Thiazole Synthesis Research Articles

Synthesis, characterization, and evaluation of pyrimidinone-linked thiazoles: DFT analysis, molecular docking, corrosion inhibition, and bioactivity studies

The paper describes the construction of a new series of pyrimidinone-linked thiazole derivatives through bromination of the initial Biginelli reaction product followed by the Hantzsch thiazole synthesis route. Various analytical techniques, including FT-IR, 1H NMR, 13C NMR, and LCMS analysis, were employed to confirm the formation of the products. The synthesized compounds were primarily evaluated for their antibacterial activity, with a specific focus on their IC50 values. Compound 4c demonstrated the most potent efficacy, displaying MIC and MBC values that varied from 0.23 to 0.71 mg/mL and 0.46–0.95 mg/mL, respectively. The anti-inflammatory potential was also observed in analogs 4a and 4c with marked activity in the 33.2–82.9 μM concentration range. Moreover, compounds 4a, and 4c demonstrated strong antioxidant effects, as reflected by their excellent IC50 values of 38.6–43.5 μM respectively. DFT investigation showed that B. cereus was more susceptible, and E. coli was more resistant, with chloro-substituted compounds exhibiting potential reactivity. Some molecules with chloro-substituents showed promising results in density functional theory when compared to other substituents. In addition, the molecules underwent a corrosion study and demonstrated a high level of inhibition efficiency (4c) in comparison to other molecules. Further in silico studies of the synthesized thiazoles confirmed the good interactions with the target.

Electrochemical Enaminone-Thioamide Annulation and Thioamide Dimeric Annulation for the Tunable Synthesis of Thiazoles and 1,2,4-Thiadiazole.

A green and sustainable electrochemical oxidative cyclization of enaminones with thioamides under metal- and oxidant-free conditions has been developed, providing an efficient approach for thiazole synthesis. Furthermore, 1,2,4-thiadiazoles can be selectively accessed via the electrochemical dimerization of thioamides in the absence of enaminones.

Enhancing C-S and C-N bond formation with ultrasound assistance: lipase-catalyzed synthesis of 2,4-disubstituted thiazole derivatives from arylethanones and thioamides.

The present study explores an innovative approach for the efficient synthesis of 2,4-disubstituted thiazole derivatives, a class of compounds with diverse biological and pharmaceutical significance. This research presents lipase as a highly effective and environmentally friendly catalyst for thiazole synthesis. Under mild circumstances, the condensation of aryl ethenone, KBrO3, and thioamide is aided by using ultrasonic energy. Moreover, we harness the power of ultrasound irradiation to accelerate the reaction, reducing reaction times and improving product yields. The lipase-catalyzed, ultrasound-assisted synthesis presented in this study represents a greener and more sustainable alternative to traditional synthetic pathways for these important compounds, offering promising potential for applications in medicinal chemistry and drug development. This approach holds the promise of advancing the field of thiazole synthesis, contributing to more sustainable and efficient chemical processes.

Brønsted acid-mediated thiazole synthesis from sulfoxonium ylides.

A Brønsted acid-mediated insertion of thioureas/thioamides into sulfoxonium ylides to synthesise 40 thiazoles (34-95% yields) under mild, metal-free conditions is described. This process is scalable, substrate-tolerant (including both α-substituted and heterocyclic ylides/groups) and was successfully applied to the late-stage functionalisation of the complex chemical probe molecule (+)-JQ1.

Design, Synthesis, and Molecular Docking Studies of New Quinoline-Thiazole Hybrids, Potential Leads in the Development of Novel Antileukemic Agents

This work describes the multigram-scale synthesis of the building-block N1 -(7-chloroquinolin4-yl)ethane-1,2-diamine via sonochemistry and its use in the synthesis of seven new quinoline-thiazole hybrids endowed with interesting anticancer activity. Target compounds were planned based on the drugs chloroquine and primaquine and the desired thiazoles were obtained through the Hantzsch thiazole synthesis, without the use of catalysts, by reacting key intermediate 1-(2-((7-chloroquinolin-4-yl)amino)ethyl)thiourea, obtained in two-steps from N1-(7-chloroquinolin-4-yl)ethane-1,2-diamine, with different 2-bromoacetophenones. The novel molecules were assessed against four different leukemia cell lines (HL60, K562, KASUMI-1, and KG-1) plus normal fibroblasts (L929), using the 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl2H-tetrazolium bromide (MTT) assay, and showed, overall, a high cytotoxic profile, but with interesting selectivity index, especially against K562 cells (1.89 to 5.50), when compared to standard doxorubicin (3.51). Docking studies suggest that all tested derivatives are able to interact with BCR-ABL1 tyrosine kinase enzyme, and, therefore, these molecules may be promising leads against chronic myeloid leukemia.

