Synthesis Of Thiazoles Research Articles

Synthesis of New Thiazolidinones and Thiazoles in Indole Series

Abstract: Recent findings confirm that thiosemicarbazones and thiazoles offer a wide range of biological properties. We report here the synthesis of two series of highly functionalized thiazole-derived compounds from the reactions of various indole-derived thiosemicarbazones with diethyl acetylenedicarboxylate and 4-bromophenacyl bromide. As a result, a series of new derivatives of thiosemicarbazone, thiazolidinone, and thiazole bearing an indole moiety was synthesized and developed in good yields.

In silico Study, Molecular Docking and Synthesis of 2-Amino thiazole Derivatives using Green Chemistry Approach as Antioxidant Agent

A series of novel 2-aminothiazole derivatives were synthesized by microwave assisted method as a green chemistry approach and characterized by spectral techniques and elemental analysis. The antioxidant potential of the derivatives was determined by using molecular docking against two different oxidoreductase protein (PDB: 2CDU and 3NM8). Compounds 3a and 3d show the stronger binding affinity to the target protein. The synthesized drug was pharmacologically evaluated for the antioxidant activity using ascorbic acid as a reference drug, where compound 3a showed the highest inhibition.

Microwave-Assisted Synthesis, Molecular Docking Studies and Biological Evaluation of Novel Thiazole, Imidazole-Indole Hybrids

The present work deals with the synthesis of novel thiazole, imidazole-indole hybrids 3a-l using microwave assisted method as a green chemistry approach. The title compounds were synthesized in a good yield between 68-85%. All the synthesized structures were confirmed by FT-IR, LC-Mass, 1H NMR and 13C NMR analytical data. All the novel indole derivatives were screened for anticancer activity by MTT assay method against the MCF-7 and SKVO3 cell lines. Compound 3i (IC50 value of 26.98 μg, 36.12 μg) and 3j (IC50 value of 24.11 μg, 38.43 μg) exhibited good anticancer activity as compared to doxorubicin. Further, the synthesized compounds were also screened for antibacterial activity using agar diffusion method, where compounds 3c, 3d, 3f and 3j exhibited good antibacterial activity. Furthermore, the binding pattern and affinity of these new indole towards the active region of EGFR were studied using molecular docking studies and the results were in good agreement with the biological results.

Synthesis, biological evaluation and molecular docking of new triphenylamine-linked pyridine, thiazole and pyrazole analogues as anticancer agents

A new series of pyridine, thiazole, and pyrazole analogues were synthesized. The pyridone analogues 4a-e were synthesized by treating N-aryl-2-cyano-3-(4-(diphenylamino)phenyl)acrylamides 3a-e with malononitrile. Many 4-arylidene-thiazolidin-5-one analogues 6a-d were obtained by Knoevenagel reactions of 4-(diphenylamino)benzaldehyde (1) with their corresponding thiazolidin-5-one derivatives 5a-d. The structural elucidation of the products was proven by the collections of spectroscopic methods such as IR, 1H NMR, 13C NMR, and MS data. Their anti-cancer activity was examined against two cell lines, MDA-MB-231 (mammary carcinomas) and A-549 (lung cancer). Compared with cisplatin as a reference standard drug, 6-amino-4-(4-(diphenylamino)phenyl)-2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3,5-dicarbonitrile (4b) and 6-amino-4-(4-(diphenylamino)phenyl)-1-(4-nitrophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (4e) exhibited better efficiency against the A-549 cell line, with IC50 = 0.00803 and 0.0095 μM, respectively. Also, these compounds 4b and 4e showed the most potency among the examined compounds against MDA-MB-231 with IC50 = 0.0103 and 0.0147 μM, respectively. The newly synthesized compounds were docked inside the active sites of the selected proteins and were found to demonstrate proper binding. 2-Cyano-2-(4,4-(diphenylamino)benzylidene)-5-oxo-3-phenylthiazolidin-2-ylidene)-N-(p-tolyl)acetamide (6c) offered the highest binding affinity (− 8.1868 kcal/mol) when docked into (PDB ID:2ITO), in addition to 2-cyano-N-(4-(diethylamino)phenyl)-2-(4-(4-(diphenylamino)benzylidene)-5-oxo-3-phenylthiazolidin-2-ylidene)acetamide (6a) gave the highest energy score (− 9.3507 kcal/mol) with (PDB ID:2A4L).

