Thiazolidine Compounds Research Articles

Synthesis, characterization and Antibacterial Evaluation of Novel Thiazolidine Derivatives

Background: Heterocyclic compounds, which incorporate atoms such as nitrogen and sulfur alongside carbon, play a crucial role in nature and organic chemistry. Thiazolidine derivatives, characterized by sulfur and nitrogen atoms with a carbonyl group at the -4 position, are particularly noteworthy for their stability and diverse biological activities. We synthesized novel thiazolidine derivatives and determined their antibacterial properties. the synthesis of novel thiazolidine compounds was perforemd using thioglycolic acid with hydrazides, generated from the combination of hydrazides with benzaldehyde. Methods: The esters, hydrazides, hydrazones, and thiazolidines, were synthesized and characterized using infrared spectroscopy, nuclear magnetic resonance, and melting point analysis. Assessment of anti-bacterial activity was carried out against Gram-positive and Gram-negative bacterial strain of Staphylococcus aureus, Acinetobacter baumannii, Aeromonas sobria, and Escherichia coli. . Results: We synthesized ethyl 2-acetate (benzo[d]thiazol-2-yloxy), followed by the formation of 2-(benzo[d]thiazol-2-yloxy)acetohydrazide (hydrazide) through the reaction of this acetate with hydrazine. 16 compounds were synthesized with rigorous validation at each stage through spectral analysis. Thiazolidine derivatives exhibited promising inhibitory effects against bacterial growth, indicating their potential as antibacterial agents.Compound SH8 exhibited moderate to strong inhibitory effects against all tested species, notably Aeromonas sobria and Staphylococcus aureus, at a concentration of 0.1 mg/ml. Conclusion: In conclusion, the synthesized compounds exhibited both structural integrity and potent antibacterial activity, suggesting avenues for further exploration in pharmaceutical research.

Thiazolidine derivatives: In vitro toxicity assessment against promastigote and amastigote forms of Leishmania infantum and ultrastructural study

Neglected diseases, such as Leishmaniasis, constitute a group of communicable diseases that occur mainly in tropical countries. Considered a public health problem with limited treatment. Therefore, there is a need for new therapies. In this sense, our proposal was to evaluate in vitro two series of thiazolidine compounds (7a-7e and 8a-8e) against Leishmania infantum. We performed in vitro evaluations through macrophage cytotoxicity assays (J774) and nitric oxide production, activity against promastigotes and amastigotes, as well as ultrastructural analyzes in promastigotes. In the evaluation of cytotoxicity, the thiazolidine compounds presented CC50 values between 8.52 and 126.83 μM. Regarding the evaluation against the promastigote forms, the IC50 values ranged between 0.42 and 142.43 μM. Compound 7a was the most promising, as it had the lowest IC50. The parasites treated with compound 7a showed several changes, such as cell body shrinkage, shortening and loss of the flagellum, intense mitochondrial edema and cytoplasmic vacuolization, leading the parasite to cell inviability. In assays against the amastigote forms, the compound showed a low IC50 (0.65 μM). These results indicate that compound 7a was efficient for both evolutionary forms of the parasite. In silico studies suggest that the compound has good oral bioavailability. These results show that compound 7a is a potential drug candidate for the treatment of Leishmaniasis.

Do thiazolidine compounds act on intracellular amastigotes of Trypanosoma cruzi? A systematic review

Benznidazole (Bdz) are the drug of choice to treat Chagas Disease. However, the drug causes several side effects, and Trypanosoma cruzi, the etiological agent of Chagas disease, can be less susceptible to the action of drugs in the chronic phase, due to its reduced metabolism and dormancy in tissues. Thus, using compounds that are lethal to amastigote forms, which are prevalent in the Chagas disease chronic phase, is essential for the success of therapy. We propose to evaluate, though a systematic review, the efficacy of thiazolidine and its imidazolidine derivatives against T. cruzi intracellular amastigotes, and to compare the results with those for Bdz, A systematic search was made on eight English Language Systematic Databases - Science Direct, Scopus, Pubmed, Google Scholar, LILACS, Scielo, Trip Database and Cochrane, to collect studies, without a time scale. IC50 values, cytotoxic effects (CC50), a selective index (SI), the mechanism of action of each compound and the length of treatment was included in this review to evaluate the effectiveness of each compound. The compound 2-Iminothiazolidin-4-one 18 was more effective than Bdz, as it affected intracellular amastigotes by making a structural modification in the parasite, and by inhibiting cruzain, being promising for the antichagasic therapy.