In Silico and In Vitro Study towards the Rational Design of 4,4'-Disarylbisthiazoles as a Selective α-Synucleinopathy Biomarker.

The α-synucleinopathies are a group of neurodegenerative diseases characterized by the deposition of α-synuclein aggregates (α-syn) in the brain. Currently, there is no suitable tracer to enable a definitive early diagnosis of these diseases. We reported candidates based on 4,4'-disarylbisthiazole (DABTA) scaffold with a high affinity towards α-syn and excellent selectivity over Aβ and tau fibrils. Based on prior in silico studies, a focused library of 23 halogen-containing and O-methylated DABTAs was prepared. The DABTAs were synthesized via a modified two-step Hantzsch thiazole synthesis, characterized, and used in competitive binding assays against [3H]PiB and [3H]DCVJ. The DABTAs were obtained with an overall chemical yield of 15-71%, and showed a calculated lipophilicity of 2.5-5.7. The ligands demonstrated an excellent affinity to α-syn with both [3H]PiB and [3H]DCVJ: Ki 0.1-4.9 nM and up to 20-3900-fold selectivity over Aβ and tau fibrils. It could be concluded that in silico simulation is useful for the rational design of a new generation of DABTAs. Further investigation of the leads in the next step is encouraged: radiolabeling of the ligands with radioisotopes such as fluorine-18 or carbon-11 for in vivo, ex vivo, and translational research and for further in vitro experiments on human-derived protein aggregates.

Thiazole Ring: A Pharmacological Active Scaffold

The most important five-membered hetrocyclic molecules with a wide range of biological action are thiazoles. Sulphur atoms are found at position 1 while nitrogen atoms are found at position 3. The goal of this research is to compile a list of activities and innovative methodologies for the synthesis of thiazole derivatives. The entire review discusses thiazole's numerous properties, including antibiotics, antimalarials, antidiabetics, anticancer, anti-inflammatory, diuretics, antimycobactreial, and methods for thiazole synthesis.

Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

Reactions of thiobenzamide or thioacetamide with 4-bromo-1,1-dimethyl-1,4-dihydroisoquinoline-3(2H)-one, 4-bromoisoquinoline-1,3(2H,4H)-dione and two α-bromo(phenyl)acetamides were examined under various conditions (base, solvent, thiophile, temperature) and structure/medium features that influence product distribution (Eschenmoser coupling reaction, Hantzsch thiazole synthesis and elimination to nitriles) were identified. The key factor that enables the successful Eschenmoser coupling reaction involves the optimum balance in acidity of nitrogen and carbon atoms of the intermediary α-thioiminium salts.

Recent Advances in the Synthesis of Thiazole Ring: Mini Review

Abstract: The thiazole scaffold is an essential structural foundation in a plethora of pharmaceutical products having an extensive array of biological activities. Consequently, its synthesis has been extensively discussed in the literature. In this mini review, we have summarized the recent advances in thiazole synthesis, covering articles published between 2002 and 2021. We have reviewed and discussed various recent and novel routes for synthesizing compounds containing thiazole rings from various starting materials such as thiourea, thioamide, or thiosemicarbazone. Additionally, we have illustrated environmentally benign methods for thiazole synthesis. We hope that this review can help other researchers efficiently synthesize the thiazole ring.

Synthesis, in vitro Toxicity, and Antitrypanosomal Activity of Arylated and Diarylated Thiazoles

Chagas disease is a relevant public health threat that affects over 6 million people worldwide, resulting in devastating social and economic consequences. Moreover, the therapeutic options are limited, highlighting the urgency in searching for novel active antitrypanosomal molecules. Compounds with either thiazole or biaryl units have been described as possessing anti-Trypanosoma cruzi activities. Therefore, here, we describe the synthesis of nine arylated and diarylated thiazole derivatives and the evaluation of their in vitro toxicity on mammalian cells as well as their anti-T. cruzi activity. The compounds were prepared in straightforward synthetic routes, using Hantzsch thiazole synthesis and cross-coupling reactions as key steps. A pyridylphenyl-thiazole (PPT) derivative (4c) presented 76% of T. cruzi growth inhibition in preliminary tests using a fixed concentration of 20 µM. This compound was used as a scaffold for the synthesis of two novel PPT analogs (4g and 4h). Dose-response assays on intracellular forms of T. cruzi demonstrated that these three compounds presented high antiparasitic potency (half maximal effective concentration (EC50) values ranging from 1.15 to 2.38 μM) and low toxic profile against L929 cell lines. Hence, these findings highlight the pyridyl-phenyl-thiazole backbone as a novel privileged scaffold in the search for active molecules against T. cruzi.