Synthesis and biological evaluation of thiazole and thiadiazole derivatives as potential anticancer agents

A new series of 4-methyl-2-{2-[(aryl)methylidene]hydrazinyl}-1,3-thiazole (2a-i), N-(4-acetyl-5-aryl)4,5-dihydro-1,3,4-thiadiazol-2-yl)acetamides (3a-b) and N-(5-(4-(substituted phenyl)-1,3,4-thiadiazol-2-yl)acetamides (3c-i) were synthesized by the reaction of 2-((aryl)methylene)hydrazine-1-carbothioamides (1a-i) and acetic anhydride or chloroacetone. The cytotoxic activities of the products were evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay against Hela cervical cancer, MCF-7 breast carcinoma and HT-29 colorectal cancer cell lines. Thiazole based compounds 2a, 2b, 2f and 2i, bearing 4-bromothiophen-2-yl, naphthalen-2-yl, 2,5-difluorophenyl and 4-(trifluoromethoxy)phenyl moieties, respectively; also N-(4-acetyl-5-(naphthalen-2-yl)-4,5-dihydro-1,3,4-thiadiazol-2-yl)acetamide (3b) and N-(5-(2,6-difluorophenyl)-1,3,4-thiadiazol-2-yl)acetamide (3d) exhibited significant anticancer activity against three cancer cell lines. Moreover, these active compounds were further evaluated by apoptotic protein levels. The results showed that these thiazole and thiadiazole compounds induced apoptosis of cancer cells.

Synthesis and Anticancer Evaluation of New Thiazole and Thiadiazole Derivatives Bearing Acetanilide Moiety.

New thiazole and thiadiazole derivatives bound to the acetanilide moiety were synthesized and evaluated for their cytotoxic activity. The precursor N-(4-acetamidophenyl)-N'-phenylthiourea (2) was cyclocondensed with ethyl bromoacetate to afford a mixture of the two isomers, 2-(4-acetamidophenylimino)-3-phenylthiazolidin-4-one (3a, 23%) and 3-(4-acetamidophenyl)-2-phenyliminothiazolidin-4-one (3b, 71%). The Knoevenagel reaction of 3b with various aromatic aldehydes afforded 5-arylidene-2-phenyliminothiazolidin-4-one derivatives 5a-5e. Intramolecular cyclization of thiourea scaffold 2 with chloroacetone and/or phenacyl chloride gave the conforming thiazole derivatives 6a and 6b. A new series of thiadiazole derivatives 9a-9c and 11a-11c was synthesized by the reaction of N-(4-acetamidophenyl)-N'-phenylthiourea (2) with selected derivatives of hydrazonoyl halide in ethanol and triethylamine. The structures of the synthesized thiazole and thiadiazole compounds were elucidated by their compatible spectral data. The cytotoxic activity of the synthesized thiazole and thiadiazole derivatives was screened against four human cancer cell lines and showed promising results. Thiazolidin-4-one compound 5d showed the strongest cytotoxic effects on hepatocellular carcinoma (IC50 = 8.80 ± 0.31 μg/mL), mammary gland breast cancer (IC50 = 7.22 ± 0.65 μg/mL) and colorectal carcinoma (IC50 = 9.35 ± 0.61 μg/mL) cell lines.

Recent Development in the Synthesis of Thiazoles.