Neurolocomotor Behavior and Oxidative Stress Markers of Thiazole and Thiazolidinedione Derivatives against Nauphoeta cinerea.

Thiazolidine compounds NJ20 {(E)-2-(2-(5-bromo-2-methoxybenzylidene)hydrazinyl)-4-(4-nitrophenyl)thiazole} and NW05 [(2-(benzo (d) (1,3) dioxol-4-ylmethylene)-N-(4-bromophenyl)-thiosemicarbazone] potentiated the effect of norfloxacin in resistant bacteria; however, there are no reports on their effects on Nauphoeta cinerea in the literature. The objective of this work was to evaluate the behavioral effects and oxidative markers of NW05 and NJ20 in lobster cockroach N. cinerea. To evaluate the behavioral study, a video tracking software was used to evaluate the locomotor points and the exploratory profile of cockroaches in the horizontal and vertical regions of a new environment. The total concentration of thiol and reduced glutathione (GSH), substances reactive to thiobarbituric acid (TBARS), free iron (II) content and mitochondrial viability were determined. The antioxidant potential was evaluated by the DPPH method. Both substances induced changes in the behavior of cockroaches, showing a significant reduction in the total distance covered and in the speed. In the cell viability test (MTT), there was a significant reduction for NJ20 (1 mM). NJ20 caused a significant increase in total levels of thiol and non-protein thiol (NPSH), although it also slightly increased the content of malondialdehyde (MDA). Both compounds (NW05 and NJ20) caused a significant reduction in the content of free iron at a concentration of 10 mM. In conclusion, the compound NJ20 caused moderate neurotoxicity (1 mM), but had good antioxidant action, while NW05 did not show toxicity or significant antioxidant activity in the model organism tested. It is desirable to carry out complementary tests related to the antioxidant prospection of these same compounds, evaluating them at different concentrations.

Thiosemicarbazone and thiazole: in vitro evaluation of leishmanicidal and ultrastructural activity on Leishmania infantum

Leishmaniasis is a much-neglected tropical disease, especially in developing countries. Visceral Leishmaniasis (VL) is the most severe form of this infection caused by Leishmania infantum specie. It affects the splenic and hepatic systems and, when left untreated, it is fatal in 95% of cases. There is no human vaccine available and the recommended treatment not only presents adverse effects but it enables the development of resistant strains if interrupted. Hence, the urgent search for new leishmanicidal compounds. In the present work, we evaluated the in vitro leishmanicidal action of new thiosemicarbazone and thiazolidine compounds against the evolutionary forms of L. infantum, as well as their hemolytic activity, ultrastructural alterations, cytotoxicity, and nitric oxide levels on peritoneal macrophages. The inhibitory concentration 50% (IC50) against promastigote forms varied from 8.62 to 34.36 µM. In the evaluation of cytotoxicity, values of CC50 in peritoneal macrophages varied from 31.80 to 196.38 µM. Data showed that compounds JW-16.2 and GT-14 were the most promising in the series as they displayed the highest CC50 (184.58 and 196.38 μM), SI (19 and 15), low hemolytic activity, induced NO production in uninfected and infected macrophages and reduced survival of amastigotes (24.39 and 16.51 μM). Ultrastructural alterations, such as shrinkage of the cell body, shortening of the flagellum, and vacuolization of the cytoplasm, were identified. Promastigote forms treated with compounds GT-14 showed depolarization of mitochondria. Therefore, both compounds are promising due to low cytotoxicity to mammalian cells and leishmanicidal action.

One-pot Synthesis of Novel 2-pyrazolo-3-phenyl-1,3-thiazolidine-4-ones Using DSDABCOC as an Effective Media.