New thiazole-based bis(Schiff bases) linked to arene units as potential MRSA inhibitors

A new series of thiazole-based bis(Schiff bases) attached to different arene units were efficiently prepared using a three-component tandem protocol. The proposed protocol involved the reaction of aromatic aldehydes, thiosemicarbazide, and bis(α-haloketone) to produce the desired products. The target hybrids were formed by an initial thiosemicarbazone formation in ethanol at 80 °C for 120–150 min, followed by triethylamine-mediated Hantzsch thiazole synthesis in dioxane at 100 °C for 150–180 min. The new hybrids were screened against diverse bacterial strains. The hybrids attached to p-Cl, p-Br, and p-Me had more effective efficacy than ciprofloxacin against S. aureus, and E. coli strains, while they had comparable efficacy to ciprofloxacin against S. mutans, and K. pneumonia strains. Their MIC/MBC values ranged between 1.3–3.2 and 2.6–6.5 µM, respectively, against the previous strains. Additionally, they displayed more effective MRSA inhibitory activity than linezolid with MIC/MBC values in the range of 3.0–21.3 µM.

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.

A green synthesis and antibacterial activity of ferrocene-based thiazole derivatives in choline chloride/glycerol eutectic solvent.

In this work, a green Hantzsch synthesis of 4-ferrocenylthiazole derivatives has been accomplished successfully. The Hantzsch reaction between bromoacetylferrocene and various aryl thioureas, 1-alkylindole-3- or 9-alkylcarbazole-3-carbothioamides proceeded efficiently in a deep eutectic solvent (DES) that is, choline chloride/glycerol (ChCl/Gly) (1 : 2 molar ratio) at 80 °C, avoiding the use of common volatile organic solvents. Moreover, the DES media could be reused up to three times without any appreciable decrease in the yield. The synthetic strategy has the attractive features such as mild and environmentally benign reaction conditions, experimental simplicity, easy work-up procedure and good yields. Subsequently, a preliminary screening for in vitro antibacterial activities of all these newly-synthesized compounds revealed that the halo-substituted (F, Cl, Br) compounds 3f–h showed significant antibacterial activities against Gram (+) bacterial B. subtilis and Gram (−) E. coli, among which the fluoro-substituted 3f possessed the best activity with the MIC value of 7.8125 μg mL−1, being higher than the reference drug ciprofoxacin (15.625 μg mL−1).

Electrochemical enaminone C–H thiolation/C–N amination cascade for thiazole synthesis and its diastereoselective dearomatization

The electrochemical annulation of enaminones/analogous enamines and thioureas providing 2-aminothiazoles has been realized. Modulating the electrolyte enables the diastereoselective synthesis of 4,5-dialkoxyl thiazolines by dearomatization.

Synthesis and Structural Confirmation of the Thiazole Alkaloids Derived from Peganum harmala L.

Peganumal A and B are thiazole alkaloids isolated from the seeds of Peganum harmala L. Thiazole moieties are rarely found in natural products, but diverse compounds possessing thiazole moieties have attracted attention owing to their broad range of biological activities. Peganumals are the first natural thiazole compounds isolated from the genus Peganum. It was difficult to define the exact structure of peganumal A via spectroscopic analysis. In this paper, we report the first total synthesis of peganumal A and B. The 5-benzylthiazole skeleton possessing methyl or hydrogen at the 2-position of the peganumals was efficiently constructed via the Hantzsch thiazole synthesis of the α-bromoaldehyde intermediate. Moreover, the spectral data of the synthetic 2H–thiazole compound were identical to those previously reported for peganumal A. The synthesis allowed the confirmation of the structure of peganumal A.

