Heterocyclic Disulfides Research Articles

Allicin-Inspired Heterocyclic Disulfides as Novel Antimicrobial Agents.

In this work, a series of derivatives with disulfide bonds containing pyridine, pyrimidine, thiophene, thiazole, benzothiazole, and quinoline were designed and synthesized based on the various biological activities of allicin disulfide bond functional groups. The antimicrobial activities of the target compounds were determined, and the structure-activity relationships were discussed. Among them, compound S8 demonstrated the most potent antifungal activity in vitro against Monilinia fructicola (M. fructicola), with an EC50 value of 5.92 μg/mL. Furthermore, an in vivo bioassay revealed that compound S8 exhibited equivalent curative and higher protective effects as the positive drug thiophanate methyl at a concentration of 200 μg/mL. The preliminary mechanism experiments showed that compound S8 could inhibit the growth of M. fructicola' s hyphae in a time- and concentration-dependent manner, and compound S8 could induce the shrinkage of hyphae, disrupt the integrity of the plasma membrane, and cause the damage and leakage of cell contents. More than that, compound S5 also demonstrated an excellent antibacterial effect on Xanthomonas oryzae (X. oryzae), with a MIC90 value of 1.56 μg/mL, which was superior to the positive control, thiodiazole copper.

Synthesis and Biological Activity of Unsymmetrical Monoterpenylhetaryl Disulfides.

New unsymmetrical monoterpenylhetaryl disulfides based on heterocyclic disulfides and monoterpene thiols were synthesized for the first time in 48–88% yields. Hydrolysis of disulfides with fragments of methyl esters of 2-mercaptonicotinic acid was carried out in 73–95% yields. The obtained compounds were evaluated for antioxidant, antibacterial, antifungal activity, cytotoxicity and mutagenicity.

Determination of low molecular thiols and protein sulfhydryl groups using heterocyclic disulfides.

A promising area in the analytical chemistry of thiol-containing compounds is the use of heterocyclic disulfides as analytical agents, but now only a few of them are widely used. In this paper, we evaluate the possibility of using three different heterocyclic disulfides 2,2'-dithiobis[5-phenyl-1,3,4-oxadiazole] (I), 2,2'-dithiobis[benzoxazole] (II) and 8,8'-dithiobis-quinoline (III) as analytical reagents for the low-mass aminothiols cysteine and glutathione determination. The optimal analysis conditions were found. Spectrophotometric, kinetic, CE, and HPLC methods using I, II, III for the determination of cysteine and glutathione were developed. The obtained methods are characterized by accuracy and sensitivity (detection limits in the range of 10-5-10-6M) sufficient to quantify cysteine and glutathione in their physiological concentrations. Finally, the proposed disulfides were used to determine the SH-content in the bovine serum albumin (BSA). Considering a number of criteria (applicable pH range, absorption properties, susceptibility to hydrolysis) it was concluded that the proposed reagents have advantages over the commonly used ones (such as the Ellman reagent).

Analysis of homocysteine and thiol-containing compounds using the heterocyclic disulfides

Biological low-molecular aminothiols, such as homocysteine, are characterized by the weak absorption in the UV – visible range. Therefore, aminothiols analysis requires using thiol-specific chemosensors or derivatization procedure. Heterocyclic disulfides belong to a large group of derivatizing agents. However, the disulfides widely used in the analytical practice, such as 5,5'-dithiobis-(2-nitrobenzoic acid), have several disadvantages: limited acceptable pH range, low sensitivity, susceptibility to hydrolisys. Hence, the search for the effective derivatizing agents continues. In the current work, 2,2'-dithiobis[benzoxazole] and 8,8'-dithiobis-quinoline disulfides were used for the analysis of homocysteine. Precise and sensitive methods (homocysteine detection limit in the range of 1.1·10-6–7.8·10-6 M, relative standard deviation in the range of 1.5–4.6%) for the homocysteine determination have been developed, including spectrophotometric method, capillary electrophoresis (CE), high-performance liquid chromatography (HPLC) and kinetic method with the spectrophotometric detection. The proposed disulfides have also been successfully used in the analysis of sulfhydryl groups content in the sample of human urine.

