Thiazolium Research Articles

Directed Design, Screening and Antiglycation Activity for 3-Substituted Thiazolium Derivatives, New Analogs of Alagebrium.

Preliminary abinitio calculations led to the synthesis of novel substituted thiazolium salts, analogs of Alagebrium, which were further explored invitro for their potential as inhibitors of the glycation reaction utilizing three distinct assays: inhibition of fluorescent AGEs formation, anticrosslinking, and deglycation. Despite the unidirectionality of the assays, distinct differences were observed in the mechanisms of interference and activity manifestation by the compounds. The gathered data permitted the formation of hypotheses about the molecular fragments of the studied antiglycators that are of utmost significance in each assay, thereby guiding future design endeavors. Potential mechanisms of actions are discussed therein. The compound 4-meth-yl-3-[2-(4-methylbiphenyl-4-yl)-2-oxoethyl] thiazolium bromide displayed high activity across all three assays, establishing it as a lead compound. The cytotoxicological properties of the compounds were evaluated using LDH and MTT assays. However, the lead compound exhibited cytotoxicity, indicating the need for additional investigations aimed at decreasing toxicity while maintaining activity. The targeted thiazolium salts were synthesized through an N-alkylation reaction between the corresponding thiazoles and phenacyl bromides.

Thiazolium salt mimics the non-coenzyme effects of vitamin B1 in rat synaptosomes

Long-term studies have confirmed a causal relationship between the development of neurodegenerative processes and vitamin B1 (thiamine) deficiency. However, the biochemical mechanisms underlying the high neurotropic activity of thiamine are not fully understood. At the same time, there is increasing evidence that vitamin B1, in addition to its coenzyme functions, may have non-coenzyme activities that are particularly important for neurons. To elucidate which effects of vitamin B1 in neurons are due to its coenzyme function and which are due to its non-coenzyme activity, we conducted a comparative study of the effects of thiamine and its derivative, 3-decyloxycarbonylmethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium chloride (DMHT), on selected processes in synaptosomes. The ability of DMHT to effectively compete with thiamine for binding to thiamine-binding sites on the plasma membrane of synaptosomes and to participate as a substrate in the thiamine pyrophosphokinase reaction was demonstrated. In experiments with rat brain synaptosomes, unidirectional effects of DMHT and thiamine on the activity of the pyruvate dehydrogenase complex (PDC) and on the incorporation of radiolabeled [2–14C]pyruvate into acetylcholine were demonstrated. The observed effects of thiamine and DMHT on the modulation of acetylcholine synthesis can be explained by suggesting that both compounds, which interact in cells with enzymes of thiamine metabolism, are phosphorylated and exert an inhibitory/activating effect (concentration-dependent) on PDC activity by affecting the regulatory enzymes of the complex. Such effects were not observed in the presence of structural analogues of thiamine and DMHT without a 2-hydroxyethyl substituent at position 5 of the thiazolium cycle. The effect of DMHT on the plasma membrane Ca-ATPase was similar to that of thiamine. At the same time, DMHT showed high cytostatic activity against neuroblastoma cells.

Synthesis and antiglycation activity of 3-phenacyl substituted thiazolium salts, new analogs of Alagebrium.

After preliminary abinitio calculations, 3-phenacyl substituted thiazolium salts, analogs of Alagebrium, were synthesized and investigated invitro as glycation reaction inhibitors. The most part of investigations focused on the potential of the title compounds to attenuate the formation of fluorescent AGEs as well on their ability to disrupt the cross-linking formation among glycated proteins. Additionally, the capability of thiazolium salts to deglycate in the reaction of early glycation products with nitroblue tetrazolium was determined. Cytotoxicological properties of the title compounds were evaluated using LDH and MTT assays. The leader compound (3-[2-(biphenyl-4-yl)-2-oxoethyl]-1,3-thiazol-3-ium bromide) in a 50 mg/kg dose (p.o. 14 days) was further tested within an invivo carbonyl stress model (rats, methylglyoxal 86.25 mg/kg/d, i.p., 14 days). As a result, the leader-molecule revealed a high effectiveness against all three examined mechanisms of glycation reaction inhibition in invitro tests and was able to suppress capacity of methylglyoxal to form AGEs invivo.