Design and synthesis of novel 2,4,5-thiazole derivatives as 6-APA mimics and antimicrobial activity evaluation

Nine new thiazole derivatives were synthesized considering 6-acetyl penicillanic acid (6-APA) and investigated for their antimicrobial activity. Ethyl 2-(2-mercaptoacetamido)-4-methylthiazole-5-carboxylate derivatives (3a–3i) were gained with a two-step synthetic method using conventional Hantzsch thiazole synthesis. The structural elucidation of the compounds was performed by 1H-NMR, 13C-NMR spectral data and HRMS. All compounds were tested on eleven bacteria and sixteen fungi species and minimum inhibitory concentration (MIC) was determined for each. Compounds 3d (4-methyl-2-(2-((5-methyl-1,3,4-thiadiazol-2-yl), 3f (4-methyl-2-(2-((5-nitro-1H-benzimidazol-2-yl) and 3g (4-methyl-2-(2-((5-methyl-4H-1,2,4-triazol-3-yl) bearing thiazole, 5-nitrobenzimidazole and triazole rings respectively exhibited high antimicrobial activity against most of the strains. In silico physicochemical properties were calculated for the compounds and it was detected that they comply with the rules of drug availability.

Thiazolyl-pyrazoline derivatives: In vitro and in silico evaluation as potential acetylcholinesterase and carbonic anhydrase inhibitors

Alzheimer's disease (AD) is a complex, predominant, and progressive form of dementia. The treatment of AD alters depending on the cognitive and behavioral symptoms. The utility of cholinergic replacement by acetylcholinesterase (AChE) inhibitors in AD treatment has been well-documented so far. Recent studies have also demonstrated that human carbonic anhydrases (hCAs) serve as important targets for AD treatment. In an attempt to identify potent AChE and hCA inhibitors, new thiazolyl-pyrazolines (3a-k) were designed based on the molecular hybridization of thiazole and pyrazoline scaffolds. A facile and versatile synthetic route consisting of three steps, namely Claisen-Schmidt reaction, the formation of the 2-pyrazoline ring system, and Hantzsch thiazole synthesis was used to prepare compounds 3a-k. The synthesized derivatives were experimentally validated for efficacy by in vitro and direct enzymatic assays. Furthermore, the compounds were subjected to in silico screening using Schrödinger Suite software to identify the binding affinities of potential compounds based on Glide XP scoring, MM-GBSA calculating, and validation. The results of in vitro and in silico studies revealed that compounds 3a, 3f, and 3d were the most promising derivatives in this series due to their significant effects on AChE, hCA I, and hCA II, respectively.

A perspective on environmentally benign protocols of thiazole synthesis

Thiazole has widespread importance in materials and medicines. Several reviews are reported which cover essential properties of thiazoles such as pharmacological activities, structure-activity relationship studies, and various synthetic routes. However, synthesis based on a greener approaches, particularly metal-free reactions, usage of mild, nontoxic, recyclable catalysts, eco-sustainable protocols, efficient solvents have not been exclusively reviewed. Current review emphasizes green synthetic approaches for substituted thiazoles that have been performed within the last decade.

Synthesis, Antimicrobial, and Docking Investigations of Remarkably Modified Sulfathiazole Derivatives

Some new sulfathiazole derivatives were synthesized. The sulfathiazole starting material was reacted with ethyl bromoacetate and gave unpredictably an ester product 2. The substitution occurred selectively at the tautomeric proton of the NH thiazolyl nitrogen rather than the aromatic NH2 protons. The ester was further hydrazinolysed followed by condensation with several aldehydes to establish hydrazones (4a-h). Hantzesch thiazole synthesis was also applied to build antimicrobial agents containing multi-thiazole moieties. The structures of the synthesized compounds were confirmed by 1H, 13C, 2D 1H NMR, MS, and microanalyses. The synthesized compounds were tested for their antimicrobial activity towards Gram-positive and Gram-negative bacteria, and fungi strains. Some of the investigated compounds showed prominent high potency. The docking study revealed the mode of action between the modified sulfathiazole ligands and the binding site of DHPS.

Brønsted acid-promoted thiazole synthesis under metal-free conditions using sulfur powder as the sulfur source.

A Brønsted acid-promoted sulfuration/annulation reaction for the one-pot synthesis of bis-substituted thiazoles from benzylamines, acetophenones, and sulfur powder has been developed. One C–N bond and multi C–S bonds were selectively formed in one pot. The choice of the Brønsted acid was the key to the high efficiency of this transformation under metal-free conditions.