Thiazole-containing compounds are widely found in natural products as well as synthetic sources. Many thiazole-based compounds possess a broad spectrum of bioactivities, and some of them are well-known drugs in the markets. The use of thiazole derivatives in other fields such as organic materials, cosmetics, and organic synthesis has also been widely reported. Due to a wide range of applicability, the synthesis of thiazole-containing compounds has attracted extensive interest from chemists, and many studies in the synthesis of thiazole skeleton have been reported recently. This review article will discuss recent studies in the synthesis of thiazoles (from2012). Besides the well-established Hantzsch thiazole synthesis, a large number of novel methods have been developed for the synthesis of thiazole derivatives. In most cases, reaction mechanisms have also been described. The synthesis of thiazole derivatives has drawn great attention from chemists, and many studies in the synthesis of these heterocycles have been reported recently. The classical method, the Hantzsch thiazole synthesis has received great research interest from chemists. Moreover, many new methods have been established to synthesize thiazole-derived compounds. Unquestionably, more and more approaches to access thiazole skeleton will appear in the literature. The application of well-established thiazole synthesis methods to the synthesis of drugs, organic materials, and natural products will almost certainly be studied.

Thiazole and Related Heterocyclic Systems as Anticancer Agents: A Review on Synthetic Strategies, Mechanisms of Action and SAR Studies.

Cancer is the second leading cause of death worldwide. Many anticancer drugs are commercially available, but lack of selectivity, target specificity, cytotoxicity, and development of resistance lead to serious side effects. Several experiments have been going on to develop compounds with minor or no side effects. This review mainly emphasizes synthetic strategies, SAR studies, and mechanism of action if thiazole, benzothiazole, and imidazothiazole-containing compounds as anticancer agents. Recent literature related to thiazole and thiazole-related derivatives endowed with encouraging anticancer potential is reviewed. This review emphasizes contemporary strategies used for the synthesis of thiazole and related derivatives, mechanistic targets, and comprehensive structural activity relationship studies to provide perspective into the rational design of high-efficiency thiazole-based anticancer drug candidates. Exhaustive literature survey indicated that thiazole derivatives are associated with properties of inducing apoptosis and disturbing tubulin assembly. Thiazoles are also associated with the inhibition of NFkB/mTOR/PI3K/AkT and regulation of estrogenmediated activity. Furthermore, thiazole derivatives have been found to modulate critical targets, such as topoisomerase and HDAC. Thiazole derivatives seem to be quite competent and act through various mechanisms. Some of the thiazole derivatives, such as compounds 29, 40, 62, and 74a with IC50 values of 0.05 μM, 0.00042 μM, 0.18 μM, and 0.67 μM, respectively, not only exhibit anticancer activity, but they also have lower toxicity and better absorption. Therefore, some other similar compounds could be investigated to aid in the development of anticancer pharmacophores.

Multicomponent Synthesis of Fluorescent Thiazole-Indole Hybrids and Thiazole-Based Novel Polymers.

Herein, we report an efficient multicomponent reaction for the synthesis of trisubstituted thiazoles involving a one-pot C-C, C-N, and C-S bond-forming process from the readily available starting materials. The reaction of arylglyoxal, indole, and aryl thioamides in the acetic acid medium under sealed heating conditions provided 3-(2,4-diarylthiazol-5-yl)-1H-indoles (4) in good to excellent yields. Using a similar reaction strategy, the reaction of arylglyoxal, aryl thioamide, and 2,5-dihydroxy-1,4-benzoquinone provided structurally interesting bis-thiazoles having dihydroxy-1,4-benzoquinone linker (9). All of the products were fully characterized by spectroscopic techniques. We also recorded single-crystal X-ray diffraction (XRD) of compounds 4b and 9a for unambiguous structure determination. Indole-linked trisubstituted thiazoles (4) exhibit prominent fluorescence properties. The relative fluorescence quantum yields of all of the thiazole-linked indoles were measured in the dimethyl sulfoxide (DMSO) medium with respect to quinine sulfate in 0.1 M H2SO4 as reference. The scope of this reaction was further explored by preparing novel polymers 11a and 11b using naphthalene/benzene-1,4-bis(carbothioamide) in multicomponent polymerization.