Ring‐Opening‐Recombination Strategy Based on 2‐Methylbenzothiazole Salts: Syntheses of Thiazinopyrrole Fused‐Ring Derivatives

AbstractThis study presents a method for the synthesis of thiazinopyrrole fused ring derivatives utilizing a ring‐opening recombination strategy with benzothiazole salts. Thiazolium salts, aldehydes, and amines undergo a cascade cyclization reaction in a one‐pot under the solvent conditions of ethanol.

Synthesis and antioxidant activity evaluation of some new 4-thiomethyl functionalised 1,3-thiazoles

The 4-bromomethyl-substituted thiazolium salts and corresponding thiazoles obtained through the condensation of 1,3-dibromoacetone with thioamide derivatives were utilised as efficient alkylating reagents for a series of thiophenols and heterylthiols. As a result, a small library of 4-thiomethyl-functionalised 1,3-thiazoles was synthesised in high yields, and their structures were characterised by 1H, 13C NMR, LC-MS and IR spectra. Antioxidant activity of obtained compounds was studied in vitro using the DPPH test. The synthesised compounds showed high absorption level of DPPH radicals in the 70-98% range. For the most active derivatives 7e,m,p,t IC50 values were determined, which were in the range 191-417 µM (for ascorbic acid (reference) IC50 value was 29 µM). Obtained radical scavenging activity screening data suggest in-depth study of the antioxidant potential for these types of heterocyclic compounds.

Diastereoselective Radical Aminoacylation of Olefins through N-Heterocyclic Carbene Catalysis.

There have been significant advancements in radical-mediated reactions through covalent-based organocatalysis. Here, we present the generation of iminyl and amidyl radicals via N-heterocyclic carbene (NHC) catalysis, enabling diastereoselective aminoacylation of trisubstituted alkenes. Different from photoredox catalysis, single electron transfer from the deprotonated Breslow intermediate to O-aryl hydroxylamine generates an NHC-bound ketyl radical, which undergoes diastereocontrolled cross-coupling with the prochiral C-centered radical. This operationally simple method provides a straightforward access to a variety of pyrroline and oxazolidinone heterocycles with vicinal stereocenters (77 examples, up to >19:1 d.r.). Electrochemical studies of the acyl thiazolium salts support our reaction design and highlight the reducing ability of Breslow-type derivatives. A detailed computational analysis of this organocatalytic system suggests that radical-radical coupling is the rate-determining step, in which π-π stacking interaction between the radical intermediates subtly controls the diastereoselectivity.

Identification of a potent NAFLD drug candidate for controlling T2DM-mediated inflammation and secondary damage in vitro and in vivo.

Accumulation of glucose/sugar results in the formation of reactive di-carbonyl compounds such as MGO and GO that interact with several amino acids and proteins to form toxic advanced glycation end products (AGEs). Induction of AGEs breakdown can control symptoms and severity in T2DM and other related complications like NAFLD where AGEs are the key players. Therefore, an AGE cross-link breaker has been suggested for preventing the onset/progression of NAFLD. In this study, we reported novel synthetic naphthalene-2-acyl thiazolium derivatives (KHAGs). Among synthesized KHAG derivatives, we observed that a novel KHAG-04, a 1,4-dimethoxynaphthalen-2-acyl thiazolium salt which is an analog of alagebrium, dramatically cleaves MGO/GO-AGE cross-links, and it also inhibited inflammation by lowering the level of nitric oxide production and IL-1β and TNF-α secretion in LPS and/or MGO-AGE–activated macrophage. Moreover, it also reduced FFA and MGO-AGE–induced lipogenesis in Hep-G2 cells. In mice, KHAG-04 significantly reduced the level of glyoxal in the liver, which was induced by DMC. Furthermore, KHAG-04 treatment significantly reduced blood glucose levels, lipid accumulation, and inflammation in the NAFLD/T2DM animal model. Novel KHAG-04–mediated induction of AGEs breakdown could be the possible reason for its anti-inflammatory, antihyperglycemic, and anti-lipidemic effects in cells and NAFLD in the T2DM animal model, respectively. Further research might explore the pharmacological efficacy and usefulness and consider the ability of this compound in the treatment strategy against various models of NAFLD in T2DM where MGO/GO-AGEs play a key role in the pathogenesis.