The palladium‐catalyzed C‐N cross‐coupling reaction of diheteroaryl disulfides with heterocyclic amines

The Pd‐catalyzed cross‐coupling reaction of 1, 2‐di(pyrimidin‐2‐yl) disulfides with heterocyclic amines including 2‐amino pyrimidines and 1,3,4‐thiadiazol‐2‐amines to deliver symmetrical C‐N coupling products in moderate to good yields is reported. This method provides an opportunity for synthesis of bioactive molecules and pharmaceutically interesting compounds containing heterocycle motifs. The reported protocol shows good functional group compatibility, and provides a new strategy for preparation of C2‐amination pyrimidine derivatives from heterocyclic disulfides.

Dynamic in situ solvothermal reactions between ZnX2 (X = Cl, ClO4) and a heterocyclic disulfide

Solvothermal reactions of 2-ppds (2-ppds = di[4-(pyridin-2-yl)pyrimidinyl]disulfide) with ZnX2 (X = Cl, ClO4) in mixed CH3OH–CH2Cl2 solvent have been investigated. To better understand these reactions, solution analysis was conducted in parallel with single-crystal X-ray diffraction analysis of the in situ generated coordination complexes. At 120 °C, solvothermal reaction of 2-ppds with ZnCl2 resulted in a discrete mononuclear coordination complex formulated as [ZnCl2(L1)] (1), in which the zwitterion L1 (1-methyl-4-(pyridin-2-yl)pyrimidin-1-ium-2-olate) was formed in situ from 2-ppds, and solution analyses based on TLC and ESI–MS further showed that the reaction solution also contains in situ transformed products of L2 (bis(4-(pyridin-2-yl)pyrimidin-2-yl)sulfane) and L3 (2-methoxy-4-(pyridin-2-yl)pyrimidine). At 90 °C, solvothermal reaction between 2-ppds and Zn(ClO4)2 led to a discrete mononuclear coordination complex formulated as [Zn(SH)(L2)]ClO4 (2) that features a terminally bound –SH group, while the reaction solution was also found to contain a library of in situ reaction products of 2-ppds including L1, L2, L3 and L4 ((4-(pyridin-2-yl)pyrimidin-2-yl) 4-(pyridin-2-yl)pyrimidine-2-sulfonothioate). Thus, the heterocyclic disulfide 2-ppds is transformed in situ into various organic products in a series of reactions involving C–S/S–S bond cleavage.

Unprecedented metal-mediated in situ reactions of heterocyclic disulfide of di[4-(pyridin-2-yl)pyrimidinyl]disulfide.

By the combination of different metal salts and solvents, four unprecedented in situ reactions have been discovered for heterocyclic disulfide of 2-ppds (2-ppds = di[4-(pyridin-2-yl)pyrimidinyl]disulfide). In the CH3CN-DMF solvent, reaction of 2-ppds with AgNO3 produced a one-dimensional chain structure of {[Ag2(1L)2]·2CH3CN}n (1), wherein 2-ppds was converted into its sulfonate of 1L by means of oxidative cleavage of the S-S bond. In the CH3CN-DCM solvent, reaction between 2-ppds and Cu(ClO4)2 yielded a discrete mononuclear Cu(II) coordination structure of [Cu(2L)2H2O)](ClO4)2 (2), of which 2-ppds was turned into a totally unexpected zwitterion product of 2L via C-S bond scission followed by O substitution. In the MeOH-DCM solvent, reaction of 2-ppds with Co(ClO4)2 resulted in a mononuclear Co(III) coordination structure of [Co(3L)2]ClO4·2CH3OH·H2O (3), in which 2-ppds was transformed into its persulfide of 3L via selective single C-S bond rupture. In the CH3CN-DMF solvent, reaction between 2-ppds and CuI afforded a binuclear mixed-valence Cu(I)Cu(II) coordination structure of [Cu2I(4L)2] (4), wherein 2-ppds was converted into its thiolate of 4L through homolytic S-S bond cleavage. The reaction mechanisms of these reactions have also been discussed on the basis of these in situ generated coordination structures coupled with our previous observations on 2-ppds.