Synthesis and computational characterization of aryl-fluorinated thiazoles: Experimental, DFT and molecular coupling studies

Three series of fluorinated aromatic thiazoles were synthesized through the Hantzsch reaction. This occurred between the corresponding fluorinated aromatic carbothioamides and the semi aromatic α-halo ketones. The structures of the synthesized compounds were elucidated by spectroscopic studies such as infrared spectroscopy (IR), nuclear magnetic resonance (1H and 19F-NMR) and mass spectrometry (HR-MS). Global reactivity descriptors such as absolute electronegativity (χ), hardness (η), softness (S) and chemical potential (μ) were calculated by means of the density functional theory (DFT), from which the compounds substituted with nitro group display the best reactivity indicators. A molecular coupling study was carried out using the rat enzyme tyrosine hydroxylase (1toh) to test the biological activity of our compounds against Toxoplasma gondii, where the 5d compound shows binding energies and inhibition constants that suggest inhibitory activity on this enzyme.

Design, Synthesis, Anticancer Activity and Docking Studies of Thiazole Linked Phenylsulfone Moiety as Cyclin-Dependent Kinase 2 (CDK2) Inhibitors

Inhibition of the cyclin dependent kinase 2 (CDK2) is a well-known cancer treatment approach. Based on the molecular docking simulation analysis, two new series of 2-(1-(4-methoxyphenyl)-2-(phenylsulfonyl)ethylidene)hydrazineylidene)-2,5-dihydrothiazole as CDK-2 inhibitors were designed. The lead compound IV (5-benzoyl-N2-phenyl-1,3-thiazole-2,4-diamine) was modified and optimized prior to this analysis. In contrast to Roniciclib (−8.6 kcal/mol), docking results of CDK2 hits showed high affinity and docking scores ranging from −9.1 to −10.3 kcal/mol. All of the compounds studied were evaluated in vitro for CDK2 inhibitory activity. In comparison to Roscovitine's IC50 of 0.432 µM, compound 11b had a maximum IC50 of 0.416 µM. Additionally, all hits were tested for antiproliferative activities against PC-3 human prostate cancer cells, HEPG-2 human hepatocellular carcinoma, and MCF-7 breast adenocarcinoma cell lines. The arylhydrazine moiety of the tested compounds 11a–e demonstrated high potency against HEPG-2, with 11b (IC50 = 0.11 µM) being more active than doxorubicin (IC50 = 0.12 µM). In addition, compound 11b (IC50 = 0.245 µM) was nearly as effective as doxorubicin (IC50 = 0.246 µM) against MCF-7 cancer cells. 11d showed superior antiproliferative activity against PC-3 cell line (IC50= 0.23 µM) relative to doxorubicin (IC50 = 0.29 µM).

Bromine‐Mediated C‐S Bond Formation: Synthesis of Thiazoles from α‐Methylene Ketones by Using Oxone Oxidative System

AbstractA novel method for the synthesis of various 2,4,5‐trisubstituted thiazoles from methylketones and thiourea/thioacetamide/amidinothiourea using NaBr/Oxone oxidative system has been developed. The three intimately connected advantages of this method, which form a whole, are that the reaction underwent a one‐pot α‐bromination/cyclization process, the use of more common methylene ketones as the raw material rather than α‐halomethylene ketones and a cheap and easily available catalytic amount sodium bromide as the bromine source instead of stoichiometric bromine or NBS.

Thiazoles: A Retrospective Study on Synthesis, Structure-activity Relationship and Therapeutic Significance

Abstract: Thiazole or 1,3-thiazole is a distinct heterocyclic compound which incorporates sulphur and nitrogen atoms. It is a vital framework present in numerous pharmacologically active compounds, be it of natural origin or of synthetic nature. Many thiazoles having antitumor and antiviral activities, originate from microbes and marine organisms. A variety of synthetic drugs, having thiazole group, like antimicrobial sulfathiazole, antibiotic penicillin, antidepressant pramipexole, antineoplastic agent bleomycin, antiretroviral drug ritonavir, histamine H2 receptor antagonist nizatidine, anti-inflammatory drug meloxicam, antifungal stilbene derivatives have been in the markets for quite some time. Hofmann and Hantzsch laid the groundwork for further development in the field of thiazole chemistry. The interaction of α-haloketones or α-halogenaldehyde and thioamide to obtain thiazoles is beautifully described by Hantzsch. Various studies have reported methods for the synthesis of the thiazoles; thioforamide, thiourea, α-thiocyanotoketones, and vinyl bromide have been extensively employed to synthesize thiazoles. The thiazoles have immense potential and this study tries to enlighten the crucial role of thiazoles for the betterment of society. The review provides different directions in the synthesis of novel thiazoles and also reveals diverse targets for augmentation in the field of designing of novel thiazoles. Keywords: Thiazoles, Synthesis, QSAR, Molecular Docking, Biological Activity

Synthesis, antimicrobial activity and modeling studies of thiazoles bearing pyridyl and triazolyl scaffolds.

