-dihydrofuran derivatives as aromatase inhibitors

Aromatase inhibitors used against hormone-dependent breast cancer, especially in post-menopausal women, are very susceptible to the development of resistance due to their limited number and long-term use. In this study, it is aimed to obtain new aromatase inhibitors including thiazole and dihydrofuran ring systems. Synthesis of compounds (2a-2l) were performed according to literature methods. Their structures were elucidated by 1H NMR, 13C NMR and APCI-MS spectroscopic methods. MTT test was carried out to assess the cell proliferation effects of the different compounds on two different pulmonary cell lines (A549, CCD-19Lu) and mammary cell line (MCF7). According to MTT assay, it was observed that the calculated IC50 values of some compounds for the CCD-19Lu cell line were found higher than for the A549 and MCF7 cell lines. Considering the viability results, it was found that the selected compounds (2a, 2c, 2e, 2g, 2h, 2l) showed favourable safety profile and have anticancer activities. Apoptotic activities of the selected compounds were investigated by flow cytometry analysis. And were found that have apoptotic effects on cancerous cell lines. In the light of this information, the aromatase inhibition potentials of 2g and 2l compounds, which are the most active derivatives, were examined in vitro and it was determined that they showed a similar inhibition profile with letrazole. Interaction modes between aromatase enzyme and compounds 2g and 2l were investigated by docking studies. In conclusion, findings of these study indicate that compounds 2g and 2l possess significant anticancer activity.

Synthesis and Antibacterial Activity of New Imidazo[1,2-a]pyridines Festooned with Pyridine, Thiazole or Pyrazole Moiety

A series of new 6,8-dichloro-imidazo[1,2-a]pyridine derivatives incorporating pyridine, thiazole, and pyrazole ring systems was synthesized. The synthetic strategy of imidazopyridinyl-pyridine hybrids 2 and 3 involves one pot reaction of the precursor 3-acetyl-6,8-dichloro-2-methylimidazo[1,2-a] pyridine (1) with aldehydes, malononitrile, and/or ethyl cyanoacetate. Treatment of 1 with thiosemicarbazide and/or bromine followed by subsequent cyclization with ethyl bromoacetate, chloroacetone, phenacyl chloride, and/or thiourea was applied as synthetic routes for accessing the imidazopyridinyl-thiazole hybrids 5, 6, and 8–10. The reaction of 1 with dimethylformamide-dimethylacetal followed by subsequent treatment with hydrazine was employed to prepare the imidazopyridinyl-pyrazole motif 12. The antibacterial potency of these imidazopyridine hybrids has been evaluated against some model bacteria. The results indicated that the imidazopyridine-thiazole hybrids revealed remarkable antibacterial activities.

Crystal structure and Hirshfeld surface analysis of (E)-N-(4-propyl-oxybenzyl-idene)benzo[d]thia-zol-2-amine.

The title compound, C17H16N2OS, was synthesized by a condensation reaction between 2-amino benzo-thia-zole and 4-N-propoxybenzaldehyde. The benzo[d]thia-zole ring system is nearly planar (r.m.s. deviation 0.0088 Å) and makes a dihedral angle of 3.804 (12)° with the phenyl ring. The configuration about the C=N double bond is E. In the crystal structure, pairs of C-H⋯N hydrogen bonds and C-H⋯π inter-actions link the mol-ecules into inversion dimers with an R 2 2(16) ring motif. These dimers are additionally linked by weak π-π stacking inter-actions between the phenyl rings, leading to a layered arrangement parallel to (010). Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the packing arrangement are from H⋯H (47.9%) and C⋯H/H⋯C (25.6%) inter-actions.