Two 1D Coordination Polymers with Bis[4‐(pyridin‐4‐yl)pyrimidinyl]disulfide (4‐ppds) as Bridging Ligand

AbstractSolution assembly of heterocyclic disulfide ligand, 4‐ppds {4‐ppds = bis[4‐(pyridin‐4‐yl)pyrimidinyl]disulfide}, with Cu(OAc)2 and ZnI2 resulted in two 1D (one‐dimensional) coordination polymers 1 and 2, which were well characterized by infrared spectroscopy, elemental analysis, powder X‐ray diffraction, single‐crystal X‐ray diffraction, diffuse‐reflectance UV/Vis as well as photoluminescence spectroscopy. Single crystal X‐ray crystallography discloses that 1 shows an achiral zigzag chain structure built up by alternate linking of paddlewheel Cu2(OAc)4 dicopper unit and 4‐ppds ligand with opposite configurations, whereas 2 exhibits a helical chain structure constructed by alternate linkage of tetrahedral zinc atom and 4‐ppds ligand with the same chirality (P‐ or M‐configuration). It is supposed that the flexible coordination environment around the tetrahedral ZnII ion might be beneficial to homochiral arrangement of 4‐ppds ligand.

Oxidation of thioamides with the DMSO–HCl system: a convenient and efficient method for the synthesis of 1,2,4-thiadiazoles, isothiazolo-[5,4-b]pyridines, and heterocyclic disulfides

Brief heating of 3-aryl-2-cyanothioacrylamides in the DMSO–HCl system gave (2E,2′E)-2,2′-(1,2,4-thia-diazol-3,5-diyl)bis(3-arylacrylonitriles). Under the same conditions, cyclic thioamides (derivatives of 2-thioxo-1,2-dihydropyridine-3-carbonitrile and quinoxaline-2(1H)-thione) gave good yields of the bis(hetaryl) disulfides. Ethyl 4-(4-chlorophenyl)-5-cyano-2-phenyl-6-thioxo-1,4,5,6-tetra-hydropyridine-3-carboxylate gave a mixture of oxidation products at the sulfur atom and the hetero-cycle when treated with the DMSO–HCl system. Oxidation of N-aryl-4,6-dimethyl-2-thioxo-1,2-di-hydropyridine-3-carboxamides gave isothiazolo[5,4-b]pyridines.

Assembling Isomeric heterocyclic disulfide ligands with copper(I) iodide: effect of ligand structure on their assembly structures and S–S reactivity

Self-assembly of two isomeric heterocyclic disulfide ligands, n-ppds (n-ppds = di[n-(pyridin-2-yl)pyrimidinyl]disulfide, n = 3, 4), with copper(I) iodide in acetonitrile/toluene produced different assembled structures and S–S reactivity, exhibiting profound influence of disulfide structure. For 3-ppds, a 2D layered structure 1 based on [CuI(3-ppds)]2 was obtained. Homolytic cleavage of the S–S bond occurred in 4-ppds, resulting in a 1D staircase double-chain structure 2. 1 and 2 have been characterized by single-crystal X-ray diffraction; solid-state diffuse-reflectance UV–vis spectra show that 1 and 2 are semiconductors with band gaps of 2.88 and 2.16 eV, respectively.

Alternative syntheses of linear polyurethanes using masked isocyanate monomers

A range of linear polyurethanes featuring aliphatic, aromatic and ether residues have been prepared by co-polymerisation of novel ‘masked’ isocyanate A 2-type monomers and diols. The reactive isocyanate monomers were generated in situ via the triphenylphosphine mediated decomposition of the heterocyclic disulfide, 1,2,4-dithiazolidine-3,5-dione. Two different synthetic approaches were examined and assessed for the construction of the novel A 2-type monomers, which involved either coupling two 1,2,4-dithiazolidine-3,5-diones together through a spacer group or construction of 1,2,4-dithiazolidine-3,5-diones directly from diamines. The resulting polyurethanes were purified via solvent extraction and analysed using GPC, NMR and IR spectroscopic analyses. Molecular weight data were obtained and compared from both GPC and 1H NMR (via end-group analysis) spectroscopic analysis. The thermal properties of the polyurethanes were determined using DSC and their solubility in common aprotic organic solvents was also assessed and related to their structural composition.