In this study, novel 4-(5-((2/3/4-substituted benzyl)thio)-4-(4-substituted phenyl)-4H-1,2,4-triazol-3-yl)-2-(pyridin-3/4-yl)thiazoles were synthesized following a multi-step synthetic procedure. All the compounds were screened with a panel of gram positive/negative bacteria, yeasts, and molds for antimicrobial activity using the disc diffusion method. Then, the minimum inhibitor concentration (MIC) and the minimum bactericidal concentration (MBC) values of active compounds were determined against Micrococcus luteus, Bacillus cereus, Listeria monocytogenes, and Staphylococcus aureus using the broth microdilution technique. These compounds were also screened for their inhibitory activities against S.aureus DNA gyrase by supercoiling assay. Furthermore, the crystal structure of S.aureus DNA gyrase B ATPase was subjected to a docking experiment to identify the possible interactions between the most active ligand and the active site. Lastly, the in silico technique was performed to analyze and predict the drug-likeness, molecular and ADME properties of the synthesized molecules.

Synthesis, Antimicrobial Evaluation, and Molecular Docking of New Azole, Azine, Thiazole, and Chromene Derivatives

Novel heterocyclic compounds containing a benzothiazole moiety (2–16) were synthesized via the reaction of benzothiazole cyanoacetamide derivative (2) with different types of reagents. All compounds were characterized by 1H NMR, MS, and IR techniques. The newly synthesized compounds were examined for their in vitro antibacterial activity against Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and fungi (Candida albicans) microorganisms. Compounds (5, 6, 7, and 15) are promising antimicrobial agents and could be the lead compounds for more potent drugs. Binding modes of the synthesized compounds were analyzed by docking studies that showed good binding scores against the diverse amino acids of the two selected proteins (PDB Codes – 2EXB and 3HUN). The conducted docking studies were found to be consistent with antimicrobial results. Thus, the results indicate that the designed structures can be a potential lead as antimicrobial agents.

Design, synthesis, anti-infective and anti-cancer potential of thiazole based Pyrazoles bearing benzothiazole moiety

A new series of (E)-6-methyl-N-((3-phenyl-1-(4-phenylthiazol-2-yl)-1H-pyrazol-4-yl)methylene)benzo[d]thiazol-2-amine derivatives was developed. Structural investigation of the synthesized derivatives was carried out by several instrumental method of analysis like IR, and 1H-NMR spectroscopy. The titled analogues were examined for in-vitro anticancer and antiinfective activities. The biological findings specified that analogues 5a, 5b, 5d, 5e, 5f and 5g showed most potent antibacterial activity (MIC 62.5-250μg/mL) and 5a, 5e, 5f and 5g displayed most potent antifungal action (MIC 62.5-500 μg/mL) than standard drugs. Compounds 5a and 5e were reported to be most active antimalarial analogue having IC50 value of 0.24-0.49μg/mL. Compounds 5a, 5e and 5f showed shortest mean paralysis time of (25.6±4.56 min, 26.4±4.97 min and 26.8±4.76 min) and mean death time (47.6±8.01min, 45.6±3.04min and 46.6±7.40min), respectively. Compound 5e showed moderate cytotoxicity with IC50 value of 65.4 against MCF-7. The results proved that 1,3-thiazolyl-pyrazole clubbed benzothiazole derivatives showed considerable antiinfective and cytotoxic activity. Keywords: Anti-infective activity, Cytotoxic activity, Spectroscopic methods, Thiazole, Pyrazole, Benzothiazole.