Thiazolidine compounds are known to show interesting pharmacological activity. In particular, they are used as antiseizure, fungicidal, anti-bacterial, antitubercular, antiinflammatory, antiamoebic, anti-diabetic and local anesthetic agents. Some of these compounds have also shown antiparkinsonism, antioxidant, anticonvulsant, hypoglycemic and non-narcotic analgesic activities. On the other hand, pyrazoles have shown antibacterial, antitumor, antiviral, antifungal, anti-tubercular, antiparasitic, anesthetic, anti-diabetic, anti-inflammatory, analgesic and insecticidal activities. In order to improve the pharmacological effects of thiazolidine-4-ones, new pyrazole derivatives have been synthesized. A mixture of pyrazolcarbaldehydes, anilines, thioglycolic acid and DSDABCOC was stirred at room temperature for the required reaction times. The progress of the reaction was monitored by TLC (EtOAc: petroleum ether 1:3). After completion of the reaction as indicated by TLC, the ionic liquid was separated by extraction with 2×15 mL of water. The solid residue was separated by column chromatography. The product was recrystallized from EtOH. The pure products were collected in 82-92% yields. In continuation of our ongoing studies to synthesize heterocyclic and pharmaceutical compounds under mild and practical protocols, we wish to report herein our experimental results on the ultrasound promoted synthesis of 2-pyrazolo-3-phenyl-1,3-thiazolidine-4-ones using various synthesized pyrazolecarbaldehydes, anilines and thioglycolic acid at room temperature. The results illustrated that ionic liquid DSDABCOC certainly improved the yield of the products and reduced the reaction time. In conclusion, we have developed an efficient and simple protocol for the synthesis of novel pyrazolo-1,3-thiazolidine-4-ones using DSDABCOC as an ionic liquid. The easy workup together with the use of inexpensive, reusable and eco-friendly ionic liquid is the notable feature of this novel procedure. To the best of our knowledge, this is the first report of the synthesis of a new library of 1,3-thiazolidine-4-ones bearing a pyrazolyl moiety that enhances the biological activity under solvent-free conditions.

Thiazolidine reacts with thioreactive biomolecules

The thiazolidine ring is a biologically active chemical structure and is associated with many pharmacological activities. However, the biological molecules that can interact with the thiazolidine ring are not known. We show that thiazolidine causes sustained activation of the TRPA1 channel and chemically reacts with glutathione, and the chemical reactivity of thiazolidine ring is required for TRPA1 activation. Reducing agents reverse thiazolidine-induced TRPA1 activation, and mutagenesis studies show that nucleophilic cysteine residues in TRPA1 are critical, suggesting an activation mechanism involving thioreactive chemical reactions. In vivo studies show that thiazolidine induces acute pain and inflammation in mouse and these responses are specifically dependent on TRPA1. These results indicate that thiazolidine compounds can chemically react with biological molecules containing nucleophilic cysteines, thereby exerting biological activities.

ChemInform Abstract: New Thioureas Based on Thiazolidines with Antioxidant Potential.

Abstract Thiazolidine and pyrrolidine compounds containing a thiourea moiety were prepared using boric acid as a coupling agent in a multicomponent methodology. In addition, the antioxidant activity, as reflected by free radical scavenging, was evaluated. Some compounds were selected and tested in different antioxidant experiments and all of them were shown to be useful for the prevention of oxidative stress in biological systems and thus capable of reducing cellular injury.

Structure-guided design of thiazolidine derivatives as Mycobacterium tuberculosis pantothenate synthetase inhibitors.

The pantothenate biosynthetic pathway is essential for the persistent growth and virulence of Mycobacterium tuberculosis (Mtb) and one of the enzymes in the pathway, pantothenate synthetase (PS, EC: 6.3.2.1), encoded by the panC gene, has become an appropriate target for new therapeutics to treat tuberculosis. Herein, we report nanomolar thiazolidine inhibitors of Mtb PS developed by a rational inhibitor design approach. The thiazolidine compounds were discovered by using energy-based pharmacophore modelling and subsequent in vitro screening, which resulted in compounds with a half maximal inhibitory concentration (IC50) value of (1.12 ± 0.12) μM. These compounds were subsequently optimised by a combination of modelling and synthetic chemistry. Hit expansion of the lead by chemical synthesis led to an improved inhibitor with an IC50 value of 350 nM and an Mtb minimum inhibitory concentration (MIC) of 1.55 μM. Some of these compounds also showed good activity against dormant Mtb cells.