Spectroscopic and computational investigation of the ground and low excited states of some symmetrical heterocyclic disulfides

AbstractThe electronic absorption and emission spectra of some symmetrical heterocyclic disulfides are investigated. The reversible disulfide — thione transformation in water is discussed in view of the complex equilibrium processes present. UV irradiation and pH influence on the above transformation is also studied. The emission properties at room and low temperature are related to the computed molecular geometries of the ground and low excited states of the compounds.

Reactivity of 42 disulfides with thiol group of human haemoglobin and human serum albumin

The reactivities of disulfides of different compound families towards thiol groups of human haemoglobin and human serum albumin were determined at physiological pH 7.4 by anion-exchange liquid chromatography. The apparent second-order kinetic rate constants, K 1, were calculated for the reaction of these disulfides with each protein. The results show that the studied heterocyclic disulfides are the most reactive compounds with both proteins. The lipophilic properties of these disulfides were evaluated by reversed-phase high performance liquid chromatography, using the percentage of acetonitrile (PAC) required for eluting each compound of the chromatographic column in a water-acetonitrile gradient. The structure-reactivity correlations between log K 1 and log PAC are stated for each protein and compared. They fit a parabolic curve which permits one to define a lipophilic domain corresponding to a quantitative reaction of disulfides towards these proteins. The studied disulfides present a similar optimum of reactivity for both proteins.

Synthesis and properties of 5-membered heterocyclic disulfides: Application for enzyme modification

Synthesis of the disulfides 2,2′-dithiodithiazole, 2,2′-dithiobis(4-methylthiazole), and 5,5′-dithiobis(3-methylisothiazole), which are thiol-specific reagents, is described and the uv-absorption spectra of the disulfides and corresponding thiols and/or thiones are presented. The utility of these and several other reagents for the modification of thiol groups in enzymes has been demonstrated with lactate dehydrogenase and malate dehydrogenase and compared with the frequently applied modification reagents 5,5′-dithiobis(2-nitrobenzoic acid) and 2,2′-dithiodipyridine. The 5-membered heterocyclic disulfides permit the spectrophotometric determination of all sulfhydryl groups of malate dehydrogenase and lactate dehydrogenase without requiring their prior denaturation. Application of these reagents makes possible the determination of SH groups in the pH range ≦7.

Lumazinesulfenates - a new class of stable sulfenic acids

Hydrolysis of the SS bond in some heterocyclic disulfides leads to stable sulfenic acids. 1,3,6-Trimethyllumazine-7-sulfenic acid ( 5 ) was prepared in pure form as a crystalline solid to study its physical properties and chemical reactivity.

Biologically oriented organic sulfur chemistry. 15. Organic disulfides and related substances. 41. Inhibition of the fungal pathogen Histoplasma capsulatum by some organic disulfides

In an extension of promising inhibitory results in vitro against Histoplasma capsulatum, correlated earlier using substituent constants developed by regression analysis with 77 disulfides, one symmetrical and 14 unsymmetrical disulfides were prepared (3--17). About half were active in vitro against H. capsulatum (and one against Candida albicans). Groups that seemed most to lead to promising inhibition among the unsymmetrical disulfides were o-HO2CC6H4, (CH2)4SO2Na, Me2NC(S), p-ClC6H4, and perhaps p-CH3C6H4; the first two also might be used to increase solubility. Earlier inhibitory promise of the morpholino group did not materialize. None of the group 3--17 was significantly active in vivo. The unsymmetrical disulfides were prepared by reaction of thiols with sulfenyl chlorides or with acyclic or cyclic thiosulfonates. Two six-membered heterocyclic disulfides (5 and 6) were prepared by a novel cyclization, in which carbon disulfide reacted with an (N-alkylamino)ethyl Bunte salt, followed by ring closure; an explanation is suggested for formation of a thiazoline when the N-alkyl group is absent. One of the disulfides disproportionated with astonishing ease (31; 0.3--1 h at 25 degrees C).

The effect of some heterocyclic disulfides and thiones on the carbohydrate metabolism of Ehrlich ascites tumor.

The effect of some heterocyclic disulfides and thiones on the carbohydrate metabolism of Ehrlich ascites tumor.

The Action of Some Heterocyclic Disulfides as Agents and Accelerators of Vulcanization

The Action of Some Heterocyclic Disulfides as Agents and Accelerators of Vulcanization