N-Heterocyclic Carbene-Catalyzed Umpolung of Cyclopent-4-ene-1,3-diones for Activated Olefin-Isatin Cross-Coupling.

N-Heterocyclic carbene (NHC)-catalyzed umpolung of cyclopent-4-ene-1,3-diones that proceeds via the generation of nucleophilic deoxy-Breslow intermediates is presented. The carbene generated from a commercially available thiazolium salt catalyzed the cross-coupling between cyclopent-4-ene-1,3-diones and isatins to furnish the functionalized oxindoles in moderate to good yields with good functional group compatibility. The key deoxy-Breslow intermediates were isolated and characterized by X-ray analysis. Detailed mechanistic studies are also presented.

Thiazolium Salts as Chalcogen Bond Donors

The nitrogen atom is commonly considered to be the positive site in thiazolium cations. Counterintuitively, the shortest cation···anion contacts in thiazolium salts and their benzoderivatives involve the sulfur atom. The geometric features of these contacts allow for their rationalization as charge assisted chalcogen bonds (ChBs). Analyses of the Cambridge Structural Database and calculation of the surface electrostatic potential of benzo[d]thiazolium cations support this rationalization. The relevance and impact of the general tendency of thiazolium derivatives to function as ChB donors are exemplified by the ChBs as short as 87% of the sum of van der Waals radii of involved atoms in thiamine monophosphate, a key compound in human metabolism, and in two commonly used thiazolium organocatalysts.

Synthesis of Highly Congested Tertiary Alcohols via the [3,3] Radical Deconstruction of Breslow Intermediates.

Pericyclic processes such as [3,3]-sigmatropic rearrangements leading to the rapid generation of molecular complexity constitute highly valuable tools in organic synthesis. Herein, we report the formation of particularly hindered tertiary alcohols via rearrangement of Breslow intermediates formed in situ from readily available N-allyl thiazolium salts and benzaldehyde derivatives. Experimental mechanistic studies performed suggest that the reaction proceeds via a close radical pair which recombine in a regio- and diastereoselective manner, formally leading to [3,3]-rearranged products.

Oxidative Cyclization of 4‐(2‐Mercaptophenyl)‐Substituted 4H‐1,2,4‐Triazolium Species to Tricyclic Benzothiazolium Salts

AbstractHerein we report a generally applicable method for the preparation of N‐substituted benzo[4,5]thiazolo[2,3‐c][1,2,4]triazol‐1‐ium salts from air stable precursors. This transformation features selective deprotection of a para‐methoxybenzyl protected thiol followed by C−H functionalization of the linked 1,2,4‐triazolium salts under oxidative conditions. Using this procedure, we synthesized a variety of tricyclic thiazolium salts which contain both electron‐withdrawing and electron‐donating aromatic substituents as well as aliphatic substituents. Our approach also tolerates many functional groups including alkynes, alcohols, diols, amides, and polyethers.

Thiazolium-based ionic liquids: Synthesis, characterization and physicochemical properties

Thiazolium salts are structurally analogous to the most common imidazolium-based ionic liquids (ILs), and are supposed to be a new class of ILs. However, there are up to now only a few reports and absence of systematic study on thiazolium ILs. In this work, several thiazolium-based ILs were prepared, characterized and comparatively studied. Most of the thiazolium ILs are liquid at room temperature, with melting points below 43.0 °C. Good thermal stability was observed for thiazolium ILs, resulting in thermal decomposition temperatures up to 264 ∼ 358 °C. In comparison with the conventional imidazolium ILs, thiazolium ILs exhibit moderate density, refractive index and surface tension, which all generally decrease with temperature. According to the temperature-dependent viscosity and conductivity, thiazolium ILs follow fractional Walden’s rule, indicating strong ion-ion coupling. Besides, thiazolium ILs display relatively narrow electrochemical window (3.1 ∼ 4.0 V).