Synthesis and antioxidant assay of new nicotinonitrile analogues clubbed thiazole, pyrazole and/or pyridine ring systems

AbstractA series of novel nicotinonitrile derivatives were synthesized by hybridization with thiazole, pyrazole, and pyridine ring systems using 4‐aminobenzohydrazide as link‐bridge. The synthetic strategy of nicotinonitrile‐thiazole analogues involves cyclization of the precursor N‐phenyl thiosemicarbazide derivative 4 with chloroacetic acid and phenacyl bromide. The reaction of hydrazide 3 with acetylacetone and/or ethyl acetoacetate was applied as a synthetic route for accessing 2‐((4‐(pyrazole‐1‐carbonyl)phenyl)amino)‐nicotinonitrile derivatives 9–10. The 2‐((4‐(4‐thiazolylidene‐pyrazole‐1‐carbonyl)‐phenyl)amino)nicotinonitriles 14–15 were obtained via a nucleophilic addition of pyrazolone 10 to phenyl isothiocyanate followed by cyclization with chloroacetone, phenacyl chloride, and/or ethyl bromoacetate. The 6‐amino‐4‐aryl‐3,5‐dicyano‐2‐oxo‐1‐(4‐substitutedbenzamido)‐pyridines 19 were synthesized by Knoevenagel condensation N′‐(2‐cyanoacetyl)‐benzohydrazide derivative 16 with substituted benzaldehydes followed by heating with malononitrile. All synthesized products were evaluated for their antioxidant potentialities using of 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulphonic acid) (ABTS) radical cation delcolorization assay. The nicotinonitrile‐thiazole hybrid 6b was found the most promising antioxidant agent with inhibition activity 86.27%.

Design and Solid-Phase Parallel Synthesis of 2,4,5-Trisubstituted Thiazole Derivatives via Cyclization Reaction with a Carbamimidothioate Linker.

Preparation of 2,4,5-trisubstituted thiazole derivatives via a new solid-phase synthetic route has been conducted in this study. The synthetic route begins with the synthesis of a core skeleton 2,4-diamino(thiazol-5-yl)-substituted phenylmethanone resin obtained through a cyclization reaction with a carbamimidothioate linker. The core skeleton was substituted with diverse building blocks such as amines, alkyl halides, and acid chlorides. The products were cleaved from the solid support via a TFA/CH2Cl2 cleavage cocktail. Overall, the strategy permits the incorporation of three points of diversity into the thiazole ring system with good overall yields ( Lee , T. ; et al. J. Comb. Chem. 2009 , 11 ( 2 ), 288 - 293 ). Finally, the library of 2,4,5-trisubstituted thiazole derivatives showed oral bioavailability through calculation of the physicochemical properties.

Drug development and bioanalytical method validation for a novel anticancer molecule, 4-(dimethylamino)-2-(p-tolylamino) thiazole-5-carbonitrile.

Hit, Lead & Candidate Discovery The thiazole ring system represents a significant building block that exists in many biologically active natural products and clinically successful anticancer drugs. Modifications of the thiazole core have been a proven and highly effective method in improving anticancer potency. We designed a novel thiazole-based molecule, 4-(dimethylamino)-2-(p-tolylamino) thiazole-5-carbonitrile, which showed potent in vitro anticancer effect against targeted Bcl-2 Jurkat cell-line quantified using 3-(4, 5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Physicochemical parameters (pKa, LogP, LogD) of the molecule have also been evaluated as a part of the drug development process. Moreover, a rapid Reverse phase-high performance liquid chromatography (RP-HPLC) bioanalytical method has been developed to quantitate the molecule in human plasma. The method has been validated following the United States Food and Drug Administration bioanalytical method validation guideline. The stability studies showed no significant instability of the analyte in respective stability conditions (6 hr autosampler, 8 hr bench top, 30 days long-term, and 3 freeze-thaw cycles). The molecule was found to be stable for 3 hr in human plasma. The molecule was shown to have high plasma protein binding affinity. It showed favorable pKa (11), Log P (3.01), Log D (2.96), and plasma protein binding (90%) values toward its further exploitation as a lead anticancer candidate molecule. The developed bioanalytical method can be used for quantifying the molecule in different pharmacokinetic, toxicokinetic, or other clinical trial samples involving human plasma during development process or in routine bioavailability and bioequivalence study after its regulatory approval.