Structure-Guided Design of Novel Thiazolidine Inhibitors of O-Acetyl Serine Sulfhydrylase from Mycobacterium tuberculosis

The cysteine biosynthetic pathway is absent in humans but essential in microbial pathogens, suggesting that it provides potential targets for the development of novel antibacterial compounds. CysK1 is a pyridoxalphosphate-dependent O-acetyl sulfhydrylase, which catalyzes the formation of l-cysteine from O-acetyl serine and hydrogen sulfide. Here we report nanomolar thiazolidine inhibitors of Mycobacterium tuberculosis CysK1 developed by rational inhibitor design. The thiazolidine compounds were discovered using the crystal structure of a CysK1-peptide inhibitor complex as template. Pharmacophore modeling and subsequent in vitro screening resulted in an initial hit compound 2 (IC50 of 103.8 nM), which was subsequently optimized by a combination of protein crystallography, modeling, and synthetic chemistry. Hit expansion of 2 by chemical synthesis led to improved thiazolidine inhibitors with an IC50 value of 19 nM for the best compound, a 150-fold higher potency than the natural peptide inhibitor (IC50 2.9 μM).

Synthesis, characterization and biological evaluation of 4-oxo-thiazolidine compounds

A series of compounds 4-oxo-thiazolidine derivatives AJ5a–j were synthesized by condensation reactions. The structure of synthesized compounds was characterized by IR, 1H NMR, 13C NMR and mass spectroscopy. The present paper deals with newly synthesized thiazolidine compounds AJ5a–AJ5j that were screened for their antimicrobial activity against different strains of bacteria and fungi using serial broth dilution method (Mueller–Hinton broth dilution method). In vitro antitubercular activity of compounds AJ5a–j was carried out against Mycobacterium tuberculosis H37Rv. Compounds AJ5a, AJ5d, AJ5e, AJ5f and AJ5g were found most active against selected bacterial strains (MIC=62.5μg/mL) and compounds AJ5a–j were found moderately active against M. tuberculosis.

Synthesis and cytotoxic activity of new acridine-thiazolidine derivatives

Although their exact role in controlling tumour growth and apoptosis in humans remains undefined, acridine and thiazolidine compounds have been shown to act as tumour suppressors in most cancers. Based on this finding, a series of novel hybrid 5-acridin-9-ylmethylene-3-benzyl-thiazolidine-2,4-diones were synthesised via N-alkylation and Michael reaction. The cell viability was analysed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and DNA interaction assays were performed using electrochemical techniques.

ChemInform Abstract: Memory of Chirality in the Electrochemical Oxidation of Thiazolidine‐4‐carboxylic Acid Derivatives.

AbstractSeveral thiazolidine compounds are synthesized and electrochemically oxidized in methanol.

Screening for glucose‐triggered modifications of glutathione

Nonenzymatic protein glycation is caused by a Schiff's base reaction between the aldehyde groups of reducing sugars and the primary amines of proteins. These structures may undergo further Amadori rearrangement and free radical-mediated oxidation to finally generate irreversible advanced glycation end products (AGEs). One of the factors known to modulate the glycation of proteins is glutathione, the most abundant nonprotein thiol tripeptide with the gamma-linkage, H-Glu(Cys-Gly-OH)-OH (GSH). Screening for products formed by GSH with D-glucose is an essential step in understanding the participation of GSH in glycation (the Maillard) reaction. Under the conditions used in these studies we observed N-(1-deoxy-D-fructos-1-yl)-pyroglutamic acid as the major glycation product formed in the mixtures of GSH and glucose in vitro. A RP HPLC/MS and tandem MS analyses of the GSH/glucose mixtures revealed that cleavage of the N-terminal glutamic acid and the formation of pyroglutamic acid-related Amadori product were accompanied by generation of Cys-Gly-derived Amadori and thiazolidine compounds.