Synthesis of Heterobimetallic Complexes through Chemoselective 2,4-Metalation of a Thiazolium Salt

Synthesis of Heterobimetallic Complexes through Chemoselective 2,4-Metalation of a Thiazolium Salt

The geometry of diphtheria toxoid CRM197 channel assessed by thiazolium salts and nonelectrolytes

The geometry of the channel formed by nontoxic derivative of diphtheria toxin CRM197 in lipid bilayer was determined using the dependence of single-channel conductance upon the hydrodynamic radii of different nonelectrolytes. It was found that the cis entrance of CRM197 channel on the side of membrane to which the toxoid was added at pH 4.8 and the trans entrance on the opposite side at pH 6.0 had effective radii of 3.90 and 3.48 Å, respectively. The 3-alkyloxycarbonylmethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium salts reversibly reduced current via CRM197 channels. The potency of the blockers increased with increasing length of alkyl chain at symmetric pH 6.0 and remained high and stable at pH 4.8 on the cis side. Comparative analysis of CRM197 and amphotericin B pore size with the inhibitory action of thiazolium salts revealed a significant increase in CRM197 pore dimension at pH 6.0. Addition of thiazolium salt with nine carbons alkyl tail increased by ∼30% the viability of human carcinoma cells A431 treated with diphtheria toxin.

The catalytic effects of a thiazolium salt in the oxa-Diels-Alder reaction between benzaldehyde and Danishefsky's diene: a molecular electron density theory study.

The oxa-Diels-Alder (ODA) reaction of benzaldehyde with Danishefsky's diene in the presence of a [thiazolium][Cl] salt, as a model of an ionic liquid, has been studied within Molecular Electron Density Theory (MEDT) at the M06-2X/6-311G(d,p) computational level. The formation of two hydrogen bonds (HBs) between the thiazolium cation and the carbonyl oxygen of benzaldehyde modifies neither the electrophilic character of benzaldehyde nor its electronic structure substantially but accelerates the reaction considerably. This ODA reaction presents an activation energy of 4.5 kcal mol-1; the formation of the only observed dihydropyranone is strongly exothermic by -28.8 kcal mol-1. The presence of the [thiazolium][Cl] salt decreases the Gibbs free energy of activation of the ODA reaction between benzaldehyde and Danishefsky's diene by 5.9 kcal mol-1. This ODA reaction presents total para regioselectivity and high endo stereoselectivity. This ODA reaction takes place through a highly asynchronous polar transition state structure (TS) associated with a non-concerted two-stage one-step mechanism. ELF analysis of para/endo TSs associated with the ODA reactions in the absence and presence of the [thiazolium][Cl] salt shows that the formation of the HBs at the TSs does not modify their electronic structure substantially. This MEDT study makes it possible to conclude that the acceleration found in the ODA reaction of benzaldehyde with Danishefsky's diene in ILs is a consequence of an increase of the global electron density transfer at TS3-pn, resulting from HB formation, and the greater strength of the HBs at the polar TS3-pn compared to that at the benzaldehyde : [thiazolium][Cl] complex, and that the strength in the HB formed is more relevant that than an increase of the electrophilic character of the interaction between reagent.

N-PEGylated Thiazolium Salt: A Green and Reusable Homogenous Organocatalyst for the Synthesis of Benzoins and Acyloins

N-PEGylated-thiazolium salt is used as efficient catalyst for the benzoin condensation. The catalyst was synthesized by reaction of activated polyethylene glycol 10,000 (PEG-10000) with 4-methyl-5-thiazoleethanol (sulfurol). Reaction mixture undergoes temperature-assisted phase transition and catalyst separated by simple filtration. After reaction course, catalyst can be recycled and reused without any apparent loss of activity which makes this process cost effective and hence ecofriendly. Synthesized benzoins and acyloins by this method have been characterized on the basis of melting point and 1H-NMR spectral studies.