Synthesis of highly functionalized 2-(pyrrolidin-1-yl)thiazole frameworks with interesting antibacterial and antimycobacterial activity

A versatile, facile and concise approach to access to highly substituted functionalized 2-(pyrrolidin-1-yl)thiazole ring system is accomplished. The efficient protocol proceeds by the reaction of corresponding racemic or enantiomerically enriched pyrrolidines and readily available benzoylisothiocyanate in acetonitrile followed by sequential reaction of readily available alpha-bromo ketones in acetone. The selectivity and good yield in the desired product is another important advantage of this reaction protocol. In a few cases, the resulting N-benzoylthiourea intermediate cyclizes spontaneously before reacting with the benzophenone component. Finally, a wide study of the biological scope of this new bisheterocyclic molecules is reported.

Highly efficient microwave-assisted one-pot synthesis of 4-aryl-2-aminothiazoles in aqueous medium

The thiazole ring system is one of the most important heterocycles in nature, as it represents an important structural motif of many biological compounds, including vitamin B1 (Thiamin), carboxylase and penicillin. There is, therefore, an urgent need to design rapid, efficient and environmentally benign protocols for the synthesis of thiazoles. Herein, we have developed a one-pot protocol for the synthesis of 4-aryl-2-aminothiazoles from the reaction of aromatic ketones, NBS (N-Bromosuccinimide) and thioureas under microwave irradiation at 80–85 °C in PEG (polyethylene glycol)-400 and water as a green reaction medium. The products were obtained in 84–89% yields in 28–32 min. The method has several advantages such as use of green solvent, easy work-up, excellent yield and avoiding use of lachrymatric α-haloketones.

(Z)-N′-(3-Ethyl-4-oxothiazolidin-2-ylidene)-2-[6-(4-methoxyphenyl)imidazo[2,1-b]thiazol-3-yl]acetohydrazide

The title compound, C19H19N5O3S2, crystallizes in the triclinic space group P-1, with two independent molecules (A and B) in the asymmetric unit (Z′ = 2). The imidazo[2,1-b][1,3]thiazole ring systems in molecules A and B are essentially planar (r.m.s deviations = 0.004 and 0.005 Å, respectively), with dihedral angles of 1.1 (3) and 0.8 (3)°, respectively, between the thiazole and imidazole rings. The mean planes of these ring systems make dihedral angles of 16.0 (2) and 61.9 (2)° for molecule A, and 11.8 (2) and 74.3 (2)° for molecule B, with the 1,3-thiazolidine and methoxy-substituted benzene rings, respectively. In the crystal, molecules are linked via N—H...O hydrogen bonds, forming –A–B–A–B– chains along [100]. The chains are linked by C—H...O hydrogen bonds, forming layers parallel to the ab plane.

ChemInform Abstract: Reactivity of Dehydroacetic Acid in Organic Synthesis

AbstractReview: 130 refs.

ChemInform Abstract: Synthesis of 2‐(N‐Benzoylimino)‐N‐(9,10‐dioxo‐9,10‐dihydroanthracen‐1‐yl)thiazoles.

Abstractvia cyclocondensation of thioureas (I) with in situ generated α‐bromoacetone

Synthesis of Heterocyclic Analogs of α‐aminoadipic Acid and its Esters Based on Imidazo[2,1‐b][1,3]Thiazole

A method for the preparation of heterocyclic analogs of α‐aminoadipic acid and its esters based on the imidazo[2,1‐b][1,3]thiazole ring system was developed. In this method, free‐radical bromination of ethyl 6‐methylimidazo[2,1‐b][1,3]thiazole‐5‐carboxylate with NBS afforded a versatile building block, ethyl 6‐bromomethylimidazo[2,1‐b][1,3]thiazole‐5‐carboxylate. Coupling of ethyl 6‐bromomethylimidazo[2,1‐b][1,3]thiazole‐5‐carboxylate with Schöllkopf's chiral auxiliary followed by acidic hydrolysis generated ethyl 6‐[(2S)‐2‐amino‐3‐methoxy‐3‐oxopropyl]imidazo[2,1‐b][1,3]thiazole‐5‐carboxylate. A similar procedure using diethyl (Boc‐amino)malonate yielded racemic 2‐amino‐3‐[(5‐ethoxycarbonyl)imidazo[2,1‐b][1,3]thiazol‐6‐yl]propanoic acid.