Lead optimization of [( S)-γ-(arylamino)prolyl]thiazolidine focused on γ-substituent: Indoline compounds as potent DPP-IV inhibitors

Dipeptidyl peptidase IV (DPP-IV) inhibitors are looked to as a potential new antidiabetic agent class. A series of [( S)-γ-(arylamino)prolyl]thiazolidine compounds in which the electrophilic nitrile is removed are chemically stable DPP-IV inhibitors. To discover a structure for the γ-substituent of the proline moiety more suitable for interacting with the S 2 pocket of DPP-IV, optimization focused on the γ-substituent was carried out. The indoline compound 22e showed a DPP-IV-inhibitory activity 100-fold more potent than that of the prolylthiazolidine 10 and comparable to that of NVP-DPP728. It also displayed improved inhibitory selectivity for DPP-IV over DPP8 and DPP9 compared to compound 10. Indoline compounds such as 22e have a rigid conformation with double restriction of the aromatic moiety by proline and indoline structures to promote interaction with the binding site in the S 2 pocket of DPP-IV. The double restriction effect provides a potent inhibitory activity which compensates for the decrease in activity caused by removing the electrophilic nitrile.

( S)-γ-(Arylamino)prolyl]thiazolidine compounds as a novel series of potent and stable DPP-IV inhibitors

Dipeptidyl peptidase-IV (DPP-IV) inhibitors, or glucagon-like peptide-1 (GLP-1) enhancers, are looked to as a potential new class of antidiabetic agents. In particular, potent and long-acting inhibitors might offer advantages in exploiting DPP-IV inhibition. The series of [( S)-γ-(arylamino)prolyl]-( S)-2-cyanopyrrolidine compounds on which we reported previously has a highly potent inhibitory activity but seemed to be unstable in neutral aqueous solution. Here, we describe [( S)-γ-(arylamino)prolyl]thiazolidine compounds as a novel series of potent and stable DPP-IV inhibitors. They are the thiazolidine analogs of [( S)-γ-(arylamino)prolyl]-( S)-2-cyanopyrrolidine but with the electrophilic nitrile removed to improve chemical stability in aqueous solution. Of the compounds investigated in the present study, the [(( S)-γ-3,4-dicyanophenylamino)prolyl]thiazolidine 12m was the most potent. The structure–activity relationship (SAR) of the γ-substituent in the proline moiety of the thiazolidide was similar to that obtained with the ( S)-2-cyanopyrrolidide. The γ-substituent in the proline moiety of both the ( S)-2-cyanopyrrolidide and the thiazolidide may engage with the S 2 binding pocket of DPP-IV and thereby achieve hydrophobic interaction in the same manner. Based on pharmacokinetic experiments in rats, the representative compound 11, which displayed high oral bioavailability (BA = 83.9%) and long half-life in plasma ( t 1/2 = 5.27 h), was found to have an excellent pharmacokinetic profile.

Identification and characterisation of a new class of highly specific and potent inhibitors of the mitochondrial pyruvate carrier

Two novel thiazolidine compounds, GW604714X and GW450863X, were found to be potent inhibitors of mitochondrial respiration supported by pyruvate but not other substrates. Direct measurement of pyruvate transport into rat liver and yeast mitochondria confirmed that these agents inhibited the mitochondrial pyruvate carrier (MPC) with K i values <0.1 μM. Inhibitor titrations of pyruvate-dependent respiration by heart mitochondria gave values (±S.E.) for the concentration of inhibitor binding sites (pmol per mg protein) and their K i (nM) of 56.0±0.9 and 0.057±0.010 nM for the more hydrophobic GW604714X; for GW450863X the values were 59.9±4.6 and 0.60±0.12 nM . [ 3H]-methoxy-GW450863X binding was also used to determine the MPC content of the heart, kidney, liver and brain mitochondria giving values of 56, 40, 26 and 20 pmol per mg protein respectively. Binding to yeast mitochondria was <10% of that in rat liver mitochondria, consistent with the slow rate of pyruvate transport into yeast mitochondria. [ 3H]-methoxy-GW450863X binding was inhibited by GW604714X and by the established MPC inhibitor, UK5099. The absorbance spectra of GW450863X and GW604714X were markedly changed by the addition of β-mercaptoethanol suggesting that the novel inhibitors, like α-cyanocinnamate, possess an activated double bond that attacks a critical cysteine residue on the MPC. However, no labelled protein was detected following SDS-PAGE suggesting that the covalent modification is reversible. GW604714X and GW450863X inhibited l-lactate transport by the plasma membrane monocarboxylate transporter MCT1, but at concentrations more than four orders of magnitude greater than the MPC.