Acetylcholinesterase inhibitors with a thiazolium scaffold: structural features and binding modes

Aim. To assess the structural features of substituents and the role of a thiazolium scaffold in mechanisms of acetylcholinesterase inhibition by thiazolium salts.Results and discussion. On the basis of activities of model compounds at pH 6.5 and pH 8.0 and the results of molecular docking the binding modes of quaternized derivatives of 5-(2-hydroxyethyl)-4-methylthiazole with different substituents in position 3 and 5 were analyzed. The presence of (N)3-benzyl substituent provides the inhibitor fixation in the catalytic anionic site, whereas acyl fragments of substituents in position 5 are situated in the peripheral anionic site. Logarithms of ІС50 values of the thiazolium inhibitors, except for the compounds containing O-acyl carbocyclic groups, linearly depend on the calculated docking energies in case of a thiazolium, ion as well as a neutral tetrahedral intermediate of the thiazolium ring opening.Experimental part. Thiazolium salts were synthesized by the known methods. The activity of acetylcholinesterase was studied by Ellman’s method. Molecular docking to the active site of acetylcholinesterase was performed using an AutoDock 4.2 program.Conclusions. Structural fragments of substituents in positions 3 and 5 of the heterocyclic scaffold provide binding of the inhibitor in the catalytic anionic site and the peripheral anionic site of acetylcholinesterase, respectively. The heterocyclic scaffold can be bound to the enzyme as a thiazolium ion or a neutral tetrahedralintermediate of the ring opening reaction.

Picosecond Switchable Azo Dyes.

Azo dyes that combine electron-withdrawing thiazole/benzothiazole heterocycles and electron-donating amino groups within the very same covalent skeleton exhibit relaxation times for their thermal isomerization kinetics within milli- and microsecond timescales at room temperature. Notably, the thermal back reaction of the corresponding benzothiazolium and thiazolium salts occurred much faster, within the picosecond temporal domain. In fact, these new light-sensitive platforms are the first molecular azo derivatives capable of reversible switching between their trans and cis isomers in a subnanosecond timescale under ambient conditions. In addition, theoretical calculations revealed very low activation energies for the isomerization process, in accordance with the fast subnanosecond kinetics that were observed experimentally.

Synthesis and optical properties of novel thermally stable bis-merocyanine dyes

A new series of thermally stable linked bis-merocyanine dyes were synthesized from thiazolium salt derivatives and bis-rhodanines in good yields. The synthesized compounds were fully characterized by FT-IR, UV/Vis, NMR and mass spectrometry and their thermal properties were determined by TGA and DSC. The shape of the absorption spectra of bis-merocyanine dyes is affected both by the nature of the spacer and the polarity of the solvent. Absorption and fluorescence spectra of compound B1T6 were measured at room temperature (298 K), in various solvents to investigate their solvatochromic behaviour. The ground and excited state dipole moments of B1T6 compound were estimated experimentally by solvatochromic shift method using Bilot-Kawski, Lippert-Mataga, Bakhshiev, Kawski-Chamma-Viallet and Reidchardt's microscopic solvent polarity functions. It was observed that the excited-state dipole moment was found to be higher than the corresponding ground-state dipole moments, due to a substantial redistribution of electron densities and charges in a more polar excited-state. The geometry of this compound was optimized; HOMO-LUMO energy values and the ground state dipole moment μg were also evaluated theoretically by quantum chemical calculations using the DFT method by adopting B3LYP/G-31 G (d, p) of theory (Gaussian 09).

A Copper‐ and Phosphine‐Free Nickel(II)‐Catalyzed Method for C−H Bond Alkynylation of Benzothiazoles and Related Azoles

AbstractA phosphine‐free nickel(II)‐catalyzed method for the C(2)−H bond alkynylation of (benzo)thiazoles, (benz)imidazoles, and oxazoles is described. Well‐defined and air‐stable (Phen)NiCl2 catalyst efficiently catalyzes the coupling of diverse azoles with alkynyl bromides without the use of a copper co‐catalyst, and the method tolerates synthetically important functional groups. Preliminary mechanistic studies on this NiII‐catalyzed alkynylation emphasize the homogeneous nature of the catalyst, and rule out a radical manifold for the reaction. The synthetic utility of this Ni‐catalyzed method is demonstrated by further functionalizing the alkynylated benzothiazoles to 3‐methyl‐2‐(alkynyl)benzo[d]thiazolium salts that are known DNA cleaving agents.