Synthesis of 2-(N-Benzoylimino)-N-(9,10-Dioxo-9,10-Dihydroanthracen-1-yl)Thiazoles

N-Aroylthioureas hold a significant promise for the synthesis of such heterocycles as imidazolidine2-thiones [1, 2], 2-aroyliminothiazolines [3-5], 1,2,4-triazoles [6], 1,3-thiazines [7], and indeno[1,2-d][1,3]thiazepines [8]. Of particular interest are 2-iminothiazolines, which are characterized by a wide range of biological properties [9-11]. For example, the thiazol-2-imine fragment is a structural fragment in muscarinic agonists, as well as antifungal, hypolipidemic, antidiabetic, anti-inflammatory, analgesic, and anti-shistosomiasis compounds [5]. Thiazoline derivatives are also used as insecticides and plant growth regulators [5]. The reaction of N,N'-disubstituted thioureas with α-bromo ketones has been described in the literature [5, 12], and it provides access to various N-substituted 2-iminothiazoles. However, 2-iminothiazoles with 9,10-dioxo9,10-dihydroanthracenyl substituents at position 3 of the heterocycle remain hitherto unknown. The pronounced biological properties of anthraquinone derivatives [13-15] motivate the search for hybrid structures that include both anthraquinone and thiazole ring systems. Based on these considerations, we treated our previously described N-benzoyl-N'-(9,10-dioxo9,10-dihydroanthracen-1-yl)thioureas 1а-е [16] with in situ generated α-bromoacetone in the presence of triethylamine and obtained the 2-(N-benzoylimino)-N-(9,10-dioxo-9,10-dihydroanthracen-1-yl)thiazoles 2а-е in 48-68% yields. The formation of 2-(N-benzoyl)imine type thiazoles through a cyclocondensation with the participation of aminoanthracene nitrogen atom was in agreement with the recently described reactions of N-arylN'-aroylthioureas with α-halo ketones [4, 12, 13]. The Н NMR spectra of the compounds 2а-е contained thiazole H-5 proton singlets at 6.89-7.01 ppm and methyl group singlets at 1.97-2.04 ppm, besides the CH signals of the aromatic rings. The formation of a thiazole ring was also clearly confirmed by the С spectra containing the characteristic С-4 singlets at 106.1-107.2 ppm, С-5 singlets at 139.3-144.9 ppm, and С-2 singlets at 168.2-169.7 ppm. The C signals of the thiazole 4-СН3 substituent were found at 13.7-14.2 ppm, which was typical for 3-aryl-2-benzoylimino-4-methyl-1,3-thiazolines [4, 5]. Thus, we have prepared new 2-(N-benzoylimino)-N-(9,10-dioxo-9,10-dihydroanthracen-1-yl)thiazoles by a novel route, starting from N-benzoyl-N'-(9,10-dioxo-9,10-dihydroanthracen-1-yl)thioureas.

Chiral 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles with anti-breast cancer properties

The synthesis and biological evaluation of 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles as anticancer agents against MCF7 breast cancer cell lines is reported. The design of the new compounds has been guided considering (3R)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole as the lead compound due to its good performance against MCF7 breast cancer cell lines (IC50 = 1.0 μM). The structural changes included the removal of the phenyl group at C-3, the replacement of this group by a 3,4,5-trimethoxyphenyl group, the removal of the methyl group at C-5 from the lead scaffold and the replacement of this group by a phenyl substituent. Overall, these studies showed that the combined presence of a phenyl group at C-3 and a methyl group at C-5 in the 1H,3H-pyrrolo[1,2-c]thiazole ring system is essential to ensure high cytotoxicty against MCF7 breast cancer cell lines. To probe whether the absolute configuration of the lead compound might affect the anticancer activity, its enantiomer was prepared and the activity against MCF7 cells was evaluated. (3S)-6,7-Bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole proved to be the most active compound so far studied, with IC50 value of 0.5 μM.

A Facile Synthesis of 5,6-Dihydro-4H-pyrrolo[3,4-d]thiazole and Other Pyrrolidine-Fused Aromatic Ring Systems via One-Step Cyclization from Diols

A Facile Synthesis of 5,6-Dihydro-4H-pyrrolo[3,4-d]thiazole and Other Pyrrolidine-Fused Aromatic Ring Systems via One-Step Cyclization from Diols