Formaldehyde scavenging from peritoneal dialysis solutions using reduced aminothiol compounds.

Aldehydes were identified in clinical solutions, including peritoneal dialysis (PD) and cryoprotection solutions, which were used to freeze cells, tissues and embryos. Aldehydes are associated with increased cellular injury and may contribute to peritoneal membrane damage that occurs in patients on peritoneal dialysis. Recently, it was demonstrated that aldehydes could be 'scavenged' from these solutions by using aminothiol compounds. Although aldehydes were removed during the scavenging process, the kinetics of scavenging and the products formed were not characterized. Proton nuclear magnetic resonance (NMR) spectroscopy was used to investigate formaldehyde scavenging from an artificial PD solution supplemented with aminothiol compounds, cysteamine or l-cysteine. Artificial PD solutions were formulated on the basis of commercial PD solutions and consisted of 132 mmol/L NaCl, 0.25 mmol/L MgCl2, 1.25 mmol/L CaCl2, and buffered with lactate (4.0 mmol/L) and lacked d-glucose. Formaldehyde scavenging was a two-step process involving an intermediate step followed by the formation of stable thiazolidine compounds. These included the derivatives of cysteamine and l-cysteine; thiazolidine and thiazolidine-4-carboxylic acid, respectively. Scavenging with aminothiol compounds masked the destructive carbonyl group (C = O) of formaldehyde and formed a compound that has antioxidant properties. The addition of aminothiol compounds may improve the biocompatibility of commercial PD solutions.

THE ACID IONIZATION CONSTANTS OF SOME THIAZOLIDINE COMPOUNDS: MEDIUM EFFECTS AND THERMODYNAMIC STUDIES

The pKa values of some thiazolidine compounds in various aqueous-organic solvent mixtures were determined pH-metrically at 25 °C and at an ionic strength of I = 0.02 mol dm−3 (KNO3). The organic solvents used are methanol or ethanol (as amphiprotic solvent), DMF or DMSO (as dipolar aprotic solvent), and acetonitrile (as a low basic aprotic solvent). The pK2 values obtained are discussed in terms of solvent characteristics. The pK, values of investigated compounds are increased on increasing the mole fraction of the amphiprotic or low basic aprotic organic solvent, whereas they are decreased in the presence of a dipolar aprotic solvent. Hydrogen bonding interactions and the medium basicity, in addition to the electrostatic effect, are the main factors influencing the ionization process in aqueous-amphiprotic or a low basic aprotic solvent mixture. The high stabilization of the conjugate base by dispersion forces and of the proton by its interaction with solvent as well as the solvent basicity play a vital role in determining the ionization equilibria of the investigated compounds in aqueous mixture of dipolar aproptic solvents. The effect of molecular structures of the compounds on pKa values is also discussed. Thermodynamic functions (ΔH, ΔG°, and ΔS°) of the ionization processes of all compounds in aqueous media are determined and discussed.

Some chemical properties and biological role of thiazolidine compounds

In this study we have investigated some chemical properties and the biological role of thiazolidine compounds, obtained by condensation of aminothiols (L- or D-cysteine, cysteamine) with pyridoxal-5′-phosphate. These products have been tested in presence of rat liver extracts (supernatant and mitochondria); bacterial suspensions and enzymes (L- or D-aminoacid oxidase, xanthine oxidase) with interesting results which gives evidence to a biological role. Their formation in vivo may represent the regulation of intracellular levels of pyridoxal-5′-phosphate and aminothiols. Moreover, we have analysed the two diastereoisomers of the thiazolidine compounds derived from L-cysteine and D-cysteine: we have succeeded to distinguish by NMR analysis the cis and the trans forms, concluding that the interconversion of the free forms is extremely rapid at pH 7: thus, it may be relevant for the protein bound forms.