Synthesis and efficiency of new pyridine, chromene and thiazole containing compounds as antimicrobial and antioxidant agents

ABSTRACT. The versatile scaffold, N'-(2-cyanoacetyl)-2-hydroxybenzohydrazide (3) was utilized in the production of new pyridine, chromene and thiazole derivatives as antimicrobial and antioxidant agents. The synthetic strategy involves the treatment of precursor 3 with various arylidene-malononitrile and 3-aryl-2-cyanoacrylate compounds to furnish substituted pyridines 5 and 7. The interaction of 3 with salicylaldehyde and/or phenyl isothiocyanate followed by cyclization with chloroacetone produced the corresponding 2-imino-2H-chromene-3-carbohydrazide and (thiazol-2-ylidene-acetyl)-salicylic acid hydrazide compounds 8 and 9, respectively. The structural features of the synthesized compounds were confirmed by using spectroscopic methods such as (IR, 1H NMR, 13C NMR and MS). The new pyridine, chromene and thiazole products showed potent antioxidants and antimicrobial activities. The thiazole derivative 9 exhibited the highest anti-bacterial and antifungal activities against S. aureus (75.0%) and B. subtilis (73.9%) and C. albicans (66.6%). The combination between salicylic acid hydrazide and thiazole moieties in the hybrid 9 indicated the best antioxidant activity (87.9%).
 
 KEY WORDS: Salicylic hydrazide, Arylidene-malononitrile, Pyridine, Thiazole, Antioxidant
 
 Bull. Chem. Soc. Ethiop. 2022, 36(1), 137-148. 
 DOI: https://dx.doi.org/10.4314/bcse.v36i1.12

Iodic Acid Catalyzed Efficient Synthesis of 2-Amino Thiazoles

Abstract: This study describes a straightforward, efficient, one-step, environmentally friendly synthesis of 2-aminothiazoles. This green procedure was catalyzed using an Iodic Acid catalyst and PEG-400 as green solvent. The synthesized compounds were characterized by 1H NMR, 13C NMR and HRMS analyses. Keywords: 2-aminothiazoles, Iodic acid, PEG-400: H2O

Bio-Based (Chitosan-ZnO) Nanocomposite: Synthesis, Characterization, and Its Use as Recyclable, Ecofriendly Biocatalyst for Synthesis of Thiazoles Tethered Azo Groups.

In recent years, nanotechnology has become a considerable research interest in the area of preparation of nanocatalysts based on naturally occurring polysaccharides. Chitosan (CS), as a naturally occurring biodegradable and biocompatible polysaccharide, is successfully utilized as an ideal template for the immobilization of metal oxide nanoparticles. In this study, zinc oxide nanoparticles have been doped within a chitosan matrix at dissimilar weight percentages (5, 10, 15, 20, and 25 wt.% CS/ZnO) and have been fabricated by using a simple solution casting method. The prepared solutions of the nanocomposites were cast in a Petri-dish and were subsequently shaped as a thin film. After that, the structural features of the nanocomposite film have been studied by measuring the FTIR, SEM, and XRD analytical tools. FTIR spectra showed the presence of some changes in the major characteristic peaks of chitosan due to interaction with ZnO nanoparticles. In addition, SEM graphs exhibited dramatic morphology changes on the chitosan surface, which is attributed to the surface adsorption of ZnO molecules. Based on the results of the investigated organic catalytic reactions, the prepared CS/ZnO nanocomposite film (20 wt.%) could be a viable an effective, recyclable, and heterogeneous base catalyst in the synthesis of thiazoles. The results showed that the nanocomposite film is chemically stable and can be collected and reused in the investigated catalytic reactions more than three times without loss of its catalytic activity.

A multi pathway coupled domino strategy: I2/TBHP-promoted synthesis of imidazopyridines and thiazoles via sp3, sp2 and sp C-H functionalization.

I2/TBHP-promoted, one-pot, multi pathway synthesis of imidazopyridines and thiazoles has been achieved through readily available ethylarenes, ethylenearenes and ethynearenes. I2/TBHP as an initiator and oxidant is used to realize the C–H functionalization of this domino reaction. Simple and available starting materials, wide range of functional group tolerance, high potential for drug activity of the products and application in production are the advantageous